Oxidative alkylation of azoles: VII. Adamantylation of azoles via oxidative generation of 1-adamantyl cations

Article abstract of DOI:10.1023/A:1013938527863

A procedure has been developed for oxidative N-adamantylation of azoles with 1-iodoadamantane in the presence of chromium(IV) oxide or iodine(V) oxide. The procedure is applicable to azoles whose pK_BH+ value does not exceed 2.26. * For communication VI, see [1].

Full text of DOI:10.1023/A:1013938527863

Russian Journal of Organic Chemistry, Vol. 37, No. 12, 2001, pp. 1762 1766. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 12, 2001,
pp. 1843 1847.
Original Russian Text Copyright
2001 by Tsypin, Pevzner, Golod.
Oxidative Alkylation of Azoles: VII.* Adamantylation
of Azoles via Oxidative Generation of 1-Adamantyl Cations
V. G. Tsypin, M. S. Pevzner, and E. L. Golod
St. Petersburg Technological Institute, Moskovskii pr. 26, St. Petersburg, 198013 Russia
fax: (812)1127791
Received December 24, 2000
Abstract A procedure has been developed for oxidative N-adamantylation of azoles with 1-iodoadamantane
in the presence of chromium(IV) oxide or iodine(V) oxide. The procedure is applicable to azoles whose pKBH
+
value does not exceed 2.26.
We previously showed that 1-adamantyl cations
generated in acid medium are capable of readily
alkylating triazoles [2] and tetrazoles [3] to give the
corresponding N-(1-adamantyl)azoles. Analogous
reactions with pyrazoles [4] and imidazoles [5] are
strongly limited by the basicity of substrates whose
reaction centers can be protonated. For example,
adamantylation of 4-nitropyrazole-3(5)-carboxylic
According to published data, alkyl halides, in
particular alkyl iodides, are capable of reacting with
nucleophilic species in the presence of inorganic
oxidants [6 15]. A unimolecular scheme was pro-
posed for reactions of alkyl iodides with nitric acid [7]
and other oxidants [10]. This scheme includes forma-
tion of carbocation which is converted into alkyl
chloride or alkyl bromide in the presence of HCl or
HBr. Under these conditions, optically active 2-octyl
iodide reacts with HBr to give the corresponding
racemic product [7]. It is beleived that in the presence
of nitric acid as oxidant the reaction involves genera-
tion of nitronium ion which attacks the substrate thus
favoring formation of carbocation [8].
+
acid (pKBH 3.63) can be effected by 85% sulfuric
acid (H0 8.29). Reduction of the sulfuric acid con-
centration to 72% (H0 6.2) makes it possible to per-
+
form the reaction with 4-nitropyrazole (pKBH 2.00).
The system phosphoric acid acetic acid [weight ratio
4: 1, H0(calcd.) 1.8] was proposed for adamantyla-
tion of highly basic azoles, e.g., of pyrazole-3-carb-
In the presence of NO2BF4 or NOBF4, reactions of
acetonitrile with alkanes and their derivatives R3CX
(X = Hlg, H, OAlk) at the tertiary carbon atom afford
acetamides as a result of cleavage of the carbon
heteroelement bond. It is assumed that the initial
interaction between nitronium cation and a lone elec-
tron pair of the heteroelement (Hlg or O) follows the
Lewis acid base interaction pattern [12 15]. The
oxidation of exo-2-bromonorbornane gave a racemic
mixture of the corresponding acetamides [14].
The adamantylation with 1-iodoadamantane (I) is
likely to involve generation of carbocation. The
reaction of I with acetonitrile in the presence of
chromium(VI) oxide gave N-(1-adamantyl)acetamide
+
+
oxylic acid (pKBH 0.78) [4]. Pyrazoles with pKBH
values larger than 0.8 cannot be involved in the above
reaction. As concerns imidazole derivatives, in 85%
sulfuric acid the corresponding adamantyl-substituted
product can be obtained only from 4,5-dinitroimid-
+
azole (pKBH 5.33). In the system phosphoric acid
acetic acid, the most basic imidazole substrate capable
+
of being adamantylated is 4-nitroimidazole (pKBH
0.05) [5]. Thus adamantylation of more basic azoles
can be accomplished via reduction of the acidity func-
tion H0 of the medium. However, in this case the
concentration of reactive species, adamantyl cations,
also decreases. Using 3-nitro-1,2,4-triazole as an
example, we previously demonstrated [2] that the
adamantylation process requires a sulfuric acid con-
centration no less than 70%. In order to obtain
adamantyl derivatives of more basic azoles, we tried
to take advantage of oxidative alkylation.
*
For communication VI, see [1].
1070-4280/01/3712-1762$25.00 2001 MAIK Nauka/ Interperiodica

OXIDATIVE ALKYLATION OF AZOLES: VII.
1763
(III) in 69% yield. The yield of III was raised to 87%
when the reaction was carried out with iodine(V)
oxide (IV) as oxidant.
complex, was reported in [17, 18]. The reaction was
not studied in detail, but it was assumed that the
process follows a radical mechanism [18]. However,
a ionic reaction pattern cannot be ruled out. Also,
the stage of generation of adamantyl cation could
involve formation of the AdI+ I2O5 . radical ion pair.
Its subsequent decomposition can take either radical
or ionic path. Assuming that the above radical ion pair
decomposes to give adamantyl cation, the formation
of 1-hydroxyadamantane (VIII) is likely to occur via
direct abstraction of oxygen atom from the oxidant
molecule. Another possible pathway is O-alkylation
of 1-hydroxyadamantane (VIII), which leads to ether
IX or (in the presence of a heteroaromatic substrate),
to N-adamantylazole.
We examined the possibility for oxidative ada-
mantylation of azoles with 1,2,3-benzotriazole (V) as
an example. The reaction was performed in dioxane in
the presence of CrO3 at 85 90 C (reaction time 4 h).
As a result, a mixture of 1- and 2-(1-adamantyl)-1,2,3-
benzotriazoles VI and VII [16] was obtained in
an overall yield of 16%. The isomer ratio VI: VII was
determined by GLC; it was equal to 72: 28. The same
reaction in dichloroethane occurred at a much lower
rate, and the overall yield did not exceed 8%.
As substrates we chose 4,5-dichloroimidazole (X),
+
4-nitropyrazole (XI, pKBH 2.00), 4-nitroimidazole
+
(XII, pKBH
0.05), 4-chloropyrazole (XIII,
+
pKBH 0.59), 4-bromo-3,5-dimethylpyrazole (XIV,
pKBH 2.26), pyrazole (XV, pKBH 2.48), 3(5)-methyl-
pyrazole (XVI, pKBH 3.27), 4(5)-chloroimidazole
(XVII), 4-bromoimidazole (XVIII, pKBH 3.80), and
+
+
+
+
[O] = CrO3, I2O5.
+
+
imidazole (XIX, pKBH 6.99). The pKBH values were
taken from [19].
Iodine(V) oxide (IV) turned out to be a more
efficient oxidant. In the presence of I2O5 the reaction
was complete in 1 h, and the yield of isomeric mixture
VI/VII was 67% (ratio 26: 74). It should be noted
that the adamantylation of V in sulfuric acid gave
only isomer VI [16].
The series of substrates can be divided arbitrarily
into two groups. The first group includes azoles
XI XIV; their reactions with 1-iodoadamantane were
characterized by complete conversion of the latter.
Apart from compounds VIII and IX, the correspond-
ing N-adamantylazoles were found among the prod-
ucts (see table).
Next we studied a series of diazoles (pyrazoles and
imidazoles) as substrates. They were selected in such
+
a way that their basicity ranged pKBH 2.00 to 6.99.
The reactions were carried out in dioxane at 85 90 C
using I2O5 as oxidant. The goal was to check the
possibility for adamantylation to occur and to estimate
+
the maximal pKBH value at which the alkylation
is still possible.
The oxidative alkylation process was complicated
by the ability of 1-iodoadamantane (I) to react with
compound IV in dioxane in the absence of a hetero-
aromatic substrate, yielding a mixture of 1-hydroxy-
adamantane (VIII, 53%) and 1,1 -diadamantyl ether
(IX, 9%). Here, the complete conversion of 1-iodo-
adamantane (I) is attained in 3 h. No further change
of the composition of the reaction mixture occurred
with time.
XI, XX, R1 = R3 = H, R2 = NO2; XIII, XXI,
R1 = R3 = H, R2 = Cl; XIV, XXII, R1 = R3 =
Me, R2
= Br.
The oxidative adamantylation of heteroaromatic
substrates includes two concurrent processes:
(1) adamantylation and (2) transformation of initial
1-iodoadamantane (I) into compounds VIII and IX
under the action of oxidant. The first pathway pre-
vailed in the adamantylation of relatively weakly basic
azole XI, and 1-(1-adamantyl)-4-nitropyrazole (XX)
was the major product. In the reactions with more
basic azoles XIII and XIV the contribution of path-
way (2) was greater.
The formation of ether IX by reaction of 1-bromo-
adamantane with oxidants, specifically with copper(II)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

1764
TSYPIN et al.
Reactions of 1-iodoadamantane (I) with azoles V and XI XIV in the presence of I2O5 (IV)
Yield, %
Azole no.
I-to-azole molar ratio
Reaction time, h
N-adamantylazole
VIII
IX
Vaa
V
XI
XII
XIII
XIII
XIII
XIV
XIV
1: 1.5
1: 1.5
1: 1.5
3: 1
3: 1
1: 1.5
1: 3
3: 1
1: 1.5
1: 3
4
1
3
VI, 12
VI, 17
XX, 58
XXIII, traces
XXI, 18
XXI, 15
XXI, 11
XXII, traces
XXII, 13
XXII, 17
VII, 4
VII, 50
Traces
78
Traces
Traces
9
10
10
10
10
10
10
3
61
14
32
71
71
7
Traces
15
3
18
XIV
55
5
b
53
9
a
In the presence of CrO3 (II) as oxidant.
Reaction of 1-iodoadamantane (I) with I2O5 (IV) in the absence of heteroaromatic substrate.
b
Raising the amount of 1-iodoadamantane (I) in the
IV through elimination of the chlorine atom, and the
resulting more basic azole XVII did not react with
1-iodoadamantane.
reaction with azole XIII resulted in insignificant
increase of the yield of 1-(1-adamantyl)-4-chloropyra-
zole (XXI). This may be due to increase of the con-
centration of adamantyl cations in the reaction mix-
ture. On the other hand, the highest yield of 1-(1-ada-
mantyl)-4-bromo-3,5-dimethylpyrazole (XXII) in the
reaction of I with azole XIV was attained when the
substrate was taken in excess. Presumably, this is the
result of increase in the azole concentration and its
Azoles XV XIX belonging to the second group
failed to react with 1-iodoadamantane over a period
of 10 h, and the substrates were recovered from the
reaction mixture. No reaction occurred even when
the amount of the initial azole, e.g., imidazole XIX,
was reduced from 1.5 to 0.5 mol per mole of I.
Probably, highly basic azoles having increased elec-
tron density on the nitrogen atom are capable of
reacting with the oxidant. Taking into account that
this process is heterogeneous [iodine(V) oxide is
almost insoluble in dioxane], the oxidant is com-
pletely deactivated. Therefore, the process is likely
to stop at the stage of formation of a complex with
partial electron transfer from the heteroring to the
vacant orbital of the active center in the oxidant.
The presence of N-unsubstituted azoles among the
products indicates that the electron transfer is just
partial and, probably, reversible.
+
relatively high basicity (pKBH 2.26). It should be
noted that azole XV whose basicity is greater only
+
slightly (pKBH 2.48) failed to react with 1-iodo-
adamantane under the same conditions. On the whole,
raising the azole-to-I ratio leads to decrease in the
yield of ether IX.
Only traces of 1-(1-adamantyl)-4-nitroimidazole
(XXIII) were detected among products of the reaction
of 1-iodoadamantane with azole XII. This fact may
be explained by very poor solubility of the substrate
in dioxane and hence low concentration of XII in
the reaction mixture. Compound XII could give rise
to two isomeric products; however, traces of only one
of them, compound XXIII, were detected.
Thus the reaction under study can be regarded as
a method of alkylation of azoles, where the active
species, adamantyl cation, is generated via oxidation
of 1-iodoadamantane.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Perkin
Elmer R-12 spectrometer (60 MHz) in CDCl3 using
HMDS as internal reference. GLC analysis was per-
formed on an LKhM Model 3700 chromatograph;
Our attempt to obtain adamantyl derivative of azole
X was unsuccessful: the substrate reacted with oxidant
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 12 2001

OXIDATIVE ALKYLATION OF AZOLES: VII.
1765
stationary phase 5% SE-30 on Chromaton N-AW-
DMCS (0.1 0.125 mm); oven temperature 100 to
300 C; injector and detector temperature 270 C.
water was distilled off. The initial azoles were
identified by the H NMR spectra.
1
Reaction of 1-iodoadamantane (I) with benzo-
triazole (V). To a solution of 0.5 g (1.91 mmol) of
1-iodoadamantane (I) in 5 ml of anhydrous dioxane
we added in succession 0.45 g (3.82 mmol) of benzo-
triazole (V) and 0.05 g (1.25 mmol) of chromium(VI)
oxide (II). The mixture was stirred for 4 h at 85
90 C and was then treated according to the general
procedure described above.
The initial azoles should dissolve in dioxane com-
pletely. The solvent should be purified from peroxide
compounds and thoroughly dried. Otherwise, the
reaction is strongly accelerated, and the major product
is 1-hydroxyadamantane (VIII).
Reactions of azoles with 1-iodoadamantane in
the presence of oxidant (general procedure). To
a solution of 0.5 g (1.91 mmol) of 1-iodoadamantane
(I) in 5 ml of anhydrous dioxane we added in succes-
sion a required amount of N-unsubstituted azole and
0.96 g (2.87 mmol) of iodine(V) oxide (IV), and the
mixture was stirred at 85 90 C until the initial
1-iodoadamantane disappeared (TLC). Liberation of
iodine was observed within the first hour. The mixture
was cooled and filtered, and the precipitate of I2O5
was washed with 3 ml of dioxane. The filtrate was
combined with the washings and evaporated. The
residue was dissolved in 20 ml of CHCl3, and the
solution was treated with 50 ml of 10% aqueous
Na2SO3. The organic phase was separated, and the
solvent was removed. The residue was washed with
50 ml of 5% aqueuos NaOH at 40 45 C and dried.
Compounds XX, XXI, and XXIII were identified
by TLC and GLC, by comparing with authentic
samples which were specially synthesized according
to the procedures reported in [4] (XX, XXI) and [5]
(XXIII). In the reaction with azole XI 35 ml of
dioxane was used to dissolve the substrate completely.
N-(1-Adamantyl)acetamide (III) (a) 1-Iodoada-
mantane (I), 0.5 g (1.91 mmol), and iodine(V) oxide
(IV), 0.96 g (2.87 mmol), were added in succession
to 10 ml of acetonitrile, and the mixture was stirred
for 0.5 h at 40 50 C and was then treated according
to the general procedure. Yield 0.32 g (87%),
mp 148 150 C [12].
(b) 1-Iodoadamantane (I), 0.5 g (1.91 mmol), and
chromium(VI) oxide (II), 0.05 g (1.25 mmol), were
added in succession to 10 ml of acetonitrile, and the
mixture was stirred for 2 h at 80 C and was then
treated according to the general procedure. Yield
0.26 g (69%).
Reaction of 1-iodoadamantane (I) with iodine(V)
oxide (IV). Iodine(V) oxide (IV, 0.96 g (2.87 mmol),
was added to a solution of 0.5 g (1.91 mmol) of
1-iodoadamantane (I) in 5 ml of anhydrous dioxane.
The mixture was stirred for 3 h at 85 90 C and was
then treated according to the general procedure.
A mixture of compounds VIII and IX was obtained.
Yield 0.18 g. The products were separated by frac-
tional crystallization from 2-propanol. The VIII: IX
ratio was 85: 15. Iodine(V) oxide, 0.4 g (1.2 mmol),
was added to the resulting mixture, and the mixture
was stirred for 3 h at 85 90 C. After appropriate
treatment, the composition of the mixture did not
change.
1-(1-Adamantyl)-4-bromo-3,5-dimethylpyrazole
(XXII). After treatment with aqueous NaOH, the
residue was treated with concentrated hydrochloric
acid at 20 30 C. The filtrate was neutralized with
10% aqueous NaOH and extracted with 20 ml of
CHCl3. The extract was evaporated, and the residue
was recrystallized from 70% aqueous 2-propanol.
1
mp 131 132 C. H NMR spectrum, , ppm: 1.7 m,
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