Arenium cation as the key intermediate of the electrosynthesis of N-(2,5-dimethoxyphenyl)azoles. A new approach to the synthesis of N-(dimethoxyphenyl)azoles

Article abstract of DOI:10.1007/s11172-007-0342-3

Data on the effect of the acid-base properties of the medium on the yield and composition of the products of N-dimethoxyphenylation of azoles (pyrazole, triazole, their substituted derivatives, and tetrazole) upon galvanostatic electrolysis of azole-1,4-dimethoxybenzene mixtures in nucleophilic (MeOH) and neutral (MeCN) media were considered and the trends of this process were discussed. The generation of arenium cations (1,4-dimethoxy-1-azolylbenzenium in MeCN and 1,1,4-trimethoxybenzenium in MeOH) as the key intermediates of electrosynthesis of N-(dimethoxyphenyl)azoles, was proved experimentally. A new approach to the synthesis of N-(dimethoxyphenyl)azoles through electrosynthesis of 1,1,4,4-tetramethoxycyclohexa-2,5-diene by electrooxidation of 1,4-dimethoxybenzene in MeOH as the first step and the reaction of this quinone diketal with azoles as the second step was suggested. The efficiency of this route to N-(dimethoxyphenyl)azoles is comparable with the efficiency of the purely electrochemical one-step process.

Full text of DOI:10.1007/s11172-007-0342-3

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2175—2183, November, 2007
2175
Arenium cation as the key intermediate of the electrosynthesis
of Nꢀ(2,5ꢀdimethoxyphenyl)azoles. A new approach to the synthesis
of Nꢀ(dimethoxyphenyl)azoles

V. A. Petrosyan and A. V. Burasov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: petros@ioc.ac.ru
Data on the effect of the acidꢀbase properties of the medium on the yield and composition
of the products of Nꢀdimethoxyphenylation of azoles (pyrazole, triazole, their substituted
derivatives, and tetrazole) upon galvanostatic electrolysis of azole—1,4ꢀdimethoxybenzene
mixtures in nucleophilic (MeOH) and neutral (MeCN) media were considered and the trends
of this process were discussed. The generation of arenium cations (1,4ꢀdimethoxyꢀ1ꢀ
azolylbenzenium in MeCN and 1,1,4ꢀtrimethoxybenzenium in MeOH) as the key intermediates
of electrosynthesis of Nꢀ(dimethoxyphenyl)azoles, was proved experimentally. A new approach
to the synthesis of Nꢀ(dimethoxyphenyl)azoles through electrosynthesis of 1,1,4,4ꢀtetraꢀ
methoxycyclohexaꢀ2,5ꢀdiene by electrooxidation of 1,4ꢀdimethoxybenzene in MeOH as the
first step and the reaction of this quinone diketal with azoles as the second step was suggested.
The efficiency of this route to Nꢀ(dimethoxyphenyl)azoles is comparable with the efficiency of
the purely electrochemical oneꢀstep process.
Key words: 1,4ꢀdimethoxybenzene, azoles, electrooxidation, Nꢀ(2,5ꢀdimethoxyphenyl)azoꢀ
les, arenium cation, 1,1,4,4ꢀtetramethoxycyclohexaꢀ2,5ꢀdiene.
Table 1. Azoles and their pKa values (see Ref. 7)
NꢀArylazoles represent a promising class of biologiꢀ
cally active compounds possessing a broad spectrum of
practical applications.1 Meanwhile, the synthesis of these
compounds has certain limitations, as nitrogen heteroꢀ
cycles are poorly suited to the use as partners for convenꢀ
tional arylating reagents.2 This stimulated us to initiate
the search for new, in particular, electrochemical apꢀ
proaches to the synthesis of Nꢀarylazoles. Recently,3—6
on the basis of the results of galvanostatic electrolysis of
an azole—1,4ꢀdimethoxybenzene (DMB) mixture in
MeCN in an undivided cell, a probable mechanism for
Nꢀdimethoxyphenylation of azoles has been proposed
(Scheme 1).
I
II
Azole
pKa
pKa
Highly basic azoles
3,5ꢀDimethylpyrazole (DMP)
Pyrazole (P)
1,2,4ꢀTriazole (TA)
15.0
14.2
10.0
4.1
2.5
2.5
Lowly basic azoles
3,5ꢀDimethylꢀ4ꢀnitropyrazole (DMNP)
4ꢀNitropyrazole (NP)
3ꢀNitroꢀ1,2,4ꢀtriazole (NTA)
Tetrazole (Т)
10.1
9.7
6.0
4.9
–0.5
–2.0
–3.7
–2.7
I
II
Note. The pKa and pKa values correspond to the equilibria
Az– + H+ AzH и AzH + H+ AzH2+, respectively.
According to the drawn conclusions,4—6 radical catꢀ
ion 1´ formed upon DMB oxidation can alternatively
(steps 1´ → 2 or 1´ → 3) react with a nucleophile repreꢀ
sented here by the nonionized azole existing in solution as
hydrogenꢀbonded Az—H•B complexes5,6 (B is a base,
which may be represented by most basic azoles or
symꢀcollidine (CL) molecules added to the solution for
the final reaction mixtures to the acidꢀbase properties of
initial azoles and thus to describe systematically the reꢀ
sults of electrolysis.
The cathodic process includes deprotonation of the
starting azoles and, partially, of onium compounds, reꢀ
sulting from the reaction of azoles or CL type bases with
the protons generated in the anodic transformations of
the reactants.
II
electrolysis). In terms of the pKa values (Table 1) charꢀ
acterizing the susceptibility of azoles (AzH) to protonaꢀ
tion, they all were divided4—6 into strongly and weakly
basic ones. Although this classification is obviously arbiꢀ
trary, this made it possible to relate the composition of
An important item of the process mechanism (see
Scheme 1) is related to the hypothesis5,6 of the presence
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2101—2109, November, 2007.
1066ꢀ5285/07/5611ꢀ2175 © 2007 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Petrosyan and Burasov
Scheme 1
B = AzH, сollidine
of a rearrangement of arenium cations 4 → 5. This was
assumed to occur for strongly basic azoles as intramoꢀ
lecular βꢀalkylation through transition state 4″, whereas
for weakly basic azoles incapable of such transformation,
this occurs as intermolecular interaction through the tranꢀ
sition state 4´ by the cineꢀsubstitution mechanism.
Apart from the orthoꢀsubstitution products of type 6,
the final reaction mixture contained ipsoꢀbisꢀaddition
products 7; the yield of products 6 increased continuously
during the electrolysis, while the yield of products 7 passed
through a maximum. According to the available data,5,6
this is due to the fact that product 7 is converted during
electrolysis into 6 along the path 7 → 4 → 5 → 6. Note
that in this case, the step 4 → 7 (see Scheme 1) should be
reversible, although the driving force of the back reaction
(7 → 4) has remained obscure, together with the reasons
for dependence of the yield and ratio of products 6 and 7
on the acidꢀbase properties of the initial azoles and the
medium.4—6
Therefore, this work aims at the development of the
views on Nꢀdimethoxyphenylation of azoles and experiꢀ
mental substantiation of the steps involving the arenium
cation as the key intermediate of the process. It should be
emphasized that some of these issues have already been
addressed in the study of electrochemical Nꢀdimethoxyꢀ
phenylation in MeOH.8 Therefore, here we compare
the results of azole Nꢀdimethoxyphenylation in MeCN
and MeOH.
The study was performed with azoles (see Table 1)
selected out of those studied previously4—6 (for conveꢀ
nient comparison of the results).
Results and Discussion
As noted above, the transformations 7 → 4 → 5 → 6
(see Scheme 1) take place during the electrochemical
Nꢀdimethoxyphenylation of azoles only in the case where
the step 4 → 7 is reversible. To substantiate this concluꢀ
sion, it is pertinent to consider data on the influence of
the acidꢀbase properties of the medium on the ratio of
products 6 and 7 in the reaction medium. It can be seen
from the data presented in Table 2 that in the electrolysis
involving pyrazole (P), the addition of CL as a base to the
initial reaction mixture sharply increases the yield of the
ipsoꢀbisꢀaddition product 7. Conversely, the AcOH addiꢀ
tives decrease the yield of this product and simultaneously
increase the yield of the orthoꢀsubstituted product 6. The
addition of stronger chloroacetic acid gives only product 6.
A similar effect has been described previously3 for elecꢀ
trolysis involving DMP*.
This result is quite surprising: generally, the addition
of acids should induce protonation of any species that
* Here and below, in substantiation of the conclusions of this
work, apart from the newly obtained results, we used some exꢀ
perimental data obtained previously3—5 and interpreted them
from a new standpoint.

Electrosynthesis of Nꢀ(dimethoxyphenyl)azoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2177
Table 2. Effect of acid and base additives on the yield and comꢀ
position of the products of electrolysis of an azole—DMB
mixturea
exhibit nucleophilic properties and, consequently, retard
the process. This was actually the case when a considerꢀ
able excess of an acid with respect to the azole was added;
however, this was not the case with a considerably defiꢀ
cient amount (see Table 2). In our opinion, the effect
observed upon the addition of acids into the mixture for
electrolysis is attributable to the electrophilic assistance
from the acid molecule A—H to the elimination of the
azole fragment from the product molecule 7, thus proꢀ
moting steps 7 → 7´ → 4 (Scheme 2). As a result, transforꢀ
mation 4 → 7 becomes reversible and, as a consequence,
the yield of 6 in the electrolysis products grows and the
yield of 7 drops (see Table 2). The CL additive as a base
induces the opposite effect as it makes the step 4 → 7 fully
irreversible thus increasing the yield of product 7.
It is important that the composition of the final reacꢀ
tion mixture depends also on the acidꢀbase properties of
azoles. This is well illustrated by the results of earlier
studies. A mixture of products 7 and 6 obtained by elecꢀ
trolysis involving T is easily converted into product 6
during separation or even storage.5 Conversely, the parꢀ
tial transformation of the products 7 → 6 formed upon
electrolysis involving the least acidic DMP requires not
only addition of an acid but also heating of the reaction
mixture.4
I
Entry Azole
pKa
(pKa
Additive
Current yieldb (%)
II
)
6
7
1
2
3
4
5
6
7
8
P
P
P
14.2
(2.5)
—
CL
3
28
38
17
—
30
42
14
—
—
52
—
29
<2
13
25
28
15
38
63
<2
4
AcOH
ClCH2COOH
P
DMPc
DMPc
DMPc
DMPc
NPc
NPc
Tc
15
(4.06)
—
CL
AcOH
ClCH2COOH
9
9.64
(–2.0)
4.9
—
CL
—
10
11
12
4
50
Tc
(–2.68)
CL
a Reactant ratio: 1.5 moles of azole, 1 mol of DMB, 0.5 mole of
the additive. Conditions of electrolysis: Pt electrodes, MeCN,
I = 50 mA, Q = 2 F per mole of DMB, 0.022 M Bu4NClO4
supporting solution.
b Under the experiment conditions, the material and current
yields coincide.
c See Refs 3—5.
Scheme 2
B = AzH, CL

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Petrosyan and Burasov
Scheme 3
B = AzH, CL
Data presented in Table 2 can serve as yet another
termediates 4″ * (see Scheme 2) and arrived at the conꢀ
clusion that this rearrangement for both strongly and
weakly basic azoles can occur irreversibly as a cineꢀsubstiꢀ
tution (Scheme 3).
example; it can be seen that electrolysis of a mixture
of DMB with strongly basic azoles gives products 6
and 7 and the CL additives do not affect much their
yield (cf. entries 5 and 6). Conversely, electrolysis of
a mixture of DMB and weakly basic azoles gives alꢀ
most no Nꢀarylation products whose formation requires
the addition of CL to the mixture for electrolysis (see
Table 2; cf. entries 9 and 10, 11 and 12). These results
indicate, most likely, that most acidic azoles can also
serve as the acid A—H to catalyze the back transformaꢀ
tion 7 → 4. Most efficient in this respect is T, i.e., the
most acidic azole, which explains, in particular, an inꢀ
creased (as compared with NP) content of product 6 in
the final reaction mixture (see Table 2; cf. entries 10
and 12).
While developing these views, one can easily conclude
that the acid components A—H of the reaction mixture
catalyze also the cineꢀsubstitution 4 → 5 through electroꢀ
philic assistance to the elimination of the azole function
from the ipsoꢀposition of intermediate 4´ (see Scheme 2).
Therefore, the views on the 4 → 5 rearrangement pathꢀ
ways of arenium cations were corrected. We refuted the
conclusions drawn earlier4—6 stating that the 4 → 5 rearꢀ
rangement of strongly basic azoles proceeds through inꢀ
The foregoing leads to the conclusion concerning the
crucial role of acid catalysis in the mechanism of azole
Nꢀdimethoxyphenylation. In addition, it follows from
these data that the competing orthoꢀ and ipsoꢀreactions of
the arenium cation 4 with the azole nucleophile are the
key stages of the mechanism. Whereas the former reacꢀ
tion is reversible due to electrophilic assistance of the
A—H acid components of the reaction mixture to the
elimination of the azole residue from the ipsoꢀposition of
intermediate 7´, the latter reaction, which follows a
cineꢀsubstitution mechanism, is irreversible, the more so,
in view of the relatively fast deprotonation of cation 5 to
give the final product (see Scheme 3, 5 → 6).
The presence of two reaction pathways for the interꢀ
mediate arenium cation (5 ← 4 → 7) leads to the concluꢀ
sion that during electrolysis, the target product 6 can be
* The acid additives for the electrolysis involving strongly basic
azoles are expected to hamper the formation of a cyclic transiꢀ
tion state. However, this is not the case; conversely, the yield of
product 6 increases in the presence of acids (see Table 2).

Electrosynthesis of Nꢀ(dimethoxyphenyl)azoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2179
formed either through the sequence 1 → 1´ → 3 → 4 →
→ 5 → 6 or through the sequence 1 → 1´ → 3 → 4 → 7 →
→ 4 → 5 → 6. Either of the pathways includes the irreꢀ
versible transformation of arenium cations 4 → 5; thus,
the initially formed ipsoꢀbisaddition 7 product can be
gradually converted during electrolysis to 6, because the
step 4 → 7 is reversible (see above).
which was 1,1,4ꢀtrimethoxyarenium 8 (Scheme 4), inꢀ
stead of 1ꢀ(azolꢀ1ꢀyl)ꢀ1,4ꢀdimethoxyarenium 4, and the
structures of the ipsoꢀsubstitution products: instead of
1,4ꢀdi(azolꢀ1ꢀyl)ꢀ1,4ꢀdimethoxycyclohexaꢀ2,5ꢀdienes 7,
the reaction gave 1,1,4,4ꢀtetramethoxycyclohexaꢀ2,5ꢀdiꢀ
ene (9) and 1ꢀ(azolꢀ1ꢀyl)ꢀ1,1,4ꢀtrimethoxycyclohexaꢀ2,5ꢀ
dienes 10.
All the foregoing casts doubt on the practicability of
obtaining product 6 along the route 1´ → 2 → 5 → 6 (see
Scheme 3) involving impracticable step 1´ → 2,4,5 the
more so, because it is impossible to obtain 7 as the second
product by this route. In our opinion, in most cases, steps
1´ → 2 → 5 → 6 can be neglected when describing the
mechanism of electrosynthesis of Nꢀ(dimethoxypheꢀ
nyl)azoles.
These conclusions are in good agreement with azole
Nꢀdimethoxyphenylation data in MeOH,8 which, howꢀ
ever, has specific features due to the simultaneous presꢀ
ence of two competing nucleophiles, namely, MeOH
molecules and azoles, in the reaction mixture. This afꢀ
fected the structure of the intermediate arenium cation,
Generally, taking into account the above results and
resorting to published data,8 Nꢀdimethoxyphenylation of
azoles in neutral (MeCN) and nucleophilic (MeOH)
media can be described by Scheme 4. It can be seen that
both in neutral and nucleophilic media, the competing
orthoꢀ and ipsoꢀreactions of arenium cations 4 and 8 with
the azole nucleophile are the key steps of the process and
make the crucial contribution to the formation of the
orthoꢀsubstitution product 6. For example, it follows from
the available results8 that the higher the acidity of the
reaction mixture that undergoes electrolysis, the higher
the content of ipsoꢀbisaddition 10 and orthoꢀsubstitution 6
products in the final solution and the lower the content of
the ipsoꢀbisaddition product 9. Conversely, electrolysis
Scheme 4
RH = AzH, AzH2+, AcOH
6, 7, 10: Az = 3,5ꢀdimethylpyrazolꢀ1ꢀyl (a), pyrazolꢀ1ꢀyl (b), 1,2,4ꢀtriazolꢀ1ꢀyl (c), 4ꢀnitropyrazolꢀ1ꢀyl (d), 3,5ꢀdimethylꢀ4ꢀnitropyrazolꢀ1ꢀyl (e),
3ꢀnitroꢀ1,2,4ꢀtriazolꢀ1ꢀyl (f), tetrazolꢀ1ꢀyl (g), tetrazolꢀ2ꢀyl (h)

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Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Petrosyan and Burasov
involving strongly basic DMP and P unable to perform
acid catalysis results in a predominant content of prodꢀ
uct 9 in the reaction mixture.8
Thus, acid catalysis plays an important role in the
electrochemical Nꢀdimethoxyphenylation of azoles both
in MeCN (see above) and in MeOH by providing (see
Scheme 4) electrophilic assistance to elimination of the
azole residue from products 7 and 10, the methoxy group
from product 9 and, which is equally important, the
methoxy group from intermediate 8´.
(down to zero) of ipsoꢀbisaddition 9 and 10 products with
a simultaneous increase in the orthoꢀsubstituted prodꢀ
uct 6. It is quite obvious that temperature rise facilitates
the acidꢀcatalyzed elimination of the methoxy and azole
groups from structures 8´, 9, 10 (see Scheme 4). Thereꢀ
fore, it can be concluded that in MeOH, as in MeCN, the
electrochemical (see Scheme 4) and purely chemical proꢀ
cesses comprise the same steps 9 (10) → 8 → 5 → 6.
The aboveꢀnoted possibility of chemical transformaꢀ
tion of tetramethoxycyclohexadiene 9, which is more
readily available than products 7 and 10, into the tarꢀ
get orthoꢀsubstituted product 6 creates prerequisite for
the preparation of arylazoles via a twoꢀstep synthesis
(Scheme 5).
In conformity with the drawn conclusions,8 we beꢀ
lieve that in the electrolysis of the azole—DMB mixture,
the role of the acid catalyst can be played by not only
acids specially added to the reaction mixture or most
acidic azoles but also by the onium species formed upon
the reactions of azoles with the protons generated during
the anodic reactions.
Scheme 5
The above general trends of electrochemical Nꢀdiꢀ
methoxyphenylation of azoles (see Scheme 4) are preꢀ
sented based on the view of generation of arenium cations
(4, 8) as the key intermediates, which undergo various, in
particular, acidꢀcatalyzed transformations along the way
to the target products. The proposed mechanism (see
Scheme 4) may be validated by obtaining independent
experimental evidence for generation of arenium catꢀ
ions 4 and 8.
Meanwhile, such evidence can be gained from characꢀ
teristic features of this process mechanism (see Scheme 4).
It can be seen that, except for the early steps (1 → 4
or 1 → 8), all other steps are purely chemical. This
means that if the proposed steps (including the generation
of arenium cations 4 and 8) are correct, then having reꢀ
moved the electrochemical steps, we gain the possibilꢀ
ity of purely chemical synthesis of target product 6
from quinone bisketal 9 through steps 9 → 8 → 5 → 6 and
from ipsoꢀbisaddition products 10 (7) through steps
10 (7) → 8 (4) → 5 → 6.
Note that we have already carried out experiments of
this type without perception. As noted above, upon elecꢀ
trolysis with T, the mixture of final products 7 and 6 is
readily converted into product 6 during storage.5 A simiꢀ
lar conversion of components 7 and 6 of the reaction
mixture obtained after electrolysis involving the least
acidic DMP (see Table 1) required4 not only AcOH addiꢀ
tives but also heating for several hours, i.e., more rigorous
conditions. Thus it follows that azoles behave as betꢀ
ter (Т) or poorer (DMP) leaving groups depending on
their structure. These results alone point to the feasibility
of the purely chemical transformation 7 → 4 → 5 → 6,
thus confirming the generation of arenium cation 4.
Analogous conclusions can be drawn from the results
of an experiment described in our publication.8 Heating
of the reaction mixture formed after electrolysis of an
azole—DMB mixture in MeOH, which contained prodꢀ
ucts 6, 9, and 10, always caused a decrease in the contents
i. Electrochemical step, MeOH, –2 e, –2 H+;
ii. Chemical step, AzH.
The method comprises electrooxidation of 1,4ꢀdiꢀ
methoxybenzene in MeOH by a known procedure9 to
give quinone diketal 9 (yield 70%) as the first step and
purely chemical reaction of diketal 9 with azoles to give
product 6 as the second step.
The reaction of quinone diketal 9 with azoles was
carried out by fusing the reactants together for 5 h at
110 °C, if necessary, with basic (CL) or acidic (AcOH)
additives to the reaction mixture. If the final reaction
mixture contained the ipsoꢀaddition products, it was
heated for additional 5 h at 110 °C. The results are sumꢀ
marized in Table 3.
The possibility of implementing this process has been
already shown in our previous work:10 fusion together of
bisketal 9 with 3ꢀnitroꢀ1,2,4ꢀtriazole (or tetrazole) inꢀ
duces irreversible reaction between them, resulting in
1,4ꢀdimethoxyꢀ2ꢀ(3ꢀnitroꢀ1,2,4ꢀtriazolꢀ1ꢀyl)benzene (a
mixture of isomeric 1,4ꢀdimethoxyꢀ2ꢀ(tetrazolꢀ1ꢀyl)ꢀ and
1,4ꢀdimethoxyꢀ2ꢀ(tetrazolꢀ2ꢀyl)benzens).
However, our experiments on twoꢀstep synthesis of
Nꢀ(dimethoxyphenyl)azoles (see Table 3) showed that,
on the one hand, the product composition and yield deꢀ
pend on the structure of the azole and, on the other hand,
they depend on the acidꢀbase properties of the medium.
For example, fusion of strongly basic DMP with bisketal 9
does not result in the formation of any products, only the
addition of AcOH and heating of the reaction mixture

Electrosynthesis of Nꢀ(dimethoxyphenyl)azoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2181
Table 3. Yields of the products of chemical reaction of azoles
with quinone diketal 9a
Table 4. Yields of orthoꢀsubstitution product 6 (in relation to the
DMB taken) in oneꢀstep and twoꢀstep syntheses
I
Entry Azole
pKa
(pKa
Additiveb
Yieldc (%)
Azole
Yield (%)
Oneꢀstep methoda
II
)
6
7
10 11d
Twoꢀstep methodb
1
2
3
DMP
DMP
Imidꢀ
azole
P
P
P
TA
TA
15
—
AcOH
AcOH
—
72
—
—
—
—
—
—
—
—
—
—
DMP
P
TA
NP
NTA
T
57
18
10
00
18
52
50
46
50
31
48
46
(4.1)
14.4
(7.0)
14.2
(2.5)
4
5e
6
7
8
—
—
AcOH
—
AcOH
—
CL
AcOH
—
CL
—
AcOH
CL
—
32
65
4
70
33
—
12
44
4
11
37
69
90
66
52
58 37
—
—
—
—
—
—
—
36
—
33
44
—
—
—
—
—
20
—
—
—
а The maximum yields obtained with the azole—DMB—addiꢀ
tive (CL or AcOH) composition of choice (see Refs 3—5).
b Overall yield with allowance for the 70% yield of product 9 in
the first step.
10
(2.5)
10.1
12 56
—
—
—
—
—
—
—
—
—
—
9
DMNP
10 DMNP
11 DMNP
12
13
14e
15
16
17e
18
(–0.5)
NP
NP
NP
NP
NTA
NTA
T
9.7
(–2.0)
catalytic properties of weakly basic azoles (see Table 3,
entries 13, 16, and 19). In addition, DMNP, which reꢀ
sembles most closely in properties (see Table 3) strongly
basic azoles, is absolutely unable to perform acid catalysis
in the presence of CL additives. This arrests the reaction
of quinone diketal 9 with DMNP; hence, none of the
desired products is formed (see Table 3, entry 10).
Generally, the reaction of quinone diketal 9 with azoles
requires rather fine tuning of reaction conditions: the meꢀ
dium should be sufficiently acidic (to enable acid catalyꢀ
sis) but not too much to avoid complete suppression of
the nucleophilic properties of azoles. This is well illusꢀ
trated by the data presented in Table 3. For example, in
the presence of AcOH, the nucleophilic properties of
DMNP and NP decrease and, as a consequence, the yield
of products 6 decreases (see Table 3, cf. entries 9 and 11;
12 and 15).
28 47
44 15
—
—
—
—
—
—
28
—
—
13
6.0
(–3.7)
4.9
CL
—
CL
19
T
(–2.7)
a Fusion for 5 h at 110 °C of a solid 9—azole mixture in a
1 mmol : 1.5 mmol ratio.
b 0.5 mmol.
c In relation to bisketal 9.
d 1,2,4ꢀTrimethoxybenzene.
e Additional heating for 5 h at 110 °C.
once again initiate the efficient reaction between the comꢀ
ponents to yield the orthoꢀsubstitution product 6 (see
Table 3, cf. entries 1 and 2). Less basic P or TA do react
with bisketal 9 on fusion, giving rise to products 7 and 10,
although almost no orthoꢀsubstitution products 6 are
present (see Table 3, entries 4 and 7). The AcOH addiꢀ
tives change crucially the situation, compound 6 becomꢀ
ing the major reaction product (see Table 3, entries 6
and 8). The whole set of these results attests unambiguꢀ
ously to an important role of acid catalysis in the mechaꢀ
nisms of both purely electrochemical and the twoꢀstep
methods for the synthesis of Nꢀ(dimethoxyphenyl)azoles.
Unlike strongly basic azoles (DMP, P, and TA), more
acidic, weakly basic azoles (DMNP, NP, NTA, and T)
not only act as nucleophiles but also perform acid catalyꢀ
sis (electrophilic assistance to demethoxylation of quinone
diketal 9). Fusion of these azoles with bisketal 9 gives
predominantly the corresponding orthoꢀsubstitution prodꢀ
ucts 6 (see Table 3, entries 9, 12, and 18); an additional
heating of the reaction mixture also gives only products 6
(see Table 3, footnote d).
Generally, the results attest to obvious similarity of
the mechanisms of the chemical step of the twoꢀstep synꢀ
thesis of Nꢀ(dimethoxyphenyl)azoles to the mechanism
of the oneꢀstep electrosynthesis presented in Scheme 4.
In our opinion, this attests unambiguously to intermediꢀ
ate generation of arenium cations 8 or 4.
The results of oneꢀstep and twoꢀstep syntheses are
compared in Table 4.
An interesting feature of the twoꢀstep synthesis is the
fact that in some cases, the reaction products were found
to contain 1,2,4ꢀtrimethoxybenzene (11). Its absence in
the final reaction mixtures in our previous experiments4—6
can be attributed to the presence of three electronꢀdonatꢀ
ing substituents and, as a consequence, low oxidation
potential of 11. Therefore, compound 11 completely
burnedꢀout during galvanostatic electrolysis to give resinꢀ
ous products.* This accounts for the rather low current
yields of Nꢀ(dimethoxyphenyl)azoles upon their electroꢀ
Thus, the ipsoꢀaddition products can be detected in
reactions with such azoles only when the experiments are
carried out with CL additives, which decrease the acid
* When somewhat higher current density is used, pronounced
resinification takes place even during electrolysis involving DMP.

2182
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Petrosyan and Burasov
1,4ꢀDimethoxyꢀ2ꢀ(pyrazolꢀ1ꢀyl)benzene (6b). 1H NMR, δ:
3.79, 3.84 (both s, 6 H, MeO); 6.40 (t, 1 H, azole CH , J =
9.1 Hz); 6.84 (dd, 1 H, CH arom., J1 = 3.1 Hz, J2 = 10.0 Hz);
7.10, 7.30 (both d, 1 H each, CH arom., J = 3.1 Hz); 7.60, 8.15
(both d, 1 H each, azole CH , J = 9.1 Hz).
synthesis,4—6 because most of electricity was consumed
for the oxidation of trimethoxybenzene 11.
A special place in the series of studied azoles is occuꢀ
pied by imidazole, which is similar to DMP in acidity and
is much more basic than DMP (see Table 3). However,
the heterocyclic nucleus of this compound does not conꢀ
tain two adjacent nitrogen atoms (no αꢀeffect); therefore,
imidazole has relatively low nucleophilcity, which is too
low for efficient interaction with quinone diketal 9 to give
desired products (see Table 3, entry 3).
1,4ꢀDimethoxyꢀ2ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)benzene (6с). 1H NMR,
δ: 3.80, 3.90 (both s, 6 H, MeO); 6.94—7.35 (m, 3 H, C6H3);
8.04, 8.85 (both s, 2 H, C2H2N3).
1,4ꢀDimethoxyꢀ2ꢀ(4ꢀnitropyrazolꢀ1ꢀyl)benzene
(6d).
1H NMR, δ: 3.79, 3.91 (both s, 6 H, MeO); 7.04—7.20, 7.31
(both m, 3 H, CH arom.); 8.03, 9.02 (both s, 2 H, azole CH ).
2ꢀ(3,5ꢀDimethylꢀ4ꢀnitropyrazolꢀ1ꢀyl)ꢀ1,4ꢀdimethoxybenzene
(6e). 1H NMR, δ: 2.36, 2.48 (both s, 6 H, Me); 3.78, 3.85
(both s, 6 H, MeO); 6.70—7.20 (m, 3 H, CH arom.).
Experimental
Compounds 6f and 6g (as a mixture with 6h) were isolated
from the reaction mixture according to procedures given below.
1,4ꢀDimethoxyꢀ2ꢀ(3ꢀnitroꢀ1,2,4ꢀtriazolꢀ1ꢀyl)benzene (6f).
The reaction mixture obtained after heating of bisketal 5, NTA,
and CL (10 h, 110 °C) was dissolved in ethanol (5 mL) and
mixed with a 2 M aqueous solution of NaOH (15 mL). After
crystallization of the separated oil in a refrigerator, the precipiꢀ
tate was filtered off, washed with water (3×10 mL), dried on a
watch glass (2 h, 110 °C), and triturated with hexane. Drying in
air gave 205 mg (82%) of compound 6f, m.p. 118 °C. Found (%):
C, 48.10; H, 3.99; N, 22.50. C10H10N4O4. Calculated (%):
C, 48.00; H, 4.03; N, 22.39. 1H NMR, δ: 3.82, 3.92 (both s, 6 H,
MeO); 7.05—7.30 (m, 3 H, C6H3); 9.13 (s, 1 H, C2HN4O2).
1,4ꢀDimethoxyꢀ2ꢀ(tetrazolꢀ1ꢀyl)benzene (6g) and 1,4ꢀdiꢀ
methoxyꢀ2ꢀ(tetrazolꢀ2ꢀyl)benzene (6h) (isomer mixture, 3 : 2).
A mixture of bisketal 5, T, and CL prepared in the same proporꢀ
tions as described above was converted, after heating in a drying
oven (10 h, 110 °C) and a workup similar to that described
above, into 120 mg (58%) of a 6g + 6h mixture, m.p. 65 °C.
1H NMR, δ: 3.76—3.89 (4 s, 6 H, MeO); 7.05—7.32 (m, 3 H,
C6H3); 8.96, 9.59 (both s, 1 H, CHN4).
The 1H NMR spectra of sample solutions in
DMSOꢀd6—CCl4 mixture (1 : 1 v/v) were recorded on a Bruker
ACꢀ300 instrument.
a
The tetramethylammonium salt of NTA was synthesized by
a known procedure.9 Commercial DMB, DMP, T, TA, P, NTA,
NP, and DMNP were used (Lancaster, 98—99% purity).
Oneꢀstep electrosynthesis. Electrochemical experiments (see
Table 2) were carried out by a reported procedure3—5 according
to which DMB (2 mmol) was subjected to galvanostatic elecꢀ
trolysis (I = 50 mA) in MeCN in a 50ꢀmL undivided cell with
Ptꢀelectrodes in the presence of azole (3 mmol) by passing 2 F of
electricity per mole of DMB (see Tables 2, 4). A 0.022 M soluꢀ
tion of Bu4NClO4 was used as the supporting electrolyte; if
necessary, acids (0.5 mmol) (AcOH, ClCH2COOH) or bases
(CL) were added. After completion of the electrolysis, the solvent
was distilled off on a rotary evaporator at ~20 °C (25—30 Torr)
and the residue was analyzed by 1H NMR. The yields of elecꢀ
trolysis products were determined in relation to the twoꢀelecꢀ
tron transformation of the taken DMB by comparison of the
integral intensities of the unambiguously identified and, most
often, singlet signals of the products (azole and aromatic CH
protons, MeOꢀgroup protons) and the signals from the tetraꢀ
butylammonium cation of the supporting salt with a known
concentration (CH2 and Me group protons). The spectroscopic
characteristics of the compounds are given below.
Twoꢀstep synthesis. At the first step, bisketal 9 was prepared
by galvanostatic electrolysis of DMB in MeOH by a reported
procedure6 using an undivided cell with Pt electrodes. The yield
of bisketal 9 was 70%. At the second step, compound 9 (1 mmol)
reacted with azole (1.5 mmol). In some cases (see Table 2), CL
or AcOH additives (0.5 mmol) were used. The reactant mixture
prepared in the aboveꢀindicated proportion was heated in a dryꢀ
ing oven at 110 °C. After heating for 5 h (or 10 h if necessary),
the reaction mixture was analyzed by 1H NMR. The yield of the
products (in relation to taken bisketal 9) was determined by
comparing the integral intensities of the unambiguously identiꢀ
fied signals in the 1H NMR spectra of products with the total
integral intensity of the CH protons of the azole groups (detailed
procedure was described previously4).
1,4ꢀDimethoxyꢀ1,4ꢀdi(pyrazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene (7b)
1
(isomer mixture). H NMR, δ: 3.13, 3.20 (both s, 6 H, MeO);
6.53, 6.64 (both s, 4 H, CH arom.); 6.27, 6.33, 7.44, 7.93 (all m,
2 H each, azole CH ).
1,4ꢀDimethoxyꢀ1,4ꢀdi(1,2,4ꢀtriazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiꢀ
1
ene (7c) (isomer mixture). H NMR, δ: 3.20, 3.30 (both s, 6 H,
MeO); 6.59, 6.70 (both s, 4 H, CH arom.); 7.88, 7.92, 8.61, 8.72
(all s, 4 H, azole CH ).
1,4ꢀDimethoxyꢀ1,4ꢀdi(4ꢀnitropyrazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiꢀ
ene (7d) (isomer mixture). 1H NMR, δ: 3.28, 3.33 (both s, 6 H,
MeO); 6.60, 6.73 (both s, 4 H, CH arom.); 8.11, 8.17, 8.94, 9.00
(all s, 4 H, azole CH ).
1
1,1,4,4ꢀTetramethoxycyclohexaꢀ2,5ꢀdiene (9). H NMR, δ:
3.20 (s, 12 H, MeO); 6.00 (s, 4 H, CH arom.).
1,1,4ꢀTrimethoxyꢀ4ꢀ(pyrazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene
(10b). 1H NMR, δ: 3.20, 3.23, 3.31 (all s, 9 H, MeO); 6.18, 6.38
(both d, 4 H, CH arom., J = 12.5 Hz); 6.28 (m, 1 H, azole CH);
7.80 (d, 1 H, azole CH , J = 2.7 Hz); 7.90 (d, 1 H, azole CH,
J = 4.5 Hz).
1,1,4ꢀTrimethoxyꢀ4ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene
(10c). 1H NMR, δ: 3.20, 3.25, 3.30 (all s, 9 H, MeO); 6.25, 6.35
(both d, 4 H, CH arom., J = 12 Hz); 7.80, 8.52 (both s,
2 H, C2H2N3).
The spectroscopic (1H NMR) characteristics used for idenꢀ
tification and determined percentages of compounds 6, 7, 9,
and 10 in reaction mixtures are presented below.
2ꢀ(3,5ꢀDimethylpyrazolꢀ1ꢀyl)ꢀ1,4ꢀdimethoxybenzene (6а).
1H NMR, δ: 2.14, 2.20 (both s, 6 H, Me); 3.70, 3.78 (both s,
6 H, MeO); 5.90 (s, 1 H, azole CH ); 6.80—7.07 (m, 3 H,
CH arom.).
1,1,4ꢀTrimethoxyꢀ4ꢀ(4ꢀnitropyrazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiꢀ
1
ene (10d). H NMR, δ: 3.20, 3.23, 3.30 (all s, 9 H, MeO); 6.31
(br.s, 4 H, CH arom.); 8.10, 8.92 (both s, 2 H, C3H2N3O).

Electrosynthesis of Nꢀ(dimethoxyphenyl)azoles
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2183
1,1,4ꢀTrimethoxyꢀ4ꢀ(3ꢀnitroꢀ1,2,4,ꢀtriazolꢀ1ꢀyl)cyclohexaꢀ
2,5ꢀdiene (10f). 1H NMR, δ: 3.20, 3.25, 3.60 (all s, 9 H, MeO);
5.07—6.16 (m, 4 H, CH arom.); 8.60 (s, 1 H, C2HN4O2).
1,1,4ꢀTrimethoxyꢀ4ꢀ(tetrazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene (10g)
and 1,1,4ꢀtrimethoxyꢀ4ꢀ(tetrazolꢀ2ꢀyl)cyclohexaꢀ2,5ꢀdiene (10h)
(isomer mixture 2 : 1). 1H NMR, δ: 3.20—3.30, 3.60 (all br.s,
9 H, MeO); 4.97—6.15 (m, 4 H, CH arom.); 8.50, 8.84 (both s,
1 H, CHN4).
1,2,4ꢀTrimethoxybenzene (11). 1H NMR, δ: 3.70—3.90
(three s, 9 H, MeO); 6.31 (dd, 1 H, CH arom., J = 6.1 Hz, J =
3.2 Hz); 6.45 (d, 1 H, H arom., J = 3.2 Hz); 6.73 (d, 1 H,
CH arom., J = 6.1 Hz).
3. V. A. Chauzov, V. Z. Parchinskii, E. V. Sinel´shchikova, and
V. A. Petrosyan, Izv. Akad. Nauk. Ser. Khim., 2001, 1215
[Russ. Chem. Bull., Int. Ed., 2001, 50, 1274].
4. V. A. Chauzov, V. Z. Parchinskii, E. V. Sinel´shchikova,
N. N. Parfenov, and V. A. Petrosyan, Izv. Akad. Nauk. Ser.
Khim., 2002, 917 [Russ. Chem. Bull., Int. Ed., 2002, 51, 998].
5. V. A. Chauzov, V. Z. Parchinskii, E. V. Sinel´shchikova,
A. V. Burasov, B. I. Ugrak, N. N. Parfenov, and V. A.
Petrosyan, Izv. Akad. Nauk. Ser. Khim., 2002, 1402 [Russ.
Chem. Bull., Int. Ed., 2002, 51, 1523].
6. V. A. Petrosyan, Elektrokhimiya, 2003, 1353 [Russ.
J. Electrochem., 2003, 1211 (Engl. Transl.)].
7. J. Catalan, J. L. M. Abbaud, and J. Elguero, Adv. Heterocycl.
Chem., 1987, 250.
8. V. A. Petrosyan, A. V. Burasov, and T. S. Vakhotina, Izv.
Akad. Nauk. Ser. Khim., 2005, 1166 [Russ. Chem. Bull., Int.
Ed., 2005, 54, 1197].
9. D. R. Henton, R. L. McCreery, and J. S. Swenton, J. Am.
Chem. Soc., 1980, 369.
10. A. V. Burasov, T. S. Vakhotina, and V. A. Petrosyan,
Elektrokhimiya, 2005, 1014 [Russ. J. Electrochem., 2005, 903
(Engl. Transl.)].
This work was supported by Council for Grants at
Russian Federation President (Program for State Support
of Leading Scientific Schools of the Russian Federation,
Grant NShꢀ5022.2006.3) and by the Division of Chemisꢀ
try and Materials Science of the Russian Academy of
Sciences (Program No. 01).
References
1. P. LopezꢀAlvarado, C. Avendano, and J. C. Menendez,
J. Org. Chem., 1995, 5678.
2. C. Mann and J. F. Hartwig, J. Am. Chem. Soc., 1998, 827.
Received December 18, 2006;
in revised form June 20, 2007