Reaction of 1H-azoles with 2-hydroxybenzyl alcohols

Article abstract of DOI:10.1007/s10593-007-0166-y

Condensation of 1H-azoles with 2-hydroxybenzyl alcohols gave a series 2-(1H-azol-1-ylmethyl)phenols. 12H-Benzimidazo[2,1-b][1,3]benzoxazine was synthesized from 2-methylmercaptobenzimidazole and 2-hydroxybenzyl alcohol. The X-ray diffraction data of 7-nitro-2,3-diphenyl-5H-imidazo[2,1-b]-[1,3] benzoxazine are discussed.

Full text of DOI:10.1007/s10593-007-0166-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 8, 2007
REACTION OF 1H-AZOLES WITH
2-HYDROXYBENZYL ALCOHOLS
N. E. Sidorina1 and V. A. Osyanin2
Condensation of 1H-azoles with 2-hydroxybenzyl alcohols gave a series 2-(1H-azol-1-ylmethyl)phenols.
12H-Benzimidazo[2,1-b][1,3]benzoxazine was synthesized from 2-methylmercaptobenzimidazole and
2-hydroxybenzyl alcohol. The X-ray diffraction data of 7-nitro-2,3-diphenyl-5H-imidazo[2,1-b]-
[1,3]benzoxazine are discussed.
Keywords: 1H-azoles, 2-(1H-azol-1-ylmethyl)phenols, (benz)imidazo[2,1-b][1,3]benzoxazines, 2-hydroxy-
benzyl alcohols, o-methylenequinones, X-ray diffraction.
Recently o-methylenequinones (o-quinone methides) have frequently been used for the design of new
oxygen-containing heterocyclic systems [1, 3] and modification of those already known [4, 5]. In a continuation
of studies on the interaction of nitrogen-containing heterocycles with o-methylenequinones we have investigated
the reaction between 2-hydroxybenzyl alcohols and 1H-azoles.
N
N
N
N
N
N
N
R
N
N
R
N
H
H
OH
2a
OH
2d
HO
3e
3a
HO
X
N
R
1 a–c
N
N
N
N
H
X
N
N
N
R
2b,c
N
R
N
H
2e
OH
HO
3b–d
3f
1b, 3c R = H; 1a, 3a,b,f R = NO2; 1c, 3d,e R = Br; 2,3 b X = Me; c X = CF3
__________________________________________________________________________________________
1Samara State University, Samara 443011, Russia; e-mail: sidorinan@inbox.ru. 2Samara State Technical
University, Samara 443100, Russia; e-mail: vosyanin@mail.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, 1256-1263, August, 2007. Original article submitted March, 21, 2006.
0009-3122/07/4308-1065©2007 Springer Science+Business Media, Inc.
1065

A series of compounds with noticeable difference in basicity were chosen as azoles. The pKa values
varied from 2.20 (for 1,2,4-triazole) to 6.95 ( for imidazole) [6]. Despite the considerable difference in the pKa
values, all of the listed heterocycles reacted readily with 2-hydroxybenzyl alcohols. o-Methylenequinone was
generated thermally in situ with an azole molecule acting both as nucleophile by attacking the
o-methylenequinone and facilitating the dehydration of the alcohol as a base. During the reaction time the azole
molecules produced only a small concentration of o-methylenequinone which prevented its oligomerization and
led to high yields of the products of N-benzylation.
O
S
..
OH
O2N
+
N
N
N
N
OH
N
–
N
H
O
..
N
S
O2N
O2N
CH2
O
O
N
3a
+
–SO2
N
O
N
H
H
Compound 3a was also made by counter synthesis from bis(imidazol-1-yl) sulfoxide and 2-hydroxy-
5-nitrobenzyl alcohol (1a) in THF. This reaction was mentioned elsewhere [7, 8] but the authors did not provide
exact experimental details [9]. The process evidently occurs via formation of o-methylenequinone which is
generated at a much lower temperature in this case.
Samples of 2-(1H-imidazol-1-ylmethyl)-4-nitrophenol (3a) made by the two methods have identical
spectral data and did not give a depression of the melting point.
When a suitable substituent is present in the β-position to the NH group in the azole molecule
intramolecular heterocyclization of the 2-(1H-azol-1-ylmethyl)phenol intermediate is possible.
For example, we have shown previously [10] that 7-nitro-2,3-diphenyl-5H-imidazo[2,1-b][1,3]benzoxazine
(4) is formed by reaction of 2-bromo-4,5-diphenylimidazole (2f) with 2-hydroxy-5-nitrobenzyl alcohol (1a).
Ph
O
N
t°C
N
Ph
1a
+
N
–HBr
–H2O
Br
Ph
NO2
N
H
2f
Ph
4
Heterocyclic systems may be desighed analogously from 2-methylmercaptobenzimidazole (2g).
12H-Benzimidazo[2,1-b][1,3]benzoxazine (5) is formed from its thermal condensation with salicylic alcohol 1b.
N
SMe
..
H
N
CH2
OH
160-170°C
–H2O
2g
OH
O
1b
Me
SMe
H
N
O
N
S HO
N
O
N
–MeSH
N
N
CH2
5
1066

The monocyclic products 3a-e are readily alkylated at the basic nitrogen with alkyl and benzyl halides,
whereas in the case of the polycyclic compound 4 the process occurs only with powerful alkylating agents, in
particular Et3O·BF4.
Et
+
O
N
–
BF4
.
4
Ph
Et3O BF4
+
N
–Et2O
NO2
Ph
6
It should be noted that in the presence of strong acceptor substituents in the molecules of halo-
substituted azoles, alkylation with 2-hydroxybenzyl alcohols does not occur selectively at high temperatures
(160-170°C). When 2,4,5-tribromoimidazole, 2-chloro-5,6-dinitrobenzimidazole, or 5(4)-iodo-2-methyl-4(5)-
nitroimidazole reacted with salicylic alcohol complex mixture of products were formed from which it was not
possible to isolate individual components.
The reactions of 2-(azol-1-ylmethyl)phenols are general in nature, the azole nature has no major
influence on the yield of the required product.
The obtained products 3a-f are crystalline, thermally stable high-melting compounds, which are poorly
soluble in water and most organic solvents. In contrast to the monocyclic compounds 3a-f, the polycyclic
imidazo[2,1-b]-[1,3]benzoxazines are readily soluble in dichloromethane, dioxane, and acetone. It should be
noted that the solubility of 2-(azol-1-ylmethyl)phenol in dilute solutions of acids and alkalis is associated with
salt formation. In contrast (benz)imidazo[2,1-b][1,3]benzoxazines 4 and 5 are practically insoluble in aqueous
solutions of acids, despite the presence of a basic nitrogen atom.
1
In the H NMR spectra of all the compounds synthesized there are signals of the methylene protons in
the 5.12-5.95 ppm region. The signals at 8.9-10.4 ppm for compounds 3a-f are assigned to protons of the OH
group.
TABLE 1. Characteristics of the Synthesized Compounds 3a-f, 4, and 5
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C
C
H
N
3a
3b
C10H9N3O3
54.65
54.79
4.16
4.11
18.77
19.18
248-250
255-257
79 (A),
65 (B)
C15H13N3O3
C15H11F3N2O
C15H10BrF3N2O
C9H8BrN3O
C13H10N4O3
C22H15N3O3
C14H10N2O
63.44
63.60
4.65
4.59
14.53
14.84
9.59
71
69
73
75
70
80
65
3c
3d
3e
3f
4*
5
61.48
61.64
3.82
3.77
216-217
240-242
173-174
241-242
234-235
233-235
9.39
48.40
48.52
2.73
2.70
7.39
7.55
42.41
42.52
3.19
3.15
16.19
16.54
20.30
20.74
11.14
11.38
57.63
57.78
3.74
3.70
75.35
75.54
4.12
4.07
75.49
75.68
4.55
4.50
12.34
12.61
_______
* Data from [10].
1067

In the IR spectra there are absorption bands at 1600 cm-1 corresponding to of C=C/C=N bonds vibrations
in the aromatic rings and the CHarom bonds at 760-741 cm-1. In the spectra of compounds 4 and 5 bands of
medium intensity are present at 1269-1270 cm-1 corresponding to vibrations of the C–O–C unit, and for
compounds 3a-f there are broad absorption bands at 3400-2500 cm-1 corresponding to hydroxy group, associated
via hydrogen bonds. There are characteristic absorption bands of the nitro group in the regions of 1562-1520 and
1342-1327 cm-1 in the spectra of compounds 3a,b,f and 4.
Decomposition of the molecular ions of the compounds 4 and 5, formed by electron ionization, occurs
nonselectively: the intensity of the molecular ion peak for compound 4 is maximal, while for compound 5 the
ion [M–H]+ has maximum intensity due to loss of a hydrogen atom from the oxazine ring, which is explained by
the formation of a chain of conjugation.
1
In the H NMR spectra of compounds 4 and 5 there are no signals in the region ~9.0 ppm and there are
no broad intense absorption bands in the IR spectra, which confirms the cyclic structure of the molecules of
these compounds (Table 2).
TABLE 2. Spectral Characteristics of Compounds 3a-f
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
3а
3394, 3136-3086, 2372, 1597,
1558, 1477, 1339, 1296, 1145,
1088, 837, 748
5.40 (2H, s, CH2); 6.93 (1H, d, J = 8.0, HAz-4);
7.23 (1H, d, J = 7.2, H-6);
7.53 (1H, d, J = 8.0, HAz-5); 7.97 (1H, s, HAz-2);
8.05 (1H, d, J = 7.2, H-5); 8.20 (1H, s, H-3);
9.25 (1H, s, OH)
3b
3c
3d
3e
3f
3250-2400, 1616, 1593, 1524,
1497, 1427, 1327, 1285, 741
2.49 (3H, s, CH3); 5.31 (2H, s, CH2);
7.23 (1H, d, J = 8, H-6); 7.27-7.39 (4H, m, HAz-4-7);
7.91 (1H, s, H-3); 7.94 (1H, d, J = 8, H-5);
9.51 (1H, s, OH)
3148-3086, 1601, 1520, 1458,
1277, 1180, 1153, 1122, 1095,
744
5.62 (2H, s, CH2); 6.89 (1H, t, J = 7.8, H-4);
6.96-7.01 (2H, m, H-3, 6);
7.28-7.49 (4H, m, HAz-5,6,7, H-5);
7.98 (1H, d, J = 8.6, HAz-4); 9.75 (1H, s, OH)
3063-2955, 1593, 1520, 1477,
1423, 1265, 1195, 1138, 1095,
818, 748
5.61 (2H, s, CH2);
6.91-7.37 (4H, m, HAz-5, H-3,5,6);
7.49 (1H, t, J = 7, HAz-6); 7.78 (1H, d, J = 8, HAz-7);
7.89 (1H, d, J = 8.5, HAz-4); 9.71 (1H, s, OH)
3105-2604, 1589, 1497, 1435,
1346, 1277, 1142, 1107, 1018,
818, 760, 671, 656
5.31 (2Н, s, СН2); 6.82 (1Н, d, J = 8, H-5);
7.18 (1Н, s, H-3); 7.31 (1Н, d, J = 8, H-6);
7.94 (1Н, s, HAz-3); 8.51 (1Н, s, HAz-5);
10.08 (1Н, s, ОН)
3300-2500, 1620, 1593, 1527,
1497, 1447, 1339, 1300, 1273,
1088,748
5.95 (2H, s, CH2); 7.03 (1H, d, J = 8.3, H-6);
7.41 (1H, t, J = 8.4, HAz-6);
7.55 (1H, t, J = 8.4, HAz-5);
7.83 (2H, m, HAz-7, H-5); 7.92 (1H, s, H-3);
8.02 (1H, d, J = 8.2, HAz-4); 11.05 (1H, s, OH)
3g*
3h*
3047, 2916, 1597, 1551, 1508,
1485, 1443, 1342, 1296, 1258,
775, 744, 706
5.12 (2Н, s, СН2); 7.15 (2Н, t, J = 1.2, С6Н5);
7.21-7.25 (3Н, m, C6H5); 7.42 (1H, d, J = 8, H-9);
7.48-7.56 (5Н, m, С6Н5); 8.24 (1Н, d, J = 8, Н-8);
8.38 (1Н, s, Н-6)
3421, 3383, 3047, 2924, 1631,
1547, 1458, 1288, 1188, 756,
736, 439
5.40 (2H, s, CH2); 7.20-7.26 (5H, m, H-1,2,3,4, 10);
7.42-7.49 (3H, m, H-7,8,9)
_______
* From [10], mass spectra, m/z (Irel, %): compound 3g 369 [M]+ (100), 323
[M−NO2]+ (29), 165 (23), 89 (33), 77 [C6H5]+ (16), 63 (20); compound 3h
222 [M]+ (94), 221 [M−H]+ (100), 166 (12), 97 (13), 90 (41), 89 (36),
83 (16), 77 [C6H5]+ (23), 64 (18), 63 (32), 51 (24).
1068

The structure of compound 4 has also been confirmed by X-ray diffraction. The geometry of the
molecule, numbering of the atoms, principal bond lengths, and the principal bond and torsion angles are given in
Fig. 1 and Table 3.
Fig 1. General view of molecule 3g and numbering of the atoms.
The imidazo[2,1-b][1,3]benzoxazine ring has a practically planar cycle, despite the fact that it contains
an sp3-hybridized carbon atom; the maximal distortion of the value of the torsion angles from the ideal planar
structure is 3.87°.
The phenyl group C(11)…C(16) is practically coplanar with the imidazo[2,1-b][1,3]benzoxazine, with the
torsion angle C(3)C(2)C(11)C(16) 178.71°. The plane of the C(17)…C(22) phenyl ring forms a dihedral angle of
112.28° with the plane of the imidazo[2,1-b][1,3]benzoxazine ring.
In the crystal molecules of compound 4 form stacks along the crystal direction (0 0 1) with the molecules
within the stacks arranged "head to tail".
Thus we have shown 1H-azoles are quite easily alkylated by 2-hydroxybenzyl alcohols under conditions
of thermal condensation with formation of 2-(1H-azol-1-ylmethyl)phenols which, with presence at position 2 of
1H-azole of group capable of nucleophilic substitution, may undergo intramolecular heterocyclization with
formation of condensed imidazo[2,1-b][1,3]benzoxazine system.
TABLE 3. Bond Lengths (d), Values of theValence (ω) and Torsion (τ)
Angles in the Molecule of 7-nitro-2,3-diphenyl-5H-imidazo[2,1-b][1,3]-
benzoxazine*
Bond
d, Å
Angle
ω, deg
Angle
τ, deg
0.25
1.334(3)
1.361(3)
1.391(3)
1.375(3)
1.493(3)
1.447(3)
C
(4)N(2)C(1)
126.5(2)
122.4(2)
117.2(2)
122.2(2)
122.7(2)
108.9(2)
C(4)N(2)C(1)O(1)
N(2)C(1)O(1)C(6)
C(1)O(1)C(6)C(5)
O(1)C(6)C(5)C(10)
C(6)C(5)C(4)N(2)
C(17)C(3)N(2)C(1)
N(2)−C(1)
C(1)−O(1)
O(1)−C(6)
C(6)−C(5)
C(5)−C(4)
C(4)−N(2)
N(2)C(1)O(1)
C(1)O(1)C(6)
O(1)C(6)C(5)
C(6)C(5)C(4)
C(5)C(4)N(2)
-3.54
3.87
178.66
-2.01
-176.31
_______
* Complete listings of atomic coordinates and valence of the temperature
parameters may be obtained from the authors.
1069

EXPERIMENTAL
1
IR spectra of KBr disks were recorded with a Shimadzu FTIR-8400S spectrophotometer. H NMR
spectra of DMSO-d6 solutions with TMS as internal standard were recorded with a Bruker AM-400 (400 MHz)
instrument. Mass spectra were obtained with a JMS-D300 instrument with direct injection and an ionization
energy of 70 eV. Purity of products was monitored by TLC (Silufol UV-254, eluent 20:1 chloroform-methanol,
development with UV light).
2-Trifluoromethylbenzimidazole (2c) was obtained by a method in [11], and 2-bromo-4,5-diphenyl-
imidazole (2f) and 2-methylmercaptobenzimidazole (2g) as in [12].
Synthesis of 2-(1H-Azol-1-ylmethyl)phenols 3a-f. A. An equimolar mixture of the azole 2a-f and a
2-hydroxybenzyl alcohol 1a-c was heated at 160-170°C with intense stirring for 20 min. The reaction product
was washed with cold dichloromethane and crystallized from ethanol.
B. SOCl2 (1.19 g, 10 mmol) was added to a solution of imidazole 2a (2.72 g, 40 mmol) in dry THF, the
precipitate of imidazole hydrochloride was filtered off, and the solution of bis(imidazol-1-yl) sulfoxide was
added rapidly to a solution of benzyl alcohol 1a (1.69 g, 10 mmol) in THF. The reaction mixture was boiled for
2 h, the solvent was evaporated, and the residue was crystallized from an ethanol-DMF mixture.
12H-Benzimidazo[2,1-b][1,3]benzoxazine (5). A mixture of compound 2g (1.64 g, 10 mmol) and
2-hydroxybenzyl alcohol 1b (1.30 g, 10.5 mmol) was heated for 30 min at 160-165°C with intense stirring until
water vapor evolution ceased. The product crystallized twice from methanol.
1-Ethyl-7-nitro-2,3-diphenyl-5H-imidazo[2,1,b][1,3]benzoxazinium Tetrafluoroborate (6) [10]. A
solution of triethyloxonium tetrafluoroborate (1.9 g, 10 mmol) in dichloromethane (10 ml) was added to a
solution of compound 4 (3.69 g, 10 mmol) in absolute dichloromethane (50 ml) and the reaction mixture was
stirred at room temperature for 25 min. The precipitate was filtered off and washed successively with
dichloromethane and ethanol to give compound 6 as yellow crystals in a yield of 2.91 g (60%); mp 273-274°C
(DMF). IR spectrum, ν, cm-1: 2962, 2854 (CHarom), 1655, 1628, 1585 (C=C/C=N), 1528 (NO2), 1485 (C=C),
1346 (NO2), 1092 (B–F), 771, 702 (CHarom).
X-ray Diffraction Study of Compound 4. Crystals were grown from a mixture of DMF-ethanol (1:2)
by slow evaporation at room temperature: a monocrystal with linear dimensions 0.2×0.25×0.3 mm was chosen
for investigation. The yellow needle crystals belonged to the monoclinic system: a = 19.112(4), b = 11.207(2),
c = 8.092(2) Å, β = 94.69(3)°, V = 1727.4(6) Å3, M = 369.36, dcalc = 1.420 g/cm3, Z = 4, space group P21/n. Unit
parameters and a set of experimental reflexions were measured on an automatic four-cycle diffractometer
(KUMA DIFFRACTION, KM-4) with χ-geometry and ω/2θ scanning with monochromatized MoKα radiation
(2θ ≤50.1°); segment of the sphere: -22 ≤ h ≤ 22, 0 ≤ k ≤ 13, 0 ≤ l ≤ 9. A total of 3493 reflexions were measured
of which 3071 were symmetrically independent [R(int) = 0.0223, R(σ) = 0.0683]. Since the crystals of the
compound studied have small absorption coefficients and small sizes, corrections for absorption were not applied
(µ = 0.098 mm-1). The structure was solved by direct method using the programm SIR92 [13] with subsequent
calculations using the electron density distribution. All hydrogen atoms were found from electron density
difference syntheses and refined in the isotropic approximation. A full matrix anisotropic (non-hydrogen atoms)
least squares analysis using the SHELX97 program [14] refined to R1 = 0.0444, wR2 = 0.1119 for 1488
reflexions with I ≥ 2σ(I), GooF 0.856.
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