Adamantylation of imidazoles and benzimidazole

Article abstract of DOI:10.1023/A:1013148532518

For the first time is reported on substitution of a hydrogen atom in position 4 of the imidazole ring with an aliphatic substituent occurring in reaction between 1-bromoadamantane and imidazoles. The reaction proceeds alongside the substitution in position 1 at heating in excess imidazole. In o-dichlorobenzene solution adamantylation of benzimidazole afforded 1-(1-adamantyl)benzimidazole and 1,3-di(1-adamantyl)-benzimidazolium bromide. The specific features of the reactions course are described. The structure of compounds obtained is proved by ¹HNMR spectroscopy.

Full text of DOI:10.1023/A:1013148532518

Russian Journal of Organic Chemistry, Vol. 37, No. 8, 2001, pp. 1153 1157. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 8, 2001,
pp. 1212 1216.
Original Russian Text Copyright
2001 by Raenko, Korotkikh, Pekhtereva, Shvaika.
Adamantylation of Imidazoles and Benzimidazole
G. F. Raenko, N. I. Korotkikh, T. M. Pekhtereva, and O. P. Shvaika
Litvinenko Institute of Physical Organic and Coal Chemistry,
Ukrainian National Academy of Sciences, Donetsk, 83114 Ukraine
Received June 21, 2000
Abstract For the first time is reported on substitution of a hydrogen atom in position 4 of the imidazole
ring with an aliphatic substituent occurring in reaction between 1-bromoadamantane and imidazoles. The
reaction proceeds alongside the substitution in position 1 at heating in excess imidazole. In o-dichlorobenzene
solution adamantylation of benzimidazole afforded 1-(1-adamantyl)benzimidazole and 1,3-di(1-adamantyl)-
benzimidazolium bromide. The specific features of the reactions course are described. The structure of
compounds obtained is proved by 1H NMR spectroscopy.
Adamantyl derivatives of azoles are used in
preparation of sterically-protected stable carbenes [1].
However the adamantylation of nitrogen-containing
heterocycles is poorly understood. The direct intro-
duction of adamantyl groups into molecules of amines
and heterocyclic compounds of azole and azine series
with the use of adamantyl halides requires commonly
high temperature and pressure [2, 3] due to relatively
low reactivity of the reagent and its sublimation at
elevated temperature (>100 C). The adamantylation
of pyrazoles under pressure occurs both at nitrogen
and carbon atoms of the ring and affords a mixture of
1-, 4-, and 5-substituted pyrazoles [2]. A direct
introduction of 1-adamantyl substituent into imidazole
or benzimidazole ring was not described. In [4]
1,3-di(1-adamantyl)imidazolium salts were prepared
indirectly from 1-aminoadamantane, glyoxal, and
formaldehyde in acid medium.
responding imidazole (at molar ratio of compounds I
and II equal to 8: 1) at 110 180 C gave rise along-
side the products of substitution in position 1, 1-(1-
adamantyl)imidazoles IIIa, b (yield 46 53%), to
products of replacement in position 4 of the imidazole
ring, 4-(1-adamantyl)imidazoles IVa,
b
(yield
12 14%).
Imidazoles III apparently form via intermediate
salts A. We performed model experiments to clear
up whether compounds IV arise from thermal re-
arrangement of initially formed isomers III or
from a concurrent reaction of C-electrophilic sub-
stitution in the imidazole ring (through an inter-
mediate B). They showed that both in the presence
and in the absence of acids 1-substituted compound
IIIa did not rearrange into 4-substituted compound
IV. Neither occurred the reverse conversion of
isomer IVa into isomer IIa at 110 180 C in the
presence of excess imidazole. The model experiment
with 2-methylimidazole (Ib) carried out under the
same conditions but in the presence of potassium
carbonate for scavenging the hydrogen bromide did
not result in suppressing the substitution in 4-posi-
tion (yield of compound IVb was 13 14%).
We report here on reaction of imidazoles Ia, b and
benzimidazole Ic with 1-bromoadamantane (II) at
110 180 C and various reagents ratio.
We established that reaction of imidazoles Ia, b
with 1-bromoadamantane (II) in excess of the cor-
Thus imidazole adamantylation in positions 1 and
4 proceeds simultaneously, and acids or bases do not
considerably affect its direction. However the
imidazole excess plays an important part in the
process. Interestingly, in reaction of 1-bromo-
adamantane with sodium imidazolide prepared in situ
by treating imidazole with sodium hydride the
R = H (a), CH3 (b); Ad = 1-adamantyl.
1070-4280/01/3708-1153$25.00 2001 MAIK Nauka/Interperiodica

1154
RAENKO et al.
adamantylation into the imidazole ring nearly did not
occur.
The synthesis of isomeric adamantylimidazoles
III, IV by reaction of 1-bromoadamantane (II) with
excess imidazole (I) can be used as preparative
procedure for these compounds. This procedure has
certain advantages as compared to the other modes of
performing the process (at stoichiometric ratio of the
reagents in solution in the presence of bases, by
reaction of metal imidazolides) for it affords good
yields of imidazoles IIIa, b and also furnishes their
isomers IVa, b.
W = Br (V, VIa), ClO4 (VIb).
The reaction I
IVa also accompanies the pre-
paration of 1,3-di(1-adamantyl)imidazolium salt (V)
when the reaction of imidazole I is carried out at
slight excess of 1-bromoadamantane (II) (at molar
ratio of compounds I and II equal to 1: 2 2.4) in
various solvents (o-dichlorobenzene, nitrobenzene,
acetic acid). This process hampers isolation of the
pure salt V.
Note that tritylation, reaction related to adamantyl-
ation, occurs only to the position 1 of imidazole both
in solution and in imidazole melt. The arising
1-tritylimidazoles also do not rearrange into
4-isomers under the described conditions.
The composition and structure of the compounds
obtained were confirmed with elemental analyses,
1H NMR spectra, molecular weight measurements,
and their homogeneity was proved by TLC. Thus in
In the course of the above described reactions
alongside compounds IVa, b arise also their hydro-
bromides evidencing partial dehydrobromination of
bromoadamantane with basic imidazoles (regarding
the bromoadamantane dehydrobromination see also
[5]). The latter fact is also observed with the related
benzimidazole despite its notably lower basicity (pKa
5.5 [6]) as compared to imidazole (pKa 7.0 [6]). For
instance, we observed that quaternization of benz-
imidazole (Ic) with 1-bromoadamantane (II) in the
presence of sodium acetate alongside 1,3-di-
adamantylbenzimidazolium bromide VIa formed also
benzimidazole hydrobromide due to partial dehydro-
bromination of 1-bromoadamantane (II) although the
hydrogen bromide was partially fixed by sodium
acetate. Similarly proceeds the reaction of 1-(1-
adamantyl)benzimidazole (VII) with 1-bromo-
adamantane (II) [yield of pure salt VIa here is 61%.
but in the reaction mixture is present 1-(1-adamantyl)-
benzimidazole hydrobromide]. Yet tributylamine (pKb
11.04 [6]) does not effect the dehydrobromination of
1-bromoadamantane even in 5 h at 180 200 c
apparently due to the sterical hindrance to approach
of the reagents molecules.
1
the H NMR spectra of substituted imidazoles IIIa, b
appear the characteristic signals of protons from the
imidazole ring C2H ( 7.64 ppm), C4,5H ( 7.01
7.06 ppm), and in the spectra of compounds IVa, b
they are C2H ( 7.48 ppm), C5H ( 6.42 6.63 ppm),
NH ( 11.20 11.90 ppm). All the above signals are
singlets. The resonances from adamantyl protons
occur in the region 1.8 2.2 ppm. Alternative sub-
stitution in 2 position of the imidazole ring is
excluded since in the spectrum appear only two
signals from CH protons of equal intensity, and one
thereof is located in the region characteristic of C2H
protons; besides, there is no splitting of imidazole
protons signals originating from spin-spin coupling.
In the spectrum of model 2,2 -diimidazolyl (VIII)
that we have prepared as in [10] (see EXPERI-
MENTAL), and 2-methylimidazole [11] with sub-
stituted 2 position the signals from the protons C4,5
are observed in the 6.9 7.1 ppm region. In the
H
spectra both of 4-methylimidazole and imidazole
appear the signals from C2H protons ( 7.6 7.7 ppm)
and also from C5H ( 6.8 7.1 ppm). In the spectra of
compounds IVa, b proton signals from C5H, and in
the spectrum of imidazole IVa also those from C2H
are slightly displaced upfield as compared to the
signals in the spectra of model compound VIII and
Neither adamantylation of imidazole nor benz-
imidazole with 1-bromoadamantane provides products
of 2-substitution: It is known [7, 8] that electrophilic
reactions with imidazole systems do not affect this
position, in contrast to acylation at C2 [9] which we
presume to occur by carbene mechanism.
of 2-methylimidazole (C5H 6.4 6.6,
and C2H 7.5,
0.2 0.7 ppm
0.1 0.2 ppm). The shift is induced
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

ADAMANTYLATION OF IMIDAZOLES AND BENZIMIDAZOLE
1155
by the electron-donor effect of the adamantyl group,
stronger in the near 5 position and weaker in the
remote 2 position of the imidazole ring, The same
effect is even stronger pronounced in the shift of
signals from the more labile NH protons in the
sodium acetate, and then with water (3 30 ml) till
complete removal of imidazole. The organic phase
was dried with anhydrous sodium sulfate, the solvent
was removed. The residue obtained was treated with
30 ml of hexane. The precipitate of 4-(1-adamantyl)-
imidazole (IVa) was filtered off and washed with hot
hexane. Yield 0.7 g (12%), mp 227 228 C (from
spectra of compounds IVa, b ( 11.2 11.8,
0.5
1.5 ppm) as compared with the signals in the spectra
of related 4-methylimidazole ( 12.9 ppm) and imid-
azole ( 12.4 ppm). For the sake of comparison
should be noted that in the spectrum of 2-methylimid-
azole the signal of NH proton suffers still stronger
1
DMF). H NMR spectrum (DMSO-d6), , ppm: 1.71
m (6H), 1.85 m (6H), 1.99 m (3H) (1-adamantyl);
6.63 s (1H, C5H); 7.48 s (1H, C2H); 11.80 s (1H,
NH). Found, %: C 77.1; H 9.0; N 14.0. M 201.
C13H18N2. Calculated, %: C 77.2; H 9.0; N 13.9. M
202. The mother liquor was evaporated to dryness to
obtain 1.5 g (53%) of 1-(1-adamantyl)imidazole
shift: 10.9 ppm,
1.5 2 ppm apparently due to
symmetrical electronic influence of the methyl group
on both nitrogen atoms of the ring. Somewhat
unusual is a stronger shift of the proton signals from
1
(IIIa), mp 106 111 C (from hexane). H NMR spec-
CH3 group ( 2.19 ppm,
0.4 ppm) in the spectrum
trum (CDCl3), , ppm: 1.77 m (6H), 2.09 m (6H),
2.23 m (3H) (1-adamantyl); 7.06 s (2H, C4,5H),
7.64 s (1H, C2H). Found, %: C 77.0; H 8.9; N 13.9.
M 198. C13H18N2. Calculated, %: C 77.2; H 9.0; N
13.9. M 202. Compounds IIIb, IVb were similarly
prepared.
of compound IVb as compared with those in the
spectrum of imidazole IIIb ( 2.60 ppm) than should
be expected from the longer distance of the methyl
group from the adamantyl substituent in the imidazole
ring of compound IVb than that of the C2H in com-
pound IVa. The latter fact may be rationalized by
taking into account that in compound IVb as
compared to IIIb is leaved the deshielding of the
CH3 protons by the neighboring C H bonds of
adamantyl (in the position 2 of the substituent).
21-(1-Adamantyl)-2-methylimidazole (IIIb).
1
Yield 30%, mp 123 125 C (from hexane). H NMR
spectrum (CDCl3), , ppm: 1.75 m (6H), 2.18 m
(9H) (1-adamantyl); 2.60 s (3H, CH3); 6.85 s,
7.01 s (2H, C4,5H). Found, %: C 77.6; H 9.2;
N 13. 2. C14H20N2. Calculated, %: C 77. 7;
H 9.3; N 13.0.
1
The presence in the H NMR spectra of the proton
signals from NH groups and the molecular weight of
compounds corresponding to a monomer also exclude
for compounds IVa, b the possibility of a structure
of a product of oxidative 4,4 -coupling.
4-(1-Adamantyl)-2-methylimidazole (IVb). Yield
1
13%, mp 271 272 C (from DMF). HNMR spectrum
(DMSO-d6), , ppm: 1.70 m (6H), 1.80 m (6H),
1.97 m (3H) (1-adamantyl); 2.19 s (3H, CH3); 6.42 s
(1H, C5H); 11.20 s (1H, NH). Found, %: C 77.8; H
9.4; N 13.0. C14H20N2. Calculated, %: C 77.7; H
9.3; N 13.0.
EXPERIMENTAL
1H NMR spectra were recorded on spectrometer
Gemini 200 (200 MHz) at room temperature, internal
reference TMS or HMDS. TLC was performed on
Silufol plates (Czechia), eluent chloroform or a
mixture chloroform methanol, 10: 1. Molecular
weight of compounds IIIa and IVa was measured by
cryoscopic method in benzene and camphor respec-
tively. The model compound VIII was obtained as in
[7] from glyoxasulfate, ammonia, and formaldehyde.
Adamantylation of 2-methylimidazole in the
presence of potassium carbonate. The boiling mix-
ture of 4. 58 g (55.8 mmol) of 2-methylimidazole,
1.5 g (6.98 mmol) of 1-bromoadamantane, and 1.59 g
(13.96 mmol) of potassium carbonate in 5 ml of
o-dichlorobenzene was heated for 2.5 h. Then to the
mixture was added 20 ml of benzene. The precipitate
of inorganic salts was filtered off, the benzene solu-
tion was washed with water (3 20 ml), dried with
anhydrous sodium sulfate, and the solution was left
overnight. The formed precipitate of isomer IVb was
filtered off. Yield of azole IVb 0.21 g (14%), mp
271 272 C (from DMF). The solution was treated
with concn. HCl, stirred, 10 ml of water was added,
the benzene layer was separated, a fresh portion of
Imidazole adamantylation. To 4.74 g (70 mmol)
of imidazole Ia melt was added 3 g (14 mmol of
1-bromoadamantane (II) and 0.3 ml of o-dichloro-
benzene, and the reaction mixture was heated at
110 C for 6 h. The excess imidazole was distilled off
in a vacuum (1 mm Hg). Then the residue was dis-
solved in 20 25 ml of chloroform and washed first
with water solution containing 2.3 g (28 mmol) of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

1156
RAENKO et al.
benzene (20 ml) was added, the mixture was
neutralized with 20% water solution of sodium
hydroxide, the organic layer was washed with water
and dried on anhydrous sodium sulfate. The benzene
solution was evaporated in a vacuum, and the residue
was ground with hexane (2 3 ml). The precipitate of
isomer IIIb was filtered off. Yield 0.69 g (46%), mp
123 125 C (from hexane).
(II), and 1.64 g (20 mmol) of sodium acetate in
4 ml of acetic acid was boiled for 12 h. Then 0.2 g
(2.5 mmol) of sodium acetate and 1.07 g (5 mmol)
of 1-bromoadamantane was added, and the heating
continued for 4 h. To the cooled mixture 5 ml of
acetone was added, and the precipitate was filtered
off. The product obtained (10.5 g of salt VIa mixed
with sodium bromide) was purified by extraction
with 1 l of hot water. Yield of compound VIa 3.11 g
(33%), mp 297 298 C. According to TLC and
1H NMR data the compound obtained is identical to
that prepared by procedure a. To the crystalline
1-(1-Adamantyl)benzimidazole (VII). To a sus-
pension of 7.08 g (60 mmol) of benzimidazole (Ic)
and 8.28 g (60 mmol) of anhydrous potassium
carbonate in 30 ml of o-dichlorobenzene at bath
temperature 190 C while stirring was added by por-
tions within 1 h 14.2 g (66 mmol) of 1-bromo-
adamantane. The neck of the flask was left open for
water evaporation. The precipitate was filtered off the
hot reaction mixture, and the solution of 1-(1-
adamantyl)benzimidazole (VII) was evaporated in a
vacuum. The residue was treated with 5 ml of
hexane, and the precipitate was filtered off. Yield
8.2 g (54%), mp 180 184 C (from acetonitrile).
1H NMR spectrum (CDCl3), , ppm: 1.83 m (6H),
2.29 m (3H), 2.34 m (6H) (1-adamantyl); 7.25 m
(2H), 7.70 m (1H), 7.85 m (1H) (H arom); 8.02 s
(1H, C2H). Found, %: C 80.8; H 8.2; N 11.3.
C17H20N2. Calculated, %: C C 80.9; H 8.0; N 11.1.
residue after extraction was added
5
ml of
2-propanol, the mixture was heated to boiling,
cooled, the precipitate was filtered off and dried.
Yield of 1-(1-adamantyl)benzimidazole (VII) 1 g
(20%), mp 180 184 C (from acetonitrile).
The mother liquor (water solution after extrac-
tion and separation of salt VIa) was evaporated till
20 ml volume, then 20% solution of sodium hydr-
oxide was added dropwise till neutral reaction. The
separated precipitate was filtered off. Benzimid-
azole was separated in 0.8 g amount (34%), mp
172 174 C (from water), no depression of the melt-
ing point in the sample mixed with commercial
benzimidazole. The IR spectrum of the compound
obtained was also identical to that of the commercial
substance.
1,3-Di(1-adamantyl0benzimidazolium bromide
(VIa) and perchlorate (VIb). (a) A mixture of
1.48 g (5.9 mmol) of 1-(1-adamantyl)benzimidazole
(VII), 1.89 g (8.8 mmol) of 1-bromoadamantane (II),
and 0.5 ml of o-dichlorobenzene was heated for 2 h
at bath temperature 250 C. Then 0.48 g (2.2 mmol)
of 1-bromoadamantane was added, and the mixture
was heated for 1 h more. To the suspension of salt
VIa obtained was added 6 ml of ether, the mixture
was ground, and the precipitate was filtered off.
Yield 2.48 g (90%), mp 297 298 C (from water).
Yield of compound VIa after purification 1.69 g
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

ADAMANTYLATION OF IMIDAZOLES AND BENZIMIDAZOLE
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