A convenient procedure for preparing hetarylamides and their analogs by dehydrogenation of the corresponding imidazoles

Article abstract of DOI:10.1134/S1070427210060182

Conditions of aromatization of 2-(2-hetaryl)imidazolines and their analogs with various dehydrogenating agents were examined. A new catalytic system, Pd/C-diphenyl oxide, was studied, and the optimal catalyst:imidazoline ratio ensuring formation of 2-substituted imidazoles in high yield was found.

Full text of DOI:10.1134/S1070427210060182

ISSN 1070-4272, Russian Journal of Applied Chemistry, 2010, Vol. 83, No. 6, pp. 1024–1026. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.A. Aleksandrov, M.M. El’chaninov, 2010, published in Zhurnal Prikladnoi Khimii, 2010, Vol. 83, No. 6, pp. 971–973.
ORGANIC SYNTHESIS AND INDUSTRIAL
ORGANIC CHEMISTRY
A Convenient Procedure for Preparing Hetarylamides
and Their Analogs by Dehydrogenation
of the Corresponding Imidazoles
A. A. Aleksandrov and M. M. El’chaninov
South-Russian State Technical University (Novocherkassk Polytechnic Institute), Novocherkassk, Rostov oblast, Russia
Received November 23, 2009
Abstract—Conditions of aromatization of 2-(2-hetaryl)imidazolines and their analogs with various
dehydrogenating agents were examined. A new catalytic system, Pd/C–diphenyl oxide, was studied, and the
optimal catalyst : imidazoline ratio ensuring formation of 2-substituted imidazoles in high yield was found.
DOI: 10.1134/S1070427210060182
Bihetaryls, i.e., compounds consisting of two
heteroaromatic radicals linked by a single bond, attract
growing attention today, mainly owing to their high
practical importance. Bihetaryls are used as precursors
in synthesis of macrocyclic systems (aza crown ethers
[1, 2], cryptands [3]), and also as pharmaceuticals. For
example, antihelminthic and antifungal properties of 2-
(2'-furyl)benzimidazole (Furidazole) and especially 2-
(4-thiazolyl)benzimidazole (Thiabendazole) are well
known [4]. Derivatives of 4-(2-furyl)- and 4-(2-thienyl)-
pyridines have been patented as antiphlogistic drugs [5].
Aromatization of 2-R-imidazolines was performed
with POUB-2 commercial catalyst (2% Pd on OUB
carbon) or sulfur. As solvents we tested p-xylene,
naphthalene, dodecane, hexadecane, nitrobenzene, and
diphenyl oxide. However, all these compounds except
diphenyl oxide are unsuitable for this reaction for a
number of reasons. Diphenyl oxide well dissolves the
reactants and has sufficiently high boiling point (259°C).
In this solvent, dehydrogenation with sulfur occurs
rapidly, but the product is contaminated with difficult-
to-separate impurities. It appeared to be more con-
venient to use the palladium catalyst POUB-2 in
diphenyl oxide. The optimal PUOB-2 : imidazoline
ratio is approximately 1 : 2. A decrease in the catalyst
amount leads to the reaction deceleration, and at 1 : 1
ratio significant product loss is observed owing to
stronger sorption of imidazolines on the carbon sur-
face. An increase in the palladium content of the
catalytic system gives no noticeable advantages over
POUB-2:
The presently known procedures for dehydro-
genation of 2-substituted imidazolines do not always
give positive results. For example, nickel catalysts
have been used for preparing 2-alkylimidazoles. In
particular, synthesis of 2-methylimidazole has been
patented. However, an attempt to prepare with these
catalysts 2-(2-furyl)imidazole failed [6]. Imidazoles
with alkyl, alicyclic, alkylaromatic, and aromatic
substituents were synthesized by dehydrogenation of
imidazolines on oxides of molybdenum, nickel, cobalt,
and other metals in the gas phase at 250–300°C [7].
The yield is, as a rule, high, but the complexity of
implementation limits the possibility of using the
procedure in a laboratory.
N
N
Pd/C
Ph2O
R
R
N
H
N
H
I−VIII
IX−XVI
The goal of this study was to develop a simple and
efficient procedure for dehydrogenation of 2-substituted
imidazolines whose synthesis has been described
previously [8].
R = 2-furyl (IX), 2-thienyl (X), phenyl (XI), 2-pyridyl
(XII), 3-pyridyl (XIII), 4-pyridyl (XIV), methyl (XV),
benzyl (XVI).
1024

A CONVENIENT PROCEDURE FOR PREPARING HETARYLAMIDES
Properties of the synthesized 2-R-imidazoles and 2,2'-bisimidazoles
1025
1Н NMR spectrum,
δ, ppm, (CF3COOH)b
Found, %
Calculated, %
Comp.
no.
Yield,
%
R
Tm, °Сa
Formula
C
H
N
C
H
N
IX 2-Furyl
66 169.5–170.5 62.5 4.5 20.8 C7H6N2O 62.7 4.5 20.9 6.25 d.d (1Н, 4'-Н);
6.95 m (3Н, 3'-Н, 5-Н,
4-Н); 7.25 d ( 1Н, 5'-Н)
X
2-Thienyl
53
197–198 55.9 4.1 18.5 C7H6N2S
56.0 4.0 18.7 6.85 t (1Н, 4'-Н); 7.0 s
(2Н, 4-Н, 5-Н); 7.3 d
(1Н, 3'-Н), 7.4 s (1Н,
5'-Н)
XI Phenyl
81
148–149 74.9 5.6 19.4
C9H8N2
75.0 5.6 19.4
–
XII 2-Pyridyl
XIII 3-Pyridyl
XIV 4-Pyridyl
74
76
78
135–136c 66.0 4.8 29.0
206–207 66.1 4.9 29.0
212–213d 66.2 4.7 29.0
C8H7N3
C8H7N3
C8H7N3
66.2 4.9 29.0
66.2 4.9 29.0
66.2 4.9 29.0 7.45 s (2Н, 4-Н, 5-Н);
8.38 d (2Н, 3'-Н, 3'-
Н); 8.75 d (2Н, 2'-Н,
6'-Н)
–
–
XV CH3
XVI C6H5CH2
75
73
144–145 58.1 7.3 34.2
125–126 76.1 6.4 17.8 C10H10N2
C4H6N2
58.5 7.4 34.1
75.9 6.4 17.7 3.94 s (2Н, СН2); 6.86
m (5Н, arom); 6.94 s
–
(2Н, 4-Н, 5-Н)
XXI 1,4-Phenylene
90
84
>340
>340
68.5 4.7 26.5 C12H10N4
68.6 4.8 26.7 7.2 s (4Н, 4-Н, 5-Н,
4'-Н, 5'-Н); 7.8 s (4Н,
arom)
62.3 4.3 33.2 7.2 s (4Н, 4-Н, 5-Н,
4'-Н, 5'-Н); 8.07 d
XXII 2,5-Pyridinediyl
62.4 4.3 33.0
C11H9N5
(1Н, 4-Н); 8.4 d (1Н,
3-Н); 8.8 br.s (2NH),
9.2 s (1Н, 6-Н)
XXIII 2,6-Naphthylene
89
87
>340
74.0 4.6 21.4 C16H12N4
73.8 4.7 21.5 7.2 s (4Н, 4-Н, 5-Н,
4'-Н, 5'-Н); 7.8 m (4Н,
3-Н, 4-Н, 7-Н, 8-Н);
8.2 m (2Н, 1-Н, 5-Н)
XXIV 4,4'-(p-C6H4)2O
280–281 71.2 4.6 18.4 C18H14N4O 71.5 4.7 18.5 6.9 m (4Н, 2-Н, 2'-Н,
6-Н, 6'-Н); 7.0 s (4Н,
imode); 7.7 m (4Н, 3-
Н, 3'-Н, 5-Н, 5'-Н)
a
Compounds XV and XVI were crystallized from hexane; XI–XIV, from benzene; XXIV, from water; IX, from xylene; compounds
XXI–XXIII were reprecipitated from hydrochloric acid solution with ammonia.
b
The 1H NMR spectrum of XXII was recorded in DMSO-d6.
Dehydrogenation of imidazolines III–VIII by the
ing with sulfur-containing products of degradation of
the thiophene ring. As a result, a mixture of the initial
imidazoline II and imidazole X is formed. We failed to
separate them by crystallization. Previously unknown
2-(2-thienyl)imidazole X was isolated and purified via
silver salt. By dehydrogenation of bisimidazolines
XVII–XX, we prepared 2,2'-bisimidazoles XXI–
XXIV in high yields:
above scheme yields imidazoles IX–XVI in 74–81%
yields. 2-(2-Furyl)imidazoline I under these conditions
partially decomposes, which is responsible for
somewhat lower (66%) yield of 2-(2-furyl)imidazole
IX. 2-(2-Thienyl)imidazoline II undergoes dehydro-
genation rapidly, but the reaction does not go to
completion, apparently because of the catalyst poison-
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 83 No. 6 2010

1026
ALEKSANDROV, EL’CHANINOV
Pd/C
Ph2O
N
N
N
N
filtrate was diluted with water by a factor of 3. The
resulting product was filtered off and recrystallized
from ethanol. Yield 8 g; colorless crystals.
N
H
N
H
N
H
R
N
H
R
2,2'-Bisimidazoles XXI–XXIV. A mixture of
0.1 ml of bisimidazoline XVII–XX, POUB-2 catalyst
taken in an amount equal to the substrate weight, and
diphenyl oxide (30 ml per gram of bisimidazoline) was
refluxed with stirring for 4 h. Then the mixture was
cooled and diluted by a factor of 2 with hexane, after
which the product together with the catalyst was
filtered off and washed with hexane (2 × 100 ml). The
resulting mixture was dried in an oven at 80–100°C
and extracted with 100 ml of a hot HCl solution (50 ml
of HCl, d = 1.19 g cm–3, and 50 ml of H2O). The base
precipitated as white crystals upon neutralization of the
hydrochloric acid solution with concentrated ammonia.
Data on the bisimidazoles prepared are given in the
table.
XVII−XX
XXI−XXIV
R = 1,4-phenylene (XXI), 2,5-pyridinediyl (XXII), 2,6-
naphthylene (XXIII), 4,4'-(C6H4)2O (XXIV).
The following changes are observed in the 1H NMR
spectra of 2-R-imidazoles compared to the cor-
responding imidazolines: (1) the resonance signals of
methine protons at 3.7 ppm and NH protons at 7.7 ppm
disappear; (2) in the region of 7.0 ppm, a two-proton
singlet from 4-H and 5-H protons of the imidazole ring
appears. The majority of the synthesized diimidazoles
are symmetrical. Therefore, taking into account fast
annular tautomerism, all the four protons of the
imidazole rings give in the 1H NMR spectra a
characteristic singlet. The same is true even for
diimidazole XXII, despite the fact that it is not quite
symmetrical.
CONCLUSIONS
A general procedure was developed for dehyd-
rogenation of the majority of imidazolines and
bisimidazolines to the corresponding imidazoles and
bisimidazoles using POUB-2 palladium catalyst in
diphenyl oxide. The yield of the target products was
74–90%, except previously unknown 2-(2-thienyl)
imidazole isolated via silver salt in 53% yield.
EXPERIMENTAL
1
The H NMR spectra were recorded on a DPX-250
spectrometer (250 MHz). Elemental analysis was
performed with a Perkin–Elmer 2400 analyzer. The
melting points were determined by the capillary
method with a PTP device.
REFERENCES
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0.1 mol of 2-R-imidazoline I–VIII, POUB-2 catalyst
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weight, and diphenyl oxide (10 ml per gram of
imidazoline) was refluxed with stirring for 2 h. Then
the mixture was cooled and diluted by a factor of 2
with chloroform, after which the catalyst was filtered
off. The reaction product was precipitated from the
filtrate with hexane and crystallized from appropriate
solvent (see table).
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