N-arylation of azoles with low basicity by 1,4-dimethoxybenzene during undivided electrolysis

DOI: 10.1023/A:1020979426942

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Russian Chemical Bulletin p. 1523 - 1532 (2002)

Update date:2022-08-02

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Authors:

Chauzov Chauzov

Parchinskii

Sinel'shchikova

Burasov Burasov

Ugrak Ugrak

Parfenov

Petrosyan

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Article abstract of DOI:10.1023/A:1020979426942

The reactions of 1,4-dimethoxybenzene with 4-nitropyrazole, 3,4-dinitro-5-methylpyrazole, 1,2,4-triazole, 3-nitro-1,2,4-triazole, and tetrazole were studied during undivided amperostatic electrolysis on a Pt electrode in MeCN, CH₂Cl₂, and MeOH. The main reaction products were 2-azolyl-1,4-dimethoxybenzenes and (or) 1,4-diazolyl-1,4-dimethoxycyclohexa-2,5-dienes. In all cases except 1,2,4-triazole, N-arylation occurs only in the presence of the Alk ₄N⁺ salts of azoles or 2,4,6-trimethylpyridine as a base. The mechanism of the reactions is discussed.

Full text of DOI:10.1023/A:1020979426942

Russian Chemical Bulletin, International Edition, Vol. 51, No. 8, pp. 1523—1532, August, 2002

1523

NꢀArylation of azoles with low basicity by 1,4ꢀdimethoxybenzene

during undivided electrolysis

ꢀ

V. A. Chauzov, V. Z. Parchinskii, E. V. Sinel´shchikova, A. V. Burasov, B. I. Ugrak,

N. N. Parfenov, and V. A. Petrosyan

N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,

47 Leninsky prosp., 119991 Moscow, Russian Federation.

Fax: +7 (095) 135 5328. Eꢀmail: petros@ioc.ac.ru

The reactions of 1,4ꢀdimethoxybenzene with 4ꢀnitropyrazole, 3,4ꢀdinitroꢀ5ꢀmethylꢀ

pyrazole, 1,2,4ꢀtriazole, 3ꢀnitroꢀ1,2,4ꢀtriazole, and tetrazole were studied during undivided

amperostatic electrolysis on a Pt electrode in MeCN, CH₂Cl₂, and MeOH. The main reacꢀ

tion products were 2ꢀazolylꢀ1,4ꢀdimethoxybenzenes and (or) 1,4ꢀdiazolylꢀ1,4ꢀdimethoxyꢀ

cyclohexaꢀ2,5ꢀdienes. In all cases except 1,2,4ꢀtriazole, Nꢀarylation occurs only in the presꢀ

ence of the Alk₄N⁺salts of azoles or 2,4,6ꢀtrimethylpyridine as a base. The mechanism of the

reactions is discussed.

Key words: paired electrosynthesis, Nꢀarylation, azoles, azole anions, 1,4ꢀdimethoxyꢀ

benzene.

The reactions of 1,4ꢀdimethoxybenzene (DMB) with

various azoles (pyrazoles, triazoles, and tetrazole) under

amperostatic undivided electrolysis on Pt electrodes in

MeCN and Alk₄N⁺salts of azoles or Bu₄NClO₄as a

supporting electrolyte afford^1—4orthoꢀsubstitution prodꢀ

ucts 1, ipsoꢀbisaddition products 2, and, in some cases,

ipsoꢀsubstitution products 3. We have established^1,2for

the first time the formation of bisadducts 2 among

electrolysis products and the possibility of using

azoles or their combination with 2,4,6ꢀtrimethylpyridine

(symmꢀcollidine, CL) instead of the corresponding anꢀ

ions in the starting reaction mixture.

It has recently been found²that the regularities which

determine the yield and ratio of products 1 and 2 for

3,5ꢀdimethylpyrazole (DMP), pyrazole (Pyr), and 3,5ꢀdiꢀ

methylꢀ4ꢀnitropyrazole (DMNP) depend on the nature

of the solvent (MeCN or CH₂Cl₂), basicity of the meꢀ

dium, and amount of the electricity passed and can be

described by the stages presented in Scheme 1.

According to this scheme, the reaction of the

Hꢀbonded AzH•B azole complex (B = AzH, CL) with

the DMB radical cation 4 affords intermediates 5 and 6,

which undergo further oxidation. The key stage deterꢀ

mining the ratio of products 1 and 2 in the case of DMP

and Pyr is the intramolecular rearrangement of the

1ꢀazolylꢀ1,4ꢀdimethoxyarenonium cation (7) to the

1ꢀazolylꢀ2,5ꢀdimethoxyarenonium cation (8). In this

case, the cathodic process is related to the deprotonation

of onium intermediates BH⁺formed during electrolysis.

In development of these works, we studied the reguꢀ

larities of Nꢀarylation in systems containing DMB and

relatively less basic and more acidic (compared to DMP

and Pyr) azoles (Table 1), viz., 4ꢀnitropyrazole (NP),

3,4ꢀdinitroꢀ5ꢀmethylpyrazole (DNMP), 3ꢀnitroꢀ1,2,4ꢀ

triazole (NTA), tetrazole (T), and 1,2,4ꢀtriazole (TA).

The latter is similar in basicity to Pyr* but its acidity is

* The high basicity of TA is a result of the protonation of the

N(4) atom rather than N(2) as in pyrazoles.⁵The accepted

classification of azoles to compounds with high and low basicꢀ

ity is conventional and reflects the specific features of their

electrochemical Nꢀarylation.

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1402—1410, August, 2002.

1524

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

Chauzov et al.

Scheme 1

B is AzH, CL

much higher and close to that of NP. In order to examꢀ

ine the composition of the electrolysis products, as in

the previous studies,^1,2we widely used NMR spectroꢀ

scopic monitoring, which allowed us to detect hydrolytiꢀ

cally labile compounds 2 in the final reaction mixture.

basic azoles are compared with those for DMP, Pyr, and

DMNP obtained by us previously²(Table 2).

The general comparison of the results of electrolysis

for the highly basic azoles (DMP, Pyr, TA) and azoles

with low basicity (DMNP, NP, NTA, DNMP, and T)

indicates that in the absence of basic additives the

Nꢀarylation of azoles of the latter group occurs very

limply, and the formation of minor (in most cases, <2%)

amounts of substitution products 1 is probably deterꢀ

mined by the arylation of the azole anions formed by the

direct deprotonation⁶of the azoles on the Pt cathode

(see Table 2, cf. entries 7, 9, 17, 33 and 1, 20, 22) rather

than to the direct arylation of the azoles (as in the case

of DMP, Pyr, and TA). In turn, the addition of CL to

the electrolyte slightly affects the change in the total

current efficiency (CE) of Nꢀarylation products 1 and 2

for the first group of azoles, while in the case of lowꢀ

basic azoles, when CL or the Alk₄N⁺salts of azoles are

added, the total CE of compounds 1 and 2 multiply

increases (see Table 2, cf. entries 2, 21, 23 and 8, 10,

15, 34, 35).

Results and Discussion

An undivided electrolysis. The results presented below

for the electrolysis of systems containing DMB and lowꢀ

Table 1. The pK_avalues of some azoles⁵and collidine

Azole^a

pK_a

Azole^a

pK_a

I^b

II^c

I^b

II^c

DMP

Pyr

DMNP

4.06

2.48

–0.45

–2.00

—

NTA

Imidazole

10.04

5.98

4.90

14.4

—

2.45

14.21

10.65

9.64

–3.65

–2.68

6.99

DNMP

—

7.43

A change in the electrolysis conditions has different

effects on the ratio of products 1 and 2 for azoles with

low and high basicity. This is illustrated by the results of

Nꢀarylation of DMP and NP. For example, in the elecꢀ

trolysis with DMP, an increase in the basicity of the

medium due to the addition of CL favors the formation

of 2a and hinders the formation of 1a, and an increase in

the acidity of the medium (the addition of AcOH) has an

^aDMP is 3,5ꢀdimethylpyrazole, Pyr is pyrazole, DMNP is

3,5ꢀdimethylꢀ4ꢀnitropyrazole, NP is 4ꢀnitropyrazole, DNMP

is 3,4ꢀdinitroꢀ5ꢀmethylpyrazole, TA is 1,2,4ꢀtriazole, NTA is

3ꢀnitroꢀ1,2,4ꢀtriazole, Т is tetrazole, CL is collidine.

^bAzole under study.

^cConjugate acid.

^dThe pK_avalue is unknown but evidently close to pK_aof

3,4ꢀdinitropyrazole (5.48).

NꢀArylation of azoles during undivided electrolysis

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

1525

opposite effect. By contrast, in the electrolysis with NP,

an increase in the basicity of the medium upon replaceꢀ

ment of CL by the NP salt (the basicity of CL is lower

than that of the NP anion, see Table 1) increases the CE

of product 1d, decreases the CE of 2d, and leads to the

ipsoꢀsubstitution product 3a (see Table 2, cf. entries 10,

15, and 16). The addition of AcOH to a mixture of NP

and CL results, evidently, in the protonation of the latꢀ

ter, decreases the nucleophilicity of the NP complex

with CL, and thus hinders Nꢀarylation (see Table 2,

cf. entries 10 and 12).

CH₂Cl₂as a solvent instead of MeCN, 1a is formed

predominantly, while in the electrolysis with NP under

similar conditions only a decrease in the CE of product

2d was observed (see Table 2, cf. entries 1 and 4, 5 and 6,

10 and 12, and 13 and 14).

The results obtained in the electrolysis with NTA are

similar on the whole to those for NP, namely, comꢀ

pounds 1g and 2g are formed in low CE in the presence

of CL, and if CL is replaced by the NTA salt, their total

CE noticeably increases, primarily due to product 1g

(see Table 2, entries 31 and 32). It is of interest that in

the case of DNMP, the only Nꢀarylation product is 1e,

whose CE are the same for electrolysis in the presence

In turn, in the electrolysis with DMP by passing 2 F

electricity at the DMP : DMB = 0.5 molar ratio or with

Table 2. Yields of products of the electrochemical Nꢀarylation of azoles by 1,4ꢀdimethoxybenzene (DMB) as functions of the

electrolysis conditions^а(results of the known works^2,3necessary for comparison are included)

Entry

Azole^b

Azole : DMB (mol)

(amount of electricity

per mole of DMB/F)

Solꢀ

vent

Additive^с(moles

per mole of DMB)

Current efficiencies

of products (%)

DMP²

DMNP²

1.5 (2)

1.5 (1)

1.5 (2)

0.5 (1)

1.5 (2)

MeCN

CH₂C_l

MeCN

CH₂Cl₂

MeCN

—

CL (0.5)

AcOH (1.5)

—

CL (0.5)

—

CL (0.5)

—

AcOH (0.5)

DNMP

Pyr²

0.5 (2)

0.5 (1)

1.0 (2)

1.25 (2)

1.5 (2)

1.0 (2)

1.5 (2)

0.5 (2)

1.5 (2)

1.0 (2)

1.5 (2)

1.0 (2)

MeCN

CH₂Cl₂

MeCN

CH₂Cl₂

MeCN

CL (0.5)

—

10 ^d,e

8 ^f

6 ^g

—

CL (0.5)

—

CL (0.5)

—

CL (0.5)

AcOH (1.5)

Pyr²

—

AcOH (1.5)

Pyr²

—

CL (0.5)

—

NTA

T³

28 ⁱ

4 ^j

—

88 ^j,k

(to be continued)

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Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

Chauzov et al.

Table 2 (continued)

Entry

Azole^b

Azole : DMB (mol)

(amount of electricity

per mole of DMB/F)

Solꢀ

vent

Additive^с(moles

per mole of DMB)

Current efficiencies

of products (%)

1.5 (2)

0.5 (2)

1.5 (2)

MeCN

CH₂Cl₂

MeCN

MeOH

CL (0.5)

—

CL (0.5)

50 ^j

52 ^j

29 ^j

21 ^k

—

15 ^j

7 ^l

9 ^m

DMP²

NTA

DNMP

20 ^j,n, 52 ^j,o

5 ^j,p, 30 ^j,o,p,q

5 ^r, 18 ^o

3 ^s, 16 ^o

—

^t,u, 7 ^o

<2 ^v, 10 ^o

^aElectrolysis was carried out vs. an 0.022 М solution of Bu₄NClO₄(0.5 moles per mole of DMB).

DMP is 3,5ꢀdimethylpyrazole, DMNP is 3,5ꢀdimethylꢀ4ꢀnitropyrazole, NP is 4ꢀnitropyrazole, DNMP is 3,4ꢀdinitroꢀ5ꢀ

methylpyrazole, Pyr is pyrazole, TA is 1,2,4ꢀtriazole, and NTA is 3ꢀnitroꢀ1,2,4ꢀtriazole, and T is tetrazole.

^cCL is collidine.

^dMe₄N⁺salt of NP (0.5 moles per mole of DMB) was used instead of Bu₄NClO₄.

^eThe reaction mixture contains 1ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀnitropyrazole (3a), 8% yield.

^fMe₄N⁺salt of NP (0.25 moles per mole of DMB) was used instead of Bu₄NClO₄, the yield of compound 3a being 4%.

^gBu₄N⁺salt of DNMP (0.5 moles per mole of DMB) was used instead of Bu₄NClO₄.

^hThe yield of 1ꢀ(4ꢀmethoxyphenyl)ꢀ1,2,4ꢀtriazole (3b) was 12%.

ⁱMe₄N⁺salt of NTA (0.5 moles per mole of DMB) was used instead of Bu₄NClO₄.

^jA mixture of the Nꢀisomers.

^kBu₄N⁺salt of T (0.5 moles per mole of DMB) was used instead of Bu₄NClO₄.

^lOne Nꢀisomer.

^mThe yield of 1,1,4,4ꢀtetramethoxycyclohexaꢀ2,5ꢀdiene (12) was 52%.

ⁿA mixture of the Nꢀisomers of 1,1,4ꢀtrimethoxyꢀ4ꢀtetrazolylcyclohexaꢀ2,5ꢀdiene (10h) is also formed (38% yield).

^oAfter additional heating (5 h, 110 °C).

^pTetrazole was added to the reaction mixture after the end of electrolysis before MeOH was distilled off (70 °C, 20 Torr, 30 min).

^qA mixture of the isomers of 10h is also formed (43% yield).

^rAfter the solvent was distilled off (70 °C, 20 Torr, 30 min), the yield of 1,1,4ꢀtrimethoxyꢀ4ꢀ(3ꢀnitrotriazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀ

diene (10g) was 13%.

^sAfter the solvent was distilled off (70 °C, 20 Torr, 30 min), the yield of 1,1,4ꢀtrimethoxyꢀ4ꢀ(5ꢀmethylꢀ3,4ꢀdinitropyrazolꢀ

1ꢀyl)cyclohexaꢀ2,5ꢀdiene (10e) was 13%.

^tAfter the solvent was removed (20 °C), the yield of 12 was 12% and the yield of 1,1,4ꢀtrimethoxyꢀ4ꢀ(4ꢀnitropyrazolꢀ1ꢀyl)cyclohexaꢀ

2,5ꢀdiene (10d) was 3%.

^uAfter the solvent was distilled off (70 °C, 20 Torr, 30 min), the yield of 12 6% and the yield of 10d was 11%.

^vAfter the solvent was removed (20 °C) or distilled off (70 °C, 20 Torr, 30 min), the yield of 12 was 21% and the yield of

1,1,4ꢀtrimethoxyꢀ4ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene (10f) was 38%.

of both CL and DNMP salt (see Table 2, cf. enꢀ

tries 18 and 19).

the solvent). Perhaps, it is for this reason that the relaꢀ

tive concentration of 2h can differ substantially (not the

total CE of 1h and 2h) in parallel experiments. With

CH₂Cl₂as the solvent, the total yield of 1h and 2h and

their ratio remain virtually unchanged, and electrolysis

with an excess of DMB affords a mixture of Nꢀisomers of

1h in low yields (see Table 2, entries 36 and 37). The

latter fact and the predominant consumption of one of

the isomers at the final stages of electrolysis (see Table 2,

entry 38), as in the case of Pyr and TA, indicate, most

likely, the easiness of electrooxidation of product 1h.

The distinction in behavior of DMP and T during elecꢀ

trolysis in MeOH is of interest. In the case of DMP,

The results of Nꢀarylation of T is noteworthy in that

the CE of 1h (forms as a mixture of two Nꢀisomers in a

ratio of ∼3 : 2) is very high and the overall CE of the

Nꢀarylation product reaches 90% in most cases. This

noticeably exceeds the CE of the Nꢀarylation products

not only for the lowꢀbasic azoles but even for the most

reactive highly basic DMP (see Table 2, cf. entries 1, 2

and 34, 35). What is also unusual in this case is that the

obtained mixture of Nꢀisomers of 1h and 2h is transꢀ

formed into an almost pure mixture of Nꢀisomers of 1h

after brief heating (in particular, during distillation of

NꢀArylation of azoles during undivided electrolysis

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

1527

compound 1а is formed in a low CE (9%), and the main

reaction product is the oxidative ipsoꢀbismethoxylation

product of DMB, viz., 1,1,4,4ꢀtetramethoxycyclohexaꢀ

2,5ꢀdiene, in 52% CE (see Table 2, entry 39),²whereas

in the case of T we obtained a mixture of Nꢀisomers

(∼2 : 1) of 1h (20% CE) and 1,1,4ꢀtrimethoxyꢀ4ꢀtetrazoꢀ

lylcyclohexaꢀ2,5ꢀdiene (38% CE) (see Table 2, entry 40).

The formation of products of this type, viz., ketal derivaꢀ

tives of paraꢀquinone, upon Nꢀarylation in MeOH was

observed for other azoles with low basicity as well (see

Table 2, entries 42—45). Since these results are imporꢀ

tant for understanding the mechanisms of formation of

products 1 and 2, the corresponding experimental data

will be considered below together with the discussion of

these problems.

The electrochemical behavior of TA resembles in part

that of Pyr with similar basicity. During electrolysis with

Bu₄NClO₄as the supporting electrolyte, TA efficiently

reacts with DMB in the absence of basic additives to

form product 2f predominantly, and the CE of the latter,

as in the case of Pyr, increases when CL is added (see

Table 2, entries 20—23). However, the conditions favorꢀ

ing the formation of product 1 in the case of DMP and

Pyr (the addition of AcOH or electrolysis in CH₂Cl₂) do

not afford the desired result in the electrolysis with TA

(see Table 2, entries 24—27). In turn, electrolysis with

an excess of DMB (TA : DMB = 0.5), which also affords

predominantly 1 in the case of DMP, is accompanied

here by the formation of ipsoꢀsubstitution product 3b*

(see Table 2, cf. entries 5, 28, and 29) rather than 1f.

However, it is of note that it is the ipsoꢀbisaddition prodꢀ

uct 2f that is presumably the precursor of 3b, because

only 2f was found in the reaction mixture when a halved

amount of electricity (1 F) was passed (see Table 2,

entry 30). As for the absence or a low content of

1f among the reaction products in all experiments

with TA, this is reasoned, most probably, by its easy

electrooxidation, as in the case of 1b during Nꢀarylation

of Pyr.²

attack by 4, can also be useful for azoles with low basicꢀ

ity (NP, NTA), whose electrolysis in the presence of CL

differs from that in the presence of the salt of the correꢀ

sponding azole. By the way, this fact indicated that NP

and NTA form complexes with CL but remain in the

nonionized form. The corresponding experiment was perꢀ

formed for NP, and the conditions of entry 10 were

chosen as model with the only distinction that the double

amount of CL was used to prevent the deactivation of

the pyrazole component of the reaction mixture (anodic

electrolysis is accompanied by proton generation). In

the qualitative respect, the results obtained are compaꢀ

rable with those of the experiment in the undivided cell,

although the composition of the reaction products someꢀ

what differed. This can be explained by the objective

difference in experimental conditions. For example, elecꢀ

trolysis of the NP—DMB—CL system gave a mixture of

1d и 2d in 9 and 37% CE respectively (cf. entry 10 in

Table 2). Note that only resinꢀlike products are formed

upon electrolysis of the NP—DMB system in the abꢀ

sence of CL in the anodic compartment of the divided

cell. On the whole, our experiments additionally subꢀ

stantiate the hypothesis^1,2about the involvement of the

nonionized AzH•B complexes as nucleophilic coreactants

in the electrochemical Nꢀarylation of azoles.

Regularities of Nꢀarylation of azoles with low basicity.

The above presented, often contradictory experimental

results can be explained if we introduce several concepts

concerning the stage of interaction of the azole nucleoꢀ

phile (see Scheme 1) with intermediates bearing a posiꢀ

tive charge, such as radical cation 4 and arenonium

cation 7.

Based on the concept about the substantial differꢀ

ence in electrophilicity of the orthoꢀ and ipsoꢀpositions

of these intermediates, we believe that the involvement

of the azole anion is preferential for orthoꢀsubstitution,

whereas ipsoꢀsubstitution can involve both the azole anꢀ

ion and a complex of nonionized azole. This point needs

to be discussed in more detail. The presence of methoxy

groups in intermediates 4 and 7 undoubtedly favor

the localization of the positive charge mainly on the

ipsoꢀcarbon atoms of the ring. For these reasons, the

ipsoꢀattack on ions 4 or 7 by the azole nucleophile reꢀ

quires relatively small energy expenses. This process ocꢀ

curs, evidently, even when these ions come close to the

nonionized azole complex (dipole), as is shown in

Scheme 2, and the more so when they approach to the

azole anion.

Thus, a whole series of distinctions, which follows

from a comparison of the data of Nꢀarylation of azoles

with high and low basicity, needs Scheme 1 presented

above to be refined. This will allow the correct descripꢀ

tion of the regularities of Nꢀarylation of the lastꢀmenꢀ

tioned azoles.

Electrolysis in a divided cell. The previously estabꢀ

lished²Nꢀarylation of such a highly basic azole as DMP

during electrolysis in the anodic compartment of a diꢀ

vided cell confirmed unambiguously the possibility of

direct reaction of the nonionized form of DMP with

radical cation 4 (see Scheme 1). This procedure, which

allows the elucidation of the object of the electrophilic

By contrast, the orthoꢀattack in the interaction of

intermediates 4 or 7 with a nucleophile needs the localꢀ

ization of the positive charge on one of the orthoꢀposiꢀ

tions. This is associated with substantial polarization of

these intermediates leading to the formation of an enerꢀ

getically less favorable structure. This structure is eviꢀ

dently formed with the lowest expenses when intermediꢀ

* The formation of ipsoꢀsubstitution products 3a,b will be disꢀ

cussed elsewhere.

1528

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

Chauzov et al.

Scheme 2

the AzH•CL complex results in the appearance (or an

increase in the relative content) of 1 in the electrolysis

products (see Table 2, cf. entries 10 and 15, 31 and 32).

At the same time, unlike the data of electrolysis inꢀ

volving the NP or NTA complexes with CL, in elecꢀ

trolysis with complexes of DNMP or T with CL the

corresponding compounds 1e,h are the main or even

single products. The use of a DNMP—DNMP salt mixꢀ

ture gives the same result (see Table 2, cf. entries 18, 19

and 34, 35). We believe that complexes of less acidic

azoles (TA, NP, NTA) (see Table 1) with CL, like comꢀ

plexes of highly basic azoles,²are nonionized. In the

case of more acidic azoles (DNMP, T), the Az—H bond

in the Az—H•B complex is likely much more polar, up

to the formation of the tight Az^–H•B⁺ion pair. This

conclusion can be favored to some extent by the fact that

solutions of mixtures of DNMP or T with CL in MeCN

exhibit higher electric conductivity than solutions of TA,

NP, or NTA mixtures with CL in MeCN.* Of course,

this cannot serve as the direct proof for the ionic strucꢀ

ture of the DNMP and T complexes with CL but can

indicate its rather easy ionization upon approaching to

cationic intermediate 4 or 7. In turn, the latter explains

the differences in the experimental results mentioned

above.

ates 4 or 7 approach to the anion, as is shown in Scheme 3,

and its formation is much more difficult when they apꢀ

proach to a dipole (nonionized azole complex).

Scheme 3

An increase in the acidity of the azoles upon introꢀ

duction of nitro groups into the ring is accompanied by a

decrease in their nucleophilicity due to a considerable

shift of the electron density from the N atoms of the

rings to the nitro groups. This manifests in a decrease in

the total CE of products 1 and 2 on going, e.g., from

DMP to DMNP, from NP to DNMP, and from TA to

NTA (see Table 2, cf. entries 1 and 7, 10 and 18, 23

and 31). In turn, the high total current efficiencies of 1h

and 2h (see Table 2, entries 34—36) for the most acidic

azole studied, T, evidently point to the unexpectedly

high nucleophilicity of the corresponding anion. This is

associated, most likely, with the specificity of delocalꢀ

ization of the negative charge in the latter, viz., mainly

on the contiguous N atoms, which are, on the whole, the

object of the electrophilic attack (αꢀeffect). Note that an

increase in nucleophilicity caused by this type of effect

predetermines, most likely, the possibility of involveꢀ

ment of triazoles and pyrazoles in the process considꢀ

ered. This conclusion can be confirmed by the experiꢀ

mental fact that imidazole, which is more basic than

isomeric Pyr but does not contain contiguous N atoms

(see Table 1), does not virtually react with DMB under

Note, however, that this assumption explains only

the specific feature of the orthoꢀattack of ions 4 and 7

because the "pantophagy" of their ipsoꢀposition should

result in all cases in the formation of compounds 6, 7,

and further 2 (see Scheme 1). This forced us to introꢀ

duce the second concept about the irreversibility of the

orthoꢀattack on 4 and 7 and reversibility (equilibrium

character) of the ipsoꢀattack. The lower the nucleophiꢀ

licity and basicity of Az^–and the higher acidity of AzH,

the higher the reversibility. In fact, this differentiates the

nucleophilic attacks of the ipsoꢀ and orthoꢀpositions, deꢀ

termining the former as the kinetically controlled and

the latter as the thermodynamically controlled process.

The data presented in the Section on undivided elecꢀ

trolysis and in Table 2 agree with both concepts. For

example, in the case of NP and NTA, the use of the

Alk₄N⁺salt of azole as the azole component instead of

* This is indicated, for example, by the fact that during

amperostatic electrolysis of a mixture of DNMP or T with CL

the resistance of the cell is almost independent of the presence

or the absence of a supporting electrolyte; however, it increases

∼10ꢀfold during electrolysis of mixtures of TA, NP, or NTA

with CL in the absence of the supporting electrolyte.

NꢀArylation of azoles during undivided electrolysis

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

1529

conditions similar to those used in entries 20, 21, and 24

(see Table 2).

rearrangement 7h → 8h in the electrolysis with T occurs,

most likely, in a different manner, for example, as an

intermolecular cineꢀsubstitution (Scheme 5).

According to our data,²in the electrochemical

Nꢀarylation of DMP and Pyr, the rearrangement of the

arenonium cations 7 → 8 makes a considerable contriꢀ

bution to the formation of 1 (see Scheme 1). However,

such a rearrangement seems highly improbable for the

lowꢀbasic azoles studied in this work. This follows, for

example, from the fact that changes in the solvent and in

the acidicꢀbasic properties of the medium (see above) do

not affect the yield and the ratio of the electrolysis prodꢀ

ucts.²Nevertheless, the exceptional easiness of the transꢀ

formation of a mixture of compounds 1h и 2h, which is

formed upon electrolysis with T, into product 1h after

brief heating or even upon storage at ∼20 °C can be exꢀ

plained only by the rearrangement 7h → 8h (Scheme 4).

The fact that one of the Nꢀarylation products of T in

MeOH (Scheme 6), viz., 1,1,4ꢀtrimethoxyꢀ4ꢀtetrazolylꢀ

cyclohexaꢀ2,5ꢀdiene (10h) (see above), can also be transꢀ

formed into 1h but upon prolong heating (5 h, 110 °C) is

an argument in favor of Scheme 5. The much more

drastic conditions of this rearrangement as compared

with the transformation 2h → 1h can be explained by the

necessity to eliminate such a poorly leaving group as

methoxyl in the stage of cineꢀsubstitution.

Scheme 6

Scheme 4

The results of undivided electrolysis in MeOH proꢀ

vide a very helpful information for the understanding of

the regularities of Nꢀarylation of azoles. First, note that

under these conditions the higher CE of product 1h comꢀ

pared to that of product 1a is evidently due to the higher

nucleophilicity of the T•CL complex compared to that

of the DMP•CL complex (see Table 2, cf. entries 39

and 40). As for product 10, its formation according to

Scheme 1 could formally be explained by different selecꢀ

tivities of two consecutive ipsoꢀreactions of intermediꢀ

ates 4 and 7 with the nucleophiles present in the solution

(MeOH and T•CL complex). However, we managed to

show that in this case yet another route of formation of

compound 10h is possible, and this route is not directly

related to the electrochemically generated electrophilic

intermediates. It is shown experimentally (see Table 2,

entry 41) that under mild conditions (30 min, 70 °C) the

virtually quantitative and irreversible exchange interacꢀ

tion occurs between T and the product of electrochemiꢀ

cal methoxylation of DMB, viz., 1,1,4,4ꢀtetramethoxyꢀ

cyclohexaꢀ2,5ꢀdiene (12), to form compound 10h. A

possible route of this transformation includes the formaꢀ

tion of cation 11 due to acid catalysis performed by T

(Scheme 7). In this case, further heating of the reaction

mixture also produces product 1h according to Scheme 6.

Note. Here and in Schemes 5—7 Az is the tetrazole residue

(a mixture of Nꢀisomers).

Earlier²we concluded that during electrolysis with

highly basic azoles such a rearrangement occurs as the

intramolecular orthoꢀarylation of the adjacent N atom in

azole. However, in the case of T with very low basicity

(see Table 1), the existence of the fourꢀmembered tranꢀ

sition state 9 (see Scheme 4) casts some doubt. In fact, a

similar rearrangement is not observed (see Table 2, enꢀ

tries 22, 26, and 27) for electrolysis with TA, which is

much more basic than T (see Table 1). For this reason,

Scheme 5

1530

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

Chauzov et al.

Note that according to the published data⁷the transforꢀ

mation of cyclohexadiene 12 into orthoꢀsubstituted DMB

derivatives under the action of nucleophilic reagents

(alcohols, thiols, etc.) is catalyzed by Hꢀacids or Lewis

acids and often requires prolong heating.

in the case of NP, the major part of diene 12 is primarily

transformed by the azole into 10d (see Scheme 7) and

then into a mixture of 1d и 2d, while in the case of TA

only product 10f can likely undergo such a transforꢀ

mation. These results can be explained in terms of

Scheme 8, which differs from Scheme 6 in the alternaꢀ

tive formation of products 2d,f due to both the insuffiꢀ

cient nucleophilicity of the azole component for the exꢀ

clusive orthoꢀ(but not ipsoꢀ) attack and the relatively low

acidity of NP and TA stabilizing compounds 10d,f

and 2d,f.

Scheme 7

Scheme 8

The specific feature of this reaction is the use of the

azole—CL (3 : 1) system, which provides both acid caꢀ

talysis (AzH) and the presence of an efficient nucleoꢀ

phile (AzH•CL) even under mild conditions. In addiꢀ

tion, the intermediate formation of the ipsoꢀsubstitution

product 10 has been established for the first time for

similar processes. Thus, when the T—CL—DMB system

is used in МеОН, not only compound 10h, but also

cyclohexadiene 12 can be the real primary product of the

electrochemical reaction.

Electrolysis of the AzH—DMB—CL systems with

DNMP and NTA in MeOH (see Table 2, entries 43

and 42) is characterized by the same regularities. The

main electrolysis products are compounds 10e,g (CE 13%

for each) and 1e,g (CE 5 and 3%, respectively). As in the

case of T, heating of the obtained reaction mixtures (5 h,

110 °C) results in the transformation of 10e,g into 1e,g

in ∼100% yield (see Table 2, entries 43 and 42), which is

in accord with Scheme 6. No diene 12 was formed in the

cases considered (as in the electrolysis of T). Less acidic

NP and TA behave in a different manner (see Table 1):

the main electrolysis products are compounds 10d,f (CE 3

and 38%) and 12 (CE 12 and 28%, respectively); the

formation of product 1 was observed only in the case of

TA (CE ∼1% (1d)) (see Table 2, entries 44 and 45).

Changes in the composition of the reaction mixtures

during distillation of the solvent (70 °C, 20 Torr, 30 min)

are observed only for NP, namely, cyclohexadiene 12 is

partially transformed by the azole into 10d (CE 11%).

Under more drastic conditions (5 h, 110 °C), similar

transformations are observed in both cases, viz., the forꢀ

mation of products 1d,f (CE 7 and 10%, respectively)

and 2d,f (7 and 11%, respectively). According to the CE

The results presented demonstrate first of all the speꢀ

cific features of electrochemical Nꢀarylation of azoles

with low basicity in МеОН, which affords solvolysis prodꢀ

ucts 10 and 12. Nevertheless, some of these results are

very useful for the understanding of the general regulariꢀ

ties of the process considered. For example, the transꢀ

formations of 12 into 10 and then into 1 (see Schemes 6

and 7), which were experimentally confirmed for the

most acidic azoles, are a serious argument in favor of the

above assumptions about the reversibility of the ipsoꢀ

attack of electrophilic intermediates 4 and 7 by the azole

nucleophiles and the irreversibility of their orthoꢀattack.

The fact that heating of compounds 10d,f for the least

polar NP and TA complexes with CL produces mixtures

of 1d,f and 2d,f confirms, most likely, the second asꢀ

sumption about the preferential occurrence of the orthoꢀ

attack of cation 7 (and, probably, radical cation 4) only

in the presence of the azole anion or a sufficiently polar

AzH•CL complex.

Thus, as applied to azoles with low basicity (acidic),

Scheme 1 proposed by us previously for the electroꢀ

chemical Nꢀarylation of highly basic azoles by DMB

should be refined taking into account the above assumpꢀ

tions (see Schemes 4—7) about the reversibility of some

stages* and the possibility of the intermolecular mechaꢀ

nism of rearrangement of the arenonium ions 7 → 8

(Scheme 9).

To finish the discussion of the possible mechanisms

of Nꢀarylation of the azoles (see Schemes 1 and 9), we

* Note that the reversibility of these stages is also real for highly

basic azoles when electrolysis is carried out in the presence of

acids, e.g., AcOH.²

NꢀArylation of azoles during undivided electrolysis

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

1531

Scheme 9

(Lancaster), and NP and DNMP were prepared according to a

previously described procedure.⁸Acetonitrile was purified and

dried by boiling with and distillation from KMnO₄and double

distillation from P₂O₅followed by distillation from calꢀ

cined K₂CO₃.

note that the assumption on the possibility of formation

of orthoꢀarylation products 1 due to the intraꢀ or interꢀ

molecular transformations 7 → 8 agrees completely with

the experimental results. This transformation in the final

stage of electrolysis allows us to believe (at least forꢀ

mally) that the stage commonly accepted for similar proꢀ

cesses (methoxylation, cyanation, etc.), viz., orthoꢀatꢀ

tack of radical cation 4 by a nucleophile, can be excluded.

Moreover, the relatively high rate of the ipsoꢀattack of

arenionim cations 7 by the nucleophile compared to the

orthoꢀattack observed in several cases assumes that the

ipsoꢀattack in the case of radical cation 4 followed by the

fast oxidation of intermediate 6 (on the electrode or by

ion 4 acting as a mediator) is also preferential. For these

reasons, the stages of the orthoꢀattack of radical cation 4

with the formation of radical 5 followed by its subseꢀ

quent oxidation are designated in Scheme 9 by dotted

arrows as theoretically possible but presently having no

necessary experimental substantiation.

Amperostatic electrolysis of DMB (2 mmol) in 45 mL of

reaction mixtures with different compositions was carried out

under argon at the controlled current (I = 50 mA), passing 1 or

2 F electricity per mole of DMB (see Table 2). After terminaꢀ

tion of the electrolysis, the solvent was distilled off on a rotary

evaporator at the temperature ≤70 °C (25—30 Torr), and the

residue was analyzed by ¹H NMR. Electrolysis was performed

under conditions similar to those described previously.¹For

spectroscopic characteristics used for identification of the seꢀ

ries of compounds 1 and 2 and the procedure for the determiꢀ

nation of the current efficiencies of 1 and 2 (calculated per

twoꢀelectron transformation of DMB) without their isolation

from a solution, see Ref. 1.

A porous glass diaphragm was used for electrolysis with

divided cathodic and anodic compartments. The cell volume

and surface areas of the Pt electrodes were approximately the

same as those for undivided electrolysis.

The examples of experiments given below describe isolaꢀ

tion of the target products, which corroborate the conclusions

about their nature drawn from the spectroscopic data.

In entry 10 (see Table 2), the residue after distillation of the

solvent (20—35 °С, 25 Torr) was triturated with ether and the

ethereal extract was concentrated in vacuo. After chromatoꢀ

graphic purification of the residue on silica gel using benzene

as the eluent, 1,4ꢀdimethoxyꢀ1,4ꢀdi(4ꢀnitropyrazolꢀ1ꢀyl)cycloꢀ

hexaꢀ2,5ꢀdiene (2d) was obtained in 42% yield (220 mg)

with m.p. 110 °С. Found (%): C, 46.40; H, 3.95; N, 23.12.

C₁₄H₁₄N₆O₆. Calculated (%): C, 46.41; H, 3.89; N, 23.2. The

Experimental

NMR spectra of solutions of samples in a

DMSOꢀd₆—CCl₄(1 : 1, v/v) mixture were recorded on a Bruker

ACꢀ300 instrument.

Tetrabutylammonium perchlorate was prepared by the exꢀ

change reaction of the corresponding bromide with NaClO₄

followed by recrystallization from EtOH. Tetraalkylammonium

salts of azoles were synthesized by a general procedure³using

commercial DMB, TA, NTA, and T with 98—99% purity

1532

Russ.Chem.Bull., Int.Ed., Vol. 51, No. 8, August, 2002

Chauzov et al.

¹H NMR spectrum of cyclohexadiene 2d was identical with

that described previously.¹

Compounds 1e,g were obtained analogously (see Table 2,

entries 18 and 32).

1,4ꢀDimethoxyꢀ2ꢀ(5ꢀmethylꢀ3,4ꢀdinitropyrazolꢀ1ꢀyl)benzene

(1e). The yield was 20 mg (4%). Found (%): C, 46.60; H, 3.90;

N, 18.10. C₁₂H₁₂N₄O₆. Calculated (%): C, 46.76; H, 3.92;

N, 18.18. ¹H NMR, δ: 2.60 (s, 3 H, Me); 3.80, 3.83 (both s,

3 H, 2 MeO); 7.04—7.17 (m, 3 H, C₆H₃).

1,1,4ꢀTrimethoxyꢀ4ꢀ(3ꢀnitrotriazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene

(10g). ¹H NMR, δ: 3.20, 3.25, 3.60 (all s, 9 H, 3 MeO);

5.07—6.16 (m, 4 H, C₆H₄); 8.60 (s, 1 H, C₂HN₄O₂).

1,1,4ꢀTrimethoxyꢀ4ꢀ(tetrazolꢀ1ꢀ and ꢀ2ꢀyl)cyclohexaꢀ2,5ꢀ

diene (10h) (mixture of Nꢀisomers, 2 : 1). ¹H NMR, δ:

3.20—3.30, 3.60 (all br.s, 9 H, 3 MeO); 4.97—6.15 (m, 4 H,

C₆H₄); 8.50, 8.84 (both s, 1 H, CHN(4)).

1,1,4,4ꢀTetramethoxycyclohexaꢀ2,5ꢀdiene (12). ¹H NMR,

δ: 3.20 (s, 12 H, 4 MeO); 6.00 (s, 4 H, C₆H₄).

1,4ꢀDimethoxyꢀ2ꢀ(3ꢀnitroꢀ1,2,4ꢀtriazolꢀ1ꢀyl)benzene (1g).

The yield was 95 mg (19%), m.p. 118 °С. 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, 3 H, 2 MeO);

7.05—7.30 (m, 3 H, C₆H₃); 9.13 (s, 1 H, C₂HN₄O₂).

The spectroscopic (¹H NMR) characteristics of compounds

used for the identification and determination of their content

in reaction mixtures are presented below.

This work was financially supported by the Russian

Foundation for Basic Research (Project No. 00ꢀ03ꢀ

32870а) and the "Leading Scientific Schools" program

(Grant 00ꢀ15ꢀ97328).

References

1,4ꢀDimethoxyꢀ2ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)benzene (1f). ¹H NMR,

δ: 3.80, 3.90 (both s, 3 H, 2 MeO); 6.94—7.35 (m, 3 H, C₆H₃);

8.04, 8.85 (both s, 1 H, C₂H₂N₃).

1. 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].

2. 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].

3. Kai Hu, M. E. Niyazymbetov, and D. H. Evans, Tetraꢀ

hedron Lett., 1995, 36, 7027.

4. M. E. Niyazymbetov, L. V. Mikhal´chenko, and V. A.

Petrosyan, Tez. dokl. Vsesoyuz. konf. "Aromaticheskoe

nukleofil´noe zameshchenie" [Abstrs. AllꢀUnion Conf. "Aromatic

Nucleophilic Substitution"], Novosibirsk, 1989, 91 (in Russian).

5. J. Catalan, J. L. M. Abbaud, and J. Elguero, Adv. Heterocycl.

Chem., 1987, 41, 250.

1,4ꢀDimethoxyꢀ2ꢀ(tetrazolꢀ1 and ꢀ2ꢀyl)benzenes (1h) (mixꢀ

ture of Nꢀisomers, 3 : 2). H NMR, δ: 3.76—3.89 (four s, 6 H,

2 MeO); 7.05—7.32 (m, 3 H, C₆H₃); 8.96, 9.59 (both s, 1 H,

CHN(4)) (cf. Ref. 3).

1,4ꢀDimethoxyꢀ1,4ꢀdi(tetrazolꢀ1ꢀ and ꢀ2ꢀyl)cyclohexaꢀ2,5ꢀ

dienes (2h) (mixture of mainly two isomers, 3 : 2). H NMR, δ:

3.28, 3.40 (both s, 6 H, 2 MeO); 6.79, 6.81 (both s, 4 H,

C₆H₄); 9.56, 9.70 (both s, 2 H, CHN(4)).

1ꢀ(4ꢀMethoxyphenyl)ꢀ1,2,4ꢀtriazole (3f). H NMR, δ: 3.82

(s, 3 H, MeO); 7.05, 7.72 (both d, 4 H, C₆H₄); 8.04, 9.01

(both s, 2 H, C₂H₂N₃) (cf. Ref. 3).

1,1,4ꢀTrimethoxyꢀ4ꢀ(4ꢀnitropyrazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀ

diene (10d). ¹H NMR, δ: 3.20, 3.23, 3.30 (all s, 9 H, 3 MeO);

6.31 (br.s, 4 H, C₆H₄); 8.10, 8.92 (both s, 2 H, C₃H₂N₃O).

1,1,4ꢀTrimethoxyꢀ4ꢀ(5ꢀmethylꢀ3,4ꢀdinitropyrazolꢀ1ꢀ

yl)cyclohexaꢀ2,5ꢀdiene (10e). ¹H NMR, δ: 2.70 (s, 3 H, Me);

3.30, 3.32, 3.62 (all s, 9 H, 3 MeO); 4.93—6.20 (m, 4 H, C₆H₄).

1,1,4ꢀTrimethoxyꢀ4ꢀ(1,2,4ꢀtriazolꢀ1ꢀyl)cyclohexaꢀ2,5ꢀdiene

(10f). ¹H NMR, δ: 3.20, 3.25, 3.30 (all s, 9 H, 3 MeO); 6.25,

6.35 (both d, 4 H, C₆H₄); 7.80, 8.52 (both s, 2 H, C₂H₂N₃).

6. V. A. Petrosyan, Izv. Akad. Nauk, Ser. Khim., 1995, 1411

[Russ. Chem. Bull., 1995, 44, 1353 (Engl. Transl.)].

7. B.ꢀT. Groebel, E. Konz, H. Millaner, and R. Pistorius, Synꢀ

thesis, 1979, 608.

8. R. Hüttel, F. Büchele, and P. Jochum, Chem. Ber., 1955,

88, 1377.

Received March 26, 2002;

in revised form July 1, 2002

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N-arylation of azoles with low basicity by 1,4-dimethoxybenzene during undivided electrolysis

DOI: 10.1023/A:1020979426942

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