Alkyl-substituted 1,1'-Dihydroxy-2,2'bimidazoles: Reactions with Methyl Iodide and Trimethyl Phosphite

Article abstract of DOI:10.1134/S107042802001027X

Abstract: The alkylation of alkyl-substituted 1,1'-dihydroxy-2,2'-biimidazoles with an equimolar amount of methyl iodide occurs exclusively at the imidazole nitrogen atom, while with a three-fold excess of methyl iodide, both the imidazole nitrogen atom and two hydroxy groups are involved in alkylation. The reaction of 1,1'-dihydroxy-2,2'-biimidazoles with P(OMe)₃ forms the corresponding 2,2'-biimidazoles.

Full text of DOI:10.1134/S107042802001027X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 2, pp. 339–342. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 2, pp. 303–306.
SHORT
COMMUNICATIONS
Alkyl-substituted 1,1'-Dihydroxy-2,2'bimidazoles:
Reactions with Methyl Iodide and Trimethyl Phosphite
I. A. Os’kinaa,* and A. Ya. Tikhonova
a Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
Novosibirsk, 630090 Russia
*e-mail: oi@nioch.nsc.ru
Received July 15, 2019; revised, November 18, 2019; accepted November 27, 2019
Abstract—The alkylation of alkyl-substituted 1,1'-dihydroxy-2,2'-biimidazoles with an equimolar amount of
methyl iodide occurs exclusively at the imidazole nitrogen atom, while with a three-fold excess of methyl iodide,
both the imidazole nitrogen atom and two hydroxy groups are involved in alkylation. The reaction of 1,1'-dihy-
droxy-2,2'-biimidazoles with P(OMe)3 forms the corresponding 2,2'-biimidazoles.
Keywords: 1,1'-dihydroxy-2,2'-biimidazoles, 2,2'-biimidazoles, methylation, reduction
DOI: 10.1134/S107042802001027X
2,2'-Biimidazoles are of interest for the synthesis
of photosensitive macroheterocycles [1], new crown
ethers [2], and luminescent [3], biologically active [4],
and highly energetic compounds [5], organic conductors
[6], and compounds with two quaternary groups [7].
The reaction of alkyl-substituted 1,1'-dihydroxy-
2,2'-biimidazoles 1a–1c with methyl iodide in DMF
in the presence of KCO3 at room temperature gave
4,4',5,5'-teraalkyl-substituted2,2'-diimidazoliumiodides
3a–3c in yields of 51–97% (Scheme 1). In this case, the
imidazole nitrogen and hydroxyl oxygens are alkylated
one after another.
1,1'-Dihydroxy-2,2'-biimidazoles, unlike 2,2'-di-
imidazoles, are still poorly studied [8, 9], even though
they can present interest for the synthesis of both their
derivatives and 2,2'-biimidazoles.
The reduction of hydroxyimidazoles 1a–1c with
trimethyl phosphite (cf. [11]) results in facile formation
of imidazoles 4a–4c in yields of 56–98% (Scheme 1).
The goal of the present work was to study reactions
of alkyl-substituted 1,1'-dihydroxy-2,2'-biimidazoles
with methyl iodide and P(OMe)3.
It should be noted the yields of diimidazoles 4a
and 4b in the reactions of glyoxal, ammonia, and
corresponding diketones, employed by Kuhn and Blau
[12], were much lower (12 and 8%, respectively) than
in the present work.
The alkylation of compounds 1a–1c with an equi-
molar amount of methyl iodide occurs at the imidazole
nitrogen atom to form 4,4',5,5'-tetraalkyl-substituted
1-hydroxy-1'-methyl-2,2'-biimidazole 3-oxides 2a–2c
in yields of 57–86% (Scheme 1). The fact that the
reaction involves the imidazole nitrogen atom rather
than the hydroxyl oxygen, as would be expected [10],
is likely to be explained by the higher nucleophilicity
of the nitrogen atom compared to the hydroxyl oxygen.
The latter can be associated with the involvement of the
N-oxide form of biimidazole in this reaction [9]. The
existence of compounds 2a–2c in N-oxide form A or
their tautomerization is also not excluded [8].
Thus, the alkylation of alkyl-substituted 1,1'-di-
hydroxy-2,2'-biimidazoles with methyl iodide involves
initially the nitrogen atom rather than hydroxyl oxygen.
1,1'-Dihydroxy-2,2'-biimidazoles are reduced to form
corresponding alkyl-substituted 2,2'-biimidazoles in
good yields.
Compounds 2a–2c (general procedure). A solution
of 0.9 mmol of alkyl-substituted 1,1'-dihydroxy-2,2'-
biimidazole 1a–1c in 2 mL of anhydrous DMF and
0.9 mmol of CH3I were added to a suspension of 3 mmol
of K2CO3 in 3 mL of anhydrous DMF. The resulting
339

OS’KINA, TIKHONOV
340
Scheme 1.
R
R
R
R
R
R
N
N
R
N
N
R
N
N
MeI (1 equiv)
MeI (3 equiv)
K2CO3, DMF, rt
K2CO3, DMF, rt
N
N
R
N
N
R
I
N
N
R
R
OH
OH
OH
1a–1c
O
O
O
2a–2c
3a–3c
P(OMe)3, DMF
O
R
R
R
N
R
N
N
N
N
N
R
R
N
H
N
H
R
R
H
O
4a–4c
A
R = R = Me (a); R + R = (CH2)4 (b); R + R = (CH2)5 (c).
mixture was stirred for 72 h at room temperature,
diluted with 3 mL of water, and neutralized with 10%
HCl. The product was extracted with CHCl3 (3 × 3 mL),
the extract was dried with MgSO4, the solvent was
evaporated, and residue was subjected to TLC on SiO2
(eluent CHCl3).
175°C (decomp.). IR spectrum, ν, cm–1: 1672, 1620,
1553, 1443, 1362, 1331, 1256, 1211, 1086, 1072, 995,
1
962. H NMR spectrum, δ, ppm: 1.68–1.79 m (12H,
6CH2), 2.68–2.85 m (8H, 4CH2), 3.89 s (3H, CH3). 13C
NMR spectrum, δ, ppm: 139.06, 129.93, 129.34, 128.90,
127.27, 122.71, 32.11, 31.23, 30.57, 29.61, 27.55, 27.03,
26.44, 25.93, 24.31, 22.83, 22.10. Mass spectrum, m/z:
316.1897 [M]+. C17H24N4O2. M 316.1894.
2-(1-Hydroxy-4,5-dimethyl-1H-imidazol-2-yl)-
1,4,5-trimethyl-1H-imidazole 3-oxide (2a). Yield
0.12 g (57%), yellow crystals, mp 158°C (decomp.). IR
spectrum, ν, cm–1: 1632, 1562, 1439, 1394, 1350, 1294,
Compounds 3a–3c (general procedure). A solution
of 0.9 mmol of alkyl-substituted 1,1'-dihydroxy-2,2'-
biimidazole 1a–1c in 2 mL of anhydrous DMF and
2.8 mmol of CH3I were added to a suspension of 3 mmol
of K2CO3 in 3 mL of anhydrous DMF. The resulting
mixture was stirred for 72 h at room temperature,
diluted with 3 mL of water, and neutralized with 10%
HCl. The product was extracted with CHCl3 (3 × 3 mL),
the extract was dried over MgSO4, the solvent was
evaporated, and the residue was subjected to TLC on
SiO2 (eluent CHCl3).
1
1254, 1230, 1194, 1121, 1034, 1007, 831. H NMR
spectrum, δ, ppm: 2.17 s (3H, Me), 2.18 s (3H, Me);
2.20 s (6H, 2Me), 3.86 s (3H, Me). 13C NMR spectrum,
δ, ppm: 132.53, 128.49, 124.08, 123.87, 122.95, 122.75,
31.82, 13.45, 8.79, 7.42, 7.19. Mass spectrum, m/z:
236.1268 [M]+. C11H17N4O2. M 236.1269.
1'-Hydroxy-1-methyl-4,4',5,5',6,6',7,7'-octa-
hydro-1H,1'H-2,2'-dibenzo[d]imidazole 3-oxide (2b).
Yield0.15g(70%),yellowcrystals,mp195°C(decomp.).
IR spectrum, ν, cm–1: 1630, 1563, 1441, 1382, 1345,
1-Methoxy-2-(1-methoxy-4,5-dimethyl-1H-
imidazol-2-yl)-3,4,5-trimethyl-1H-imidazol-3-ium
iodide (3a). Yield 0.38 g (97%), yellow crystals, mp
165°C (decomp.). IR spectrum, ν, cm–1: 1641, 1591,
1564, 1508, 1446, 1404, 1342, 1105, 955, 874. 1H NMR
spectrum,δ,ppm:2.17s(3H,CH3),2.26s(3H,Me),2.40s
(3H, Me), 2.44 s (3H, Me), 3.83 s (3H, MeN), 4.12 s (3H,
MeO), 4.16 s (3H, MeO). 13C NMR spectrum, δ, ppm:
134.53, 128.43, 127.86, 125.40, 124.79, 119.35, 70.46,
69.22, 34.82, 13.15, 10.42, 8.09, 7.63. Found, %:
C 39.32; H 5.30; N 14.28; I 32.30. C13H21N4O2I.
Calculated, %: C 39.81; H 5.40; N 14.28; I 32.35.
1
1319, 1220, 1126, 1099, 958, 947, 902, 841, 808. H
NMR spectrum, δ, ppm: 1.79–1.83 m (6H, 3CH2), 1.83–
1.89 m (2H, CH2), 2.50–2.58 m (2H, CH2), 2.58–2.73 m
(6H,3CH2),3.85s(3H,Me).13CNMRspectrum,δ,ppm:
135.42, 128.46, 126.26, 126.21, 125.48, 124.37, 31.95,
24.52, 23.08, 22.12, 21.81, 21.40, 19.90, 19.58, 18.66.
Mass spectrum, m/z: 288.1582 [M]+. C15H20N4O2. M
288.1581.
1'-Hydroxy-1-methyl-1,1',4,4',5,5',6,6',7,7',8,8'-
dodecahydro-2,2'-di(cyclohepta[d]imidazole)
3-oxide (2c). Yield 0.24 g (86%), yellow crystals, mp
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 2 2020

ALKYL-SUBSTITUTED 1,1'-DIHYDROXY-2,2'-DIIMIDAZOLES
341
Mass spectrum, m/z: 241.1450 [M – H]+. C14H17N4. M
241.1448.
1,1'-Dimethoxy-3-methyl-4,4',5,5',6,6',7,7'-
octahydro-1H,1'H-2,2'-dibenzo[d]imidazol-3-ium
iodide (3b). Yield 0.80 g (60%), yellow crystals, mp
156°C (decomp.). IR spectrum, ν, cm–1: 1638, 1585,
1562, 1495, 1439, 1392, 1345, 1327, 1222, 1083, 958,
1,1',4,4',5,5',6,6',7,7',8,8'-Dodecahydro-2,2'-di-
(cyclohepta[d]imidazole) (4c). Yield 0.15 g (56%),
white crystals, decompose without melting. IR spec-
trum, ν, cm–1: 1635, 1560, 1439, 1362, 1329, 1254, 1175,
1067, 960, 868. 1H NMR spectrum, δ, ppm: 1.57–1.68 m
(4H, 2CH2), 1.68–1.76 m (4H, 2CH2), 1.76–1.86 m (4H,
2CH2), 2.50–2.64 m (4H, 2CH2), 2.71–2.88 m (4H,
2CH2). 13C NMR spectrum, δ, ppm: 133.32, 129.18,
124.75, 30.78, 28.03, 27.18, 26.78, 22.55. Mass spec-
trum, m/z: 270.1834 [M]+. C16H22N4. M 270.1839.
1
941. H NMR spectrum, δ, ppm: 1.82–1.92 m (4H,
2CH2), 1.94–2.11 m (4H, 2CH2), 2.56–2.62 m (2H,
CH2), 2.67–2.74 m (2H, CH2), 2.74–2.84 m (4H, 2CH2),
3.84 s (3H, MeN), 4.23 s (3H, MeO), 4.24 s (3H, MeO).
13C NMR spectrum, δ, ppm: 137.24, 130.57, 128.21,
127.59, 127.15, 120.19, 70.68, 68.90, 34.36, 24.22,
22.63, 21.78, 20.97, 20.81, 20.58, 19.96, 19.38. Mass
spectrum, m/z: 302.1735 [M – CH3I]+. C16H22N4O2. M
302.1737.
The IR spectra were registed on a Bruker Vector-22
instrument in KBr pellets. The 1H and 13C NMR spectra
were run on Bruker AV-400 spectrometer [400 (1H)
and 100 (13C) MHz] in CDCl3 solutions, the chemical
shifts were referred to residual proton and carbon
signals of CDCl3 [7.24 (1H) and 76.90 (13C) ppm]. The
melting points were measured on a Mettler Toledo FD-
900 melting point apparatus. The elemental analyses
were obtained on a Euro EA3000 automated CHNS
analyzer. The high-resolution mass spectra (EI, 70 eV)
were run on a Thermo Electron DFS instrument. The
reaction progress and individuality of the synthesized
compounds were controlled by TLC on Sorbfil PTSKh-
AF-A-UF plates, eluent CHCl3. Alkyl-substituted
1,1'-dihydroxy-2,2'-biimidazoles 1a–1c were prepared
by the procedure in [9].
1,1'-Dimethoxy-3-methyl-1,1',4,4',5,5',6,6',
7,7',8,8'-dodecahydro-2,2'-di(cyclohepta[d]-
imidazol)-1-iumiodide(3c).Yield0.22g(51%), yellow
crystals, decompose without melting. IR spectrum,
ν, cm–1:1632, 1554, 1502, 1446, 1398, 1356, 1325, 1055,
991, 953, 924. 1H NMR spectrum, δ, ppm: 1.66–1.81 m
(4H, 2CH2), 1.81–1.99 m (8H, 4CH2), 2.65–2.80 m
(4H, 2CH2), 2.82–3.05 m (4H, 2CH2), 3.83 s (3H,
MeN), 4.17 s (6H, MeO). 13C NMR spectrum, δ, ppm:
140.88, 133.18, 130.54, 130.11, 127.53, 118.59, 71.19,
69.42, 34.80, 30.74, 30.68, 28.67, 26.91, 26.65, 25.64,
25.51, 25.31, 23.13, 22.82. Found, %: C 48.08; H 6.22;
N 11.77; I 27.31. C19H29N4O2I. Calculated, %: C 48.31;
H 6.19; N 11.86; I 26.87.
ACKNOWLEDGMENTS
Compounds 4a–4c (general procedure). Trimethyl
phosphite, 3 mmol, was added to a solution of 1 mmol
of alkyl-substituted 1,1'-dihydroxy-2,2'-biimidazole
1a–1c in 2 mL of anhydrous DMF. The reaction mixture
was heated at 110°C for 14 h, cooled, ad diluted with
5 mL of water. The product was extracted with CHCl3
(3 × 3 mL), the extract was dried over MgSO4, the
solvent was evaporated, and the residue was subjected
to TLC on SiO2 (eluent CHCl3).
The authors express their gratitude to the Chemical Service
Center for Collective Use, Siberian Branch, RussianAcademy
of Sciences, for spectral and analytical measurements.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
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