Reactions of 1-cyanoimidazoles with phenols

Article abstract of DOI:10.1023/A:1012401028728

Phenols with pK_a ≥ 7 react with 1-cyanoimidazole and 1-cyano-2-methylimidazole to give addition products at the cyano group; phenols with pK_a ≤ 1 give rise to the corresponding quaternary salts, 1-cyanoimidazolium phenolates; phenols

Full text of DOI:10.1023/A:1012401028728

Russian Journal of Organic Chemistry, Vol. 37, No. 3, 2001, pp. 426 429. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 3, 2001,
pp. 451 454.
Original Russian Text Copyright
2001 by Pan’kov, Belyakova, Vishnyakov, Purygin.
Reactions of 1-Cyanoimidazoles with Phenols
S. V. Pan’kov, N. A. Belyakova, V. V. Vishnyakov, and P. P. Purygin
Samara State University, ul. Akademika Pavlova 1, Samara, 443011 Russia
e-mail: vishn@ssu.samara.ru
Received December 11, 1998
Abstract Phenols with pKa 7 react with 1-cyanoimidazole and 1-cyano-2-methylimidazole to give addition
products at the cyano group; phenols with pKa 1 give rise to the corresponding quaternary salts, 1-cyano-
imidazolium phenolates; phenols with pKa
4 do not react with 1-cyanoimidazoles.
We showed in [1 3] that 1-cyanoazoles are highly
reactive compounds which can be used as condensing
agents in the synthesis of various carboxylic acid
derivatives. There are also data [4 7] on the use of
1-cyanoimidazole for building up phosphorus ester
bond in the synthesis of oligonucleotides. Probably,
due to high reactivity of the cyano group, 1-cyano-
imidazoles can be used not only as condensing agents
but also as substrates for synthesis of new azole
derivatives.
Acceptor substituents at the cyano group enhance
its activity in addition reactions, both electrophilic
and nucleophilic [8]. Therefore, the cyano group in
1-cyanoimidazoles is more reactive toward hydroxyl-
containing nucleophiles than the cyano group in alkyl
or aryl cyanides. The latter react with phenols only
in the presence of an acid or base catalyst [8].
We examined reactions of 1-cyanoimidazole (I) and
1-cyano-2-methylimidazole (II) with phenols III X
in the absence of a catalyst. The acidity of phenols
III X varied in the pKa range from 10 to 0.7: phenol
(III) 10.0, 1-naphthol (VII) 9.85, 8-hydroxyquinoline
(IX) 9.81, 2-naphthol (VIII) 9.63, 4-hydroxybenz-
aldehyde (X) 7.62, 4-nitrophenol (IV) 7.15, 2,4-di-
nitrophenol (V) 4.11, 2,4,6-trinitrophenol (VI) 0.71.
The reactions were carried out in dry benzene on
heating. Depending on the reactant nature, two kinds
of products were obtained (Scheme 1).
The reactions of cyanoimidazoles I and II with
phenols IV and VII X gave aryl imidazole-1-carbox-
imidates XI XX. By reactions of I and II with
2,4,6-trinitrophenol (VI) the corresponding 1-cyano-
imidazolium picrates XXIII and XXIV were obtained.
However, no reactions with phenol (III) and 2,4-di-
Scheme 1.
I, R = H; II, R = CH3; III, R = Ph; IV, R = 4-NO2C6H4; V, R = 2,4-(NO2)2C6H3; VI, R = 2,4,6-(NO2)3C6H2; VII, R =
1-naphthyl; VIII, R = 2-naphthyl; IX, R = 8-quinolinyl; X, R = 4-OHCC6H4; XI, R = H, R = 4-NO2C6H4; XII, R = H,
R = 1-naphthyl; XIII, R = H, R = 2-naphthyl; XIV, R = H, R = 8-quinolinyl; XV, R = H, R = 4-OHCC6H4; XVI, R = Me, R =
4-NO2C6H4; XVII, R = Me, R = 1-naphthyl; XVIII, R = Me, R = 2-naphthyl; XIX, R = Me, R = 8-quinolinyl; XX, R = Me,
R = 4-OHCC6H4; XXI, R = H, R = Ph; XXII, R = Me, R = Ph; XXIII, R = H, R = 2,4,6-(NO2)3C6H2; XXIV, R = Me,
R = 2,4,6-(NO2)3C6H2.
1070-4280/01/3703-0426$25.00 2001 MAIK Nauka/Interperiodica

REACTIONS OF 1-CYANOIMIDAZOLES WITH PHENOLS
nitrophenol (V) occurred. When the reactions with Scheme 2.
427
phenol were carried out in the presence of sodium
hydride as base catalyst, we isolated phenyl imid-
azole-1-carboximidates XXI and XXII. Compounds
I and II failed to react with 2,4-dinitrophenol even
in the presence of a base catalyst.
A
The yields, melting points, spectral data, and ele-
mental analyses of the products are given in table.
The 1H NMR spectra of compounds XI XXIV
contain signals from protons of the imidazole and
benzene rings and NH group.
displaced toward the initial reactants (ionization of
phenol does not occur). Phenols with pKa in the range
from 10 to 7.15 favor formation of ion pair A, leading
to final aryl imidazole-1-carboximidates.
All aryl imidizole-1-carboximidates XI XXII
characteristically show in the IR spectra medium and
strong absorption bands in the region 3330 3240 and
1
1710 1690 cm , which correspond to stretching
vibrations of the N H and C N bonds in the newly
formed imino group.
Decrease in pKa from 7.15 to 4.11 leads to even
stronger shift of the equilibrium toward formation of
ion pair A, but the nucleophilicity of phenoxide ion
is insufficient for the reaction to proceed further. This
is also confirmed by the fact that 2,4-dinitrophenol
(V) with compounds I and II does not form addition
products in the presence of 2,4-dinitrophenoxide ion
generated by the action of a base. The reaction stops
at the stage of reversible formation of quaternary salt
which can be neither converted into aryl imidazole-
carboximidate nor isolated. Further decrease of pKa
from 4.11 to 0.71 leads to complete dosplacement of
equilibrium a to the right, and the cooresponding
picrates (XXIII and XXIV) can be isolated.
The IR spectra of 1-cyanoimidazolium picrates
XXIII and XXIV contain absorption bands of the
1
cyano group (2295 cm ) but lack bands typical of
carboximidate moiety. The CN stretching frequencies
in the spectra of XXIII and XXIV are similar to
those observed for initial 1-cyanoimidazoles, whereas
absorption bands of C H bonds in the imidazole
ring displaced to the higher-frequency region and
changed their multiplicity. The IR spectrum of
1-cyanoimidazole (I) contains two bands at 3165 and
1
3190 cm , and the corresponding picrate XXIII, three
1
bands at 3170, 3200, and 3210 cm ; 1-cyano-2-
methylimidazole shows three absorption bands at
3105, 3120, and 3160 cm ; the corresponding bands
1
EXPERIMENTAL
in the spectrum of picrate XXIV are located at 3140,
1
The IR spectra were recorded in KBr on an IKS-29
spectrometer. The H NMR spectra were obtained on
3165, and 3180 cm . These data indicate that
1
protonation of molecules I and II occurs at the N1
or N3 atom rather than at the cyano group.
a Bruker WP-200SJ instrument (200.13 MHz) using
CD3CN as solvent and TMS as internal reference.
Quantum-chemical calculations of compounds I and
II were performed by the MNDO method [9] using
HyperChem software. Flash chromatography on dry
columns was carried out according to [10]; silica gel
for TLC was used as sorbent, column length 25 mm,
diameter 15 mm, overall eluent (ethyl acetate) volume
50 ml. The pKa values of phenols were taken from
reference literature [11, 12].
4-Nitrophenyl imidazole-1-carboximidate (XI).
To a solution of 0.143 g (1.03 mmol) of 4-nitro-
phenol in 20 ml of dry benzene we added 0.096 g
(1.031 mmol) of freshly sublimed 1-cyanoimidazole.
The mixture was refluxed for 3 h, and the solvent was
removed under reduced pressure (water-jet pump).
The crystalline residue was washed with dry diethyl
ether (3 5 ml) and dried.
The IR spectra of XXIII and XXIV are consistent
with the results of MNDO quantum-chemical calcula-
tions of compounds I and II. The calculated negative
charges on the imidazole nitrogen atoms are greater
(N1, 0.182, 0.168; N3, 0.214, 0.207) than on the
nitrogen atom of the cyano group ( 0.067).
Scheme 2 shows a probable mechanism of the reac-
tions of 1-cyanoimidazoles I and II with phenols
III X. Presumably, addition of phenol at the cyano
group (steps b and c in Scheme 2) is preceded by
acid dissociation of phenol with formation of ion pair
A (step a). Step b is nucleophilic addition of phen-
oxide ion at the cyano group, which yields the final
aryl imidazole-1-carboximidate. The proposed mecha-
nism explains formation of different products in the
reactions of I and II with phenols III X. In the case
of weakly acid phenols (pKa 10) equilibrium a is
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 3 2001

428
PAN’KOV et al.
Phenyl imidazole-1-carboximidate (XXI). To
Compounds XIV XVI and XIX were synthesized
in a similar way.
a solution of 0.032 g (0.034 mmol) of freshly distilled
phenol in 3 ml of dry benzene we added 0.0004 g
(0.017 mmol) of sodium hydride. When evolution of
hydrogen ceased, we added to the resulting suspension
0.03 g (0.32 mmol) of 1-cyanoimidazole, and the
mixture was refluxed for 5 h. It was then cooled to
18 20 C and filtered, the filtrate was evaporated
under reduced pressure, the residue was dissolved in
2 ml of dry diethyl ether, 3 ml of petroleum ether was
1-Naphthyl imidazole-1-carboximidate (XII). To
a solution of 0.055 g (0.381 mmol) of 1-naphthol in
11 ml of dry benzene we added 0.036 g (0.381 mmol)
of 1-cyanoimidazole, and the mixture was heated for
5 h. Removal of the solvent left an oily substance
which was purified by flash chromatography.
Compounds XIII, XVII, XVIII, and XX were
synthesized in a similar way.
Yields, melting points or Rf values, spectral parameters, and elemental analyses of compounds XI XXIV
1
IR spectrum, , cm
Comp.
no.
Yield,
%
mp,
(Rf)a
C
1H NMR spectrum, , ppm
N H C N C N
XI
80
27
30
112 112.5
3325
3300
3340
1700
1690
1710
3.30 br.s (1H, NH), 6.72 d (2H, C6H4, J = 9.2 Hz), 6.97 s,
7.72 (2H, CH, imidazole), 7.90 d (2H, C6H4, J =
9.2 Hz), 8.32 s (1H, CH, imidazole)
4.95 br.s (1H, NH), 6.88 6.91 m (2H, C10H7), 7.24 7.34 m
(2H, C10H7), 7.38 7.47 m (3H, C10H7), 7.09 s, 7.76 s
(2H, CH, imidazole), 8.22 s (1H, CH, imidazole)
5.4 br.s (1H, NH), 7.12 7.19 m (3H, C10H7), 7.26 7.43 m
(4H, C10H7), 7.10 s, 7.75 s (2H, CH, imidazole), 8.20 s
(1H, CH, imidazole)
b
XII
XIII
(0.60)
b
(0.65)
XIV
XV
42
44
127 128
128.5 129
3315
3290
1710
1710
3.38 br.s (1H, NH), 7.07 s, 7.64 s (2H, CH, imidazole),
7.45 d (2H, C6H4, J = 8.2 Hz), 8.05 d (2H, C6H4, J =
8.2 Hz), 8.24 s (1H, CH, imidazole), 10.02 s (1H, CHO)
2.52 s (3H, CH3), 3.03 br.s (1H, NH), 6.94 d (2H, C6H4,
J = 9.2 Hz), 7.52 s, 8.33 s (2H, CH, imidazole), 8.12 d
(2H, C6H4, J 9.2 Hz)
2.35 s (3H, CH3), 3.04 br.s (1H, NH), 6.86 6.92 m (2H,
C10H7), 7.26 7.36 m (2H, C10H7), 7.40 7.50 m (3H,
C10H7), 7.82 d, 8.14 d (2H, CH, imidazole, J = 1.7 Hz)
2.36 s (3H, CH3), 3.37 br.s (1H, NH), 7.07 7.15 m (3H,
C10H7), 7.24 7.43 m (4H, C10H7), 7.73 d, 7.77 d (2H,
CH, imidazole, J = 1.7 Hz)
XVI
65
6
100 101
3300
3315
3330
1710
1690
1695
b
XVII
XVIII
(0.55)
b
12
(0.62)
XIX
XX
15
22
110 112
(0.26)
3240
3330
1700
1690
2.37 s (3H, CH3), 3.41 br.s (1H, NH), 6.92 d, 7.77 d (2H,
CH, imidazole, J = 1.8 Hz), 6.97 m, 7.72 m (4H, C6H4),
9.79 s (1H, CHO)
XXI
54
55
91
94
69.5 70.5
3240
3330
1710
1700
4.0 br.s (1H, NH), 7.15 7.29 m (5H, C6H5), 7.37 s, 7.68 s
(2H, CH, imidazole), 8.27 s (1H, CH, imidazole)
2.36 s (3H, CH3), 3.93 br.s (1H, NH), 6.74 6.87 m (5H,
C6H5), 7.15 d, 7.23 d (2H, CH, imidazole, J = 1.6 Hz)
2295 7.20 s, 8.00 s (2H, CH, imidazole), 8.50 s (1H, CH,
imidazole), 8.59 s (2H, C6H2), 9.04 br.s (1H, NH)c
2295 2.55 s (3H, CH3), 7.15 d, 7.90 d (2H, CH, imidazole, J =
1.7 Hz), 8.59 s (2H, C6H2), 9.38 br.s (1H, NH)c
b
XXII
XXIII
XXIV
(0.40)
115 116
109.5 110.5
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 3 2001

REACTIONS OF 1-CYANOIMIDAZOLES WITH PHENOLS
429
Table. (Contd.)
Found, %
Formula
Calculated, %
H
Compound
no.
C
H
N
C
N
XI
XII
51.70
70.82
70.83
69.57
61.33
53.60
71.62
71.60
66.64
62.84
64.08
65.60
37.31
39.26
3.53
4.70
4.73
4.58
4.29
4.15
5.30
5.26
4.83
4.90
5.00
5.60
1.95
2.43
24.00
17.90
17.30
18.70
19.63
22.70
16.50
16.92
22.40
18.10
22.10
20.96
25.93
24.70
C10H8N4O3
C14H11N3O
C14H11N3O
C13H10N3O
C11H9N3O2
C11H10N4O3
C15H13N3O
C15H13N3O
C14H12N4O
C12H11N3O2
C10H9N3O
C11H11N3O
C10H6N6O7
C11H8N6O7
51.72
70.86
70.86
69.62
61.38
53.65
71.69
71.69
66.65
62.87
64.15
65.65
37.28
39.29
3.48
4.68
4.68
4.50
4.22
4.10
5.22
5.22
4.80
4.85
4.86
5.52
1.88
2.40
24.13
17.71
17.71
18.74
19.52
22.75
16.72
16.72
22.21
18.33
22.44
20.88
26.08
24.99
XIII
XIV
XV
XVI
XVII
XVIII
XIX
XX
XXI
XXII
XXIII
XXIV
a
Values of Rf for oily products were determined on silica gel with ethyl acetate as eluent.
Undergoes oxidation with atmospheric oxygen on prolonged storage.
The spectrum was recorded on a Bruker WM-250 instrument (250 MHz) in DMSO-d6.
b
c
added to the solution, and the mixture was left to
stand for 12 h at 5 C.
5. Li, T. and Nicolaou, K.C., Nature, 1994, vol. 369,
no. 6477, pp. 218 221.
Phenyl 2-methylimidazole-1-carboximidate
(XXII) was synthesized as described above for com-
pound XXI. After removal of solvent from the filtrate,
the oily residue was purified by flash chromatography.
6. Zuber, G. and Behr, J.P., Biochemistry, 1994,
vol. 33, no. 26, pp. 8122 8127.
7. Li, T., Weinstein, D.S., and Nicolaou, K.C., Chem.
Biol., 1997, vol. 4, no. 3, pp. 209 214.
1-Cyanoimidazolium picrate (XXIII). To a solu-
tion of 0.073 g (0.32 mmol) of 2,4,6-trinitrophenol in
10 ml of dry benzene we added 0.03 g (0.32 mmol)
of 1-cyanoimidazole. The mixture was refluxed for
10 min, the solvent was distilled off, and the residue
was recrystallized from dry toluene. Yield 91%. The
same procedure was used to synthesize 2-methyl-1-
cyanoimidazolium picrate (XXIV).
8. March, J., Advanced Organic Chemistry. Reactions,
Mechanisms, and Structure, New York: Wiley, 1985.
Translated under the title Organicheskaya khimiya,
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10. Sharp, J.T., Gosney, I., and Rowley, A.G., Practical
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khimii, Moscow: Mir, 1993, pp. 193 197.
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