Synthesis and properties of 5-diazoimidazoles and imidazolyl-5-diazonium salts

Article abstract of DOI:10.1023/A:1025605512301

Diazotization of 4-R-5-aminoimidazoles (R = CONHAr, CONHAIk, morpholinocarbonyl, or piperidinocarbonyl) with sodium nitrite in aqueous solutions of mineral acids afforded the corresponding 5-diazoimidazoles, whereas the reactions in concentrated tetrafluoroboric acid produced imidazolyl-5-diazonium salts. In the solid phase, diazonium salts are transformed into the corresponding diazo compounds.

Full text of DOI:10.1023/A:1025605512301

1600
Russian Chemical Bulletin, International Edition, Vol. 52, No. 7, pp. 1600—1605, July, 2003
Synthesis and properties of 5ꢀdiazoimidazoles and imidazolylꢀ5ꢀdiazonium salts
ꢀ
E. V. Sadchikova and V. S. Mokrushin
Ural State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 75 4135. Eꢀmail: seb@htf.ustu.ru
Diazotization of 4ꢀRꢀ5ꢀaminoimidazoles (R = CONHAr, CONHAlk, morpholinocarbonyl,
or piperidinocarbonyl) with sodium nitrite in aqueous solutions of mineral acids afforded the
corresponding 5ꢀdiazoimidazoles, whereas the reactions in concentrated tetrafluoroboric acid
produced imidazolylꢀ5ꢀdiazonium salts. In the solid phase, diazonium salts are transformed
into the corresponding diazo compounds.
Key words: diazotization, 5ꢀdiazoimidazoles, imidazolylꢀ5ꢀdiazonium salts, nitrosoamines,
3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ1,2,3ꢀtriazinꢀ4ꢀones.
Heterocyclic diazo compounds are highly reactive and
are used for the preparation of new compounds, including
those exhibiting biological activities. For example, 5ꢀdiꢀ
azoimidazoleꢀ4ꢀcarboxamide serves as a precursor of the
antitumor drugs dacarbazine1 and temozolomide2 emꢀ
ployed in clinical practice.
We studied diazotization of 5ꢀaminoimidazoles 1a—h
in different media. Under the conditions of strict temꢀ
perature control (–5—0 °C), the reactions of amines
1a—d,f—h with NaNO2 in dilute HCl afforded solid indiꢀ
vidual 4ꢀsubstituted 5ꢀdiazoimidazoles 2a—d,f—h in
75—89% yields in spite of the fact that the latter can
undergo cyclization to give imidazotriazinones 3 analoꢀ
gously to diazoimidazolecarboxamides 2i,j.10
Under the same reaction conditions, aminoimidazole
1e gave only the intramolecular cyclization product, viz.,
3ꢀ(pꢀethoxycarbonylphenyl)ꢀ3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ
1,2,3ꢀtriazinꢀ4ꢀone (3e). In the IR spectrum of 3e, abꢀ
sorption bands in the region of 2100—2300 cm–1 are abꢀ
sent and the absorption band of the C=O bond is obꢀ
served at 1700 cm–1 (Table 1). Diazoimidazole 2e was
synthesized by diazotization of amine 1e with ethyl nitrite
in an aprotic medium.
Treatment of amines 1a—e with crystalline NaNO2 in
50% HBF4 afforded the corresponding diazonium tetraꢀ
fluoroborates 4a—e in the solid state. The fact that diazoꢀ
nium salts 4f—l were not isolated in the solid state neither
under the analogous conditions nor upon the addition of
sodium tetrafluoroborate or SbCl5 to solutions of diazo
compounds 2f—l is, apparently, attributable to high soluꢀ
bility of these salts. Because of this, we used solutions of
salts 4f—l in dilute mineral or organic acids in subsequent
studies.
Unlike the reactions of anthranilamides3 giving rise to
derivatives of annelated 1,2,3ꢀtriazinꢀ4ꢀones, diazotizaꢀ
tion of aminoazoles containing the carbamoyl substituent
in the ortho position with the respect to the amino group
afforded the corresponding diazoazoles in the solid state.4
In solutions, the resulting diazonium salts often lose the
proton5 and, hence, special conditions are required for
the preparation of these compounds.6,7 In addition, it is
known that in aprotic media, diazoazoles, like aliphatic
diazo derivatives, are involved in cycloaddition reactions,
whereas diazonium salts of azoles react analogously to
aromatic diazonium salts.8 Nitrosoamines differ from both
diazo compounds and diazonium salts in reactivity.9
1,2,3ꢀTriazinꢀ4ꢀone derivatives are not subjected to the
aboveꢀmentioned transformations.3
To study the behavior of imidazoles bearing the diazo
function in reactions typical of this class of compounds, it
is essential to prepare individual diazoimidazoles and
imidazolyldiazonium salts and examine the conditions of
their interconversions and cyclization giving rise to
imidazotriazinones.
The introduction of the aryl or cycloalkyl substituents
into the amide group of 5ꢀdiazoimidazoleꢀ4ꢀcarboxamide
opens up considerable possibilities of solving this problem.
In the present study, we synthesized new 4ꢀ(Nꢀalkyl)ꢀ and
4ꢀ(Nꢀaryl)ꢀ5ꢀdiazoimidazoleꢀ4ꢀcarboxamides and the
corresponding diazonium salts in individual form and inꢀ
vestigated the physicochemical properties of 2ꢀ and
5ꢀdiazoimidazoles.
The addition of BF3 etherate to a suspension of diazo
compound 2a in diethyl ether also afforded a solution.
However, according to the results of IR spectroscopy, the
solid residue obtained after the removal of the solvent
consisted of Nꢀ(pꢀtolyl)azahypoxanthine (3a) and diazoꢀ
nium salt 4a.
The structures of individual diazoimidazoles 2a—h and
1
diazonium salts 4a—e were studied by H NMR and IR
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1516—1521, July, 2003.
1066ꢀ5285/03/5207ꢀ1600 $25.00 © 2003 Plenum Publishing Corporation

Synthesis of 5ꢀdiazoimidazoles and their salts
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1601
Scheme 1
1, 2, 4: R1 = CONHTolꢀp (a), CONHTolꢀo (b), CONHC6H4OMeꢀp (c), CONHC6H4Clꢀp (d), CONHC6H4CO2Etꢀp (e), CONHC6H11ꢀcyclo (f),
morpholinocarbonyl (g), piperidinocarbonyl (h), CONHMe (i), CONH2 (j), CO2Et (k), NO2 (l)
3: R2 = Tolꢀp (a), Tolꢀo (b), C6H4OMeꢀp (c), C6H4Clꢀp (d), C6H4CO2Etꢀp (e), C6H11ꢀcyclo (f), Me (i), H (j)
spectroscopy. The IR spectra of compounds 2a—h (in
tion into diazonium salt 4l (see Table 1). In the 1H NMR
spectrum in D2SO4 (Me4N+I– as the standard), the signal
for the proton is shifted downfield, which is indicative of
the transformation of compound 2l into diazonium salt 4l.
The value of the shift δ given in Table 1 takes into account
the chemical shift of Me4N+I– with respect to Me4Si.
Earlier,11,12 our studies of acidꢀbase transformations
in the series of diazoimidazoles demonstrated that prodꢀ
ucts of the prototropic equilibrium between diazonium
salts 4j,k,l and diazo compounds 2j,k,l were produced
along with 4ꢀsubstituted 5ꢀnitrosoaminoimidazoles. In the
present study, we investigated the equilibrium between
diazoimidazoles 2 and the corresponding diazonium
salts 4, which were synthesized for the first time, by UV
spectroscopy.
KBr pellets) have a narrow intense stretching absorption
band of the diazo group in the region of 2160—2180 cm–1
.
In the spectra of compounds 4a—e and salts 4i—k, the
stretching absorption band of the diazonium function is
shifted to 2265—2280 cm–1 (KBr) and 2235—2265 cm–1
1
(H2SO4), respectively. The H NMR spectra of diazoꢀ
imidazoles 2a—h have a singlet for the proton at the C(2)
atom of the imidazole ring and signals characteristic of
either aromatic protons or protons of the cycloalkyl fragꢀ
ment in the carboxamide substituent. In addition, the
spectra of these compounds differ from those of salts 4a—e
(see Table 1) in that they do not show the signal for the
proton at δ 13—14 corresponding to the NH group of the
imidazole ring.
The 1H NMR spectra (DMSOꢀd6 and CF3COOD) of
diazoimidazoles 2 were compared with those of the correꢀ
sponding diazonium salts 4 (see Table 1). In the spectra of
the latter compounds, the signal for the proton bound to
the second carbon atom of the imidazole ring is shifted
downfield (δ 8.26—8.62) compared to that in the spectra
of diazo compounds 2 (δ 7.61—7.74). This provides eviꢀ
dence that the electron density in heteroaromatic comꢀ
pounds is decreased, which is, apparently, responsible for
an increase in the electrophilicity of the diazonium group
and, as a consequence, for an increase in its reactivity.
Under the conditions of 1H NMR spectroscopic exꢀ
periments in CF3COOD, diazo compounds 2i—k were
transformed into diazonium salts 4i—k. The NMR specꢀ
tra of compounds 2i,j in CF3COOD have also signals for
the protons corresponding to the imidazotriazinone strucꢀ
ture 3i,j, i.e., intramolecular cyclization proceeds rather
rapidly under these conditions. Dissolution of nitrodiazoꢀ
imidazole 2l in CF3COOD did not lead to its transformaꢀ
Analysis of the UV spectra of diazo compounds 2g,h,
which cannot undergo intramolecular cyclization, in chloꢀ
roform, water, and 5—50% aqueous solutions of HBF4
demonstrated that an increase in the concentration of the
acid led to the shift of the absorption maximum from
320—326 to 295—296 nm, which is indicative of the forꢀ
mation of diazonium salts 4g,h. This is evidence in favor
of the occurrence of the acidꢀbase equilibrium between
the diazonium salts and diazo compounds. A change in
pH of the solution can completely shift the equilibrium to
either diazo compounds or diazonium salts. However,
spectrophotometric study demonstrated that the group of
spectral curves does not pass through an isobestic point,
as in the case of compounds 2i—l.11,12 Consequently, the
equilibrium mixture under study contained not only
diazoimidazoles 2g,h and the corresponding diazonium
salts 4g,h but also nitrosoamines as third components.
Diazo compounds 2a—d in MeCN absorb at
330—338 nm, whereas the absorption maximum in the

1602
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
Sadchikova and Mokrushin
Table 1. Spectroscopic characteristics of compounds 2—4
Comꢀ
pound
IR, ν/cm–1
1H NMR (DMSOꢀd6, δ, J/Hz)
+
NH
N2 or
C=O
BF4
C=N
=N+=N–
2a
2b
3290
3330
2170
1670
1665
—
—
—
—
10.46 (br.s, 1 Н, NH); 7.74 (d, 2 Н, Ar, J = 8.2); 7.72 (s, 1 Н, Im);
7.16 (d, 2 Н, Ar, J = 8.2); 2.28 (s, 3 Н, Me)
10.54 (s, 1 Н, NH); 7.71 (s, 1 Н, Im); 7.65—7.23 (m, 4 Н, Ar);
2.18 (s, 3 Н, Me)
2170
2c
2d
3330
3275
2160
2175
1660
1670
—
—
—
—
10.82 (br.s, 1 Н, NH); 7.90 (d, 2 Н, Ar, J = 8.8); 7.74 (s, 1 Н, Im);
7.42 (d, 2 Н, Ar, J = 8.8)
2f
—
2170
1650
—
—
8.49 (m, 1 H, NHC6H11); 7.64 (s, 1 Н, Im); 3.74 (m, 1 Н, NHC6H11);
1.91—1.30 (m, 10 Н, NHC6H11)
2g
2h
—
—
2180
2170
1620
1630
—
—
—
—
7.64 (s, 1 Н, Im); 4.37 (m, 2 H, СH2); 3.65 (m, 6 H, 3 СH2)
7.61 (s, 1 Н, Im); 4.27 and 3.60 (both m, 2 H each, СH2);
1.56 (m, 6 H, 3 СH2)
2i
2j
2k
3320
3350, 3290
—
2170
2180
2190
1650
1695
1720
—
—
—
—
—
—
8.63 (m, 1 H, NHMe); 7.62 (s, 1 Н, Im); 2.77 (d, 3 Н, NHCH3, J = 4.9)
8.01 and 7.83 (both br.s, 1 H each, NH2); 7.61 (s, 1 Н, Im)
7.69 (s, 1 Н, Im); 4.36 (q, 2 Н, ОСН2Me, J = 7.0);
1.33 (t, 3 Н, ОСН2СН3, J = 7.0)
2l
3a
—
3440
2220
—
1540, 1360 (NO2) —
7.72 (s, 1 Н, Im)
1700
1705
1715
1710
—
—
—
—
—
1620, 14.33 (br.s, 1 Н, NH); 8.40 (s, 1 H, Im); 7.42 and 7.35 (both d, 2 H each,
1590 Ar, J = 8.0); 2.45 (s, 3 Н, Me)
1600, 14.38 (br.s, 1 Н, NH); 8.45 (s, 1 H, Im); 7.48—7.32 (m, 4 Н, Ar);
1590 2.11 (s, 3 Н, Me)
1620, 14.23 (br.s, 1 Н, NH); 8.39 (s, 1 H, Im); 7.45 and 7.06 (both d, 2 H each,
1595 Ar, J = 8.8); 3.86 (s, 3 Н, OMe)
1605, 14.22 (br.s, 1 Н, NH); 8.43 (s, 1 H, Im); 7.61 and 7.57 (both d, 2 H each,
1595 Ar, J = 9.3)
1610, 14.20 (br.s, 1 Н, NH); 8.44 (s, 1 H, Im); 8.15 and 7.74 (both d, 2 H each,
3b
3c
3d
3e
3420
3470
3460
3410
—
—
—
—
1700,
1680
1595
Ar, J = 8.5); 4.38 (q, 2 Н, ОСН2СН3, J = 7.0); 1.40 (t, 3 Н,
ОСН2СН3, J = 7.0)
3f
3i
3j
3390
3425
3420
—
—
—
1630
1710
1690
1670
1670
1660
1670
—
1600, 13.57 (br.s, 1 Н, NH); 8.53 (s, 1 H, Im); 3.74 (m, 1 Н, СH);
1590 1.88—1.10 (m, 10 H, 5 СH2)
1600, 12.56 (br.s, 1 H, NH); 8.49 (s, 1H, Im); 3.97 (s, 3 Н, Me)
1590 9.53 (s, 1 H, Im); 4.38 (s, 3 Н, Me)*
1605, 14.81 (br.s, 2 H, 2 NH); 8.49 (s, 1 H, Im)
—
—
1600
—
9.49 (s, 1 H, Im)*
4a 3510, 3470, 2265
1080
1075
1070
1080
1080
13.37 (br.s, 1 Н, NH); 10.56 (s, 1 Н, NH); 8.59 (s, 1 Н, Im);
7.47 and 7.39 (both d, 2 H each, Ar, J = 8.2); 2.42 (s, 3 Н, Me)
13.38 (br.s, 1 Н, NH); 10.61 (s, 1 Н, NH); 8.62 (s, 1 Н, Im);
7.58—7.43 (m, 4 Н, Ar); 2.23 (s, 3 Н, Me)
13.87 (br.s, 1 Н, NH); 10.55 (s, 1 Н, NH); 8.59 (s, 1 Н, Im);
7.51 and 7.12 (both d, 2 H each, Ar, J = 8.8); 3.85 (s, 3 Н, ОMe)
14.03 (br.s, 1 Н, NH); 9.71 (s, 1 Н, NH); 8.57 (s, 1 Н, Im);
7.64 and 7.31 (both d, 2 H each, Ar, J = 8.8)
14.21 (br.s, 1 Н, NH); 10.31 (s, 1 Н, NH); 8.59 (s, 1 Н, Im);
8.16 and 7.80 (both d, 2 H each, Ar, J = 8.2); 4.38 (q, 2 Н,
ОСН2Me, J = 7.0); 1.37 (t, 3 Н, ОСН2СН3, J = 7.0)
8.30 (s, 1 Н, Im); 4.12 and 4.06 (both m, 4 H each, СH2)*
8.29 (s, 1 Н, Im); 3.20 (s, 3 Н, Me)*
3310
4b 3500, 3450, 2260
—
—
—
—
3300
4c 3380, 3260, 2255
3200
4d 3470, 3350, 2280
3330
4e 3470, 3350, 2270
3330
1680,
1660
4g
4i
4j
4k
3440
3450
2235
2240
2265
1650
1705
—
—
1070
—
—
—
8.30 (s, 1 Н, Im)*
8.26 (s, 1 Н, Im); 4.70 (q, 2 Н, ОСН2Me, J = 7.0);
1.53 (t, 3 Н, ОСН2СН3, J = 7.0)*
4l
—
—
7.99 (s, 1 Н, Im)* or 8.43 (s, 1 Н, Im)**
* In CF3COOD.
** In D2SO4.

Synthesis of 5ꢀdiazoimidazoles and their salts
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1603
spectra in concentrated HBF4 is shifted to 293—296 nm,
which corresponds to the absorption maximum in the
spectra of crystalline diazonium salts 4a—d in MeCN.
Therefore, the diazo compounds in concentrated acids
are transformed into the corresponding diazonium salts.
However, we failed to carry out the reverse transformaꢀ
tion of diazonium salts 4a—e, which readily undergo cyꢀ
clization to azahypoxanthine derivatives 3a—e, into the
corresponding diazo compounds 2a—e by gradually deꢀ
creasing the concentration of the acid in a UV cell. The
reason is that the presence of water even in insignificant
amounts leads to the rapid transformation of the diazoꢀ
nium salts into the diazo compounds followed by the
transformation into the imidazotriazinone ring. Thus, the
IR spectrum of salt 4a washed with a minimum amount of
water shows an absorption band at 2265 cm–1 along with a
more intense band at 2170 cm–1 corresponding to diazo
compound 2a, whereas these diazonium salts in an
equimolar mixture of water and 4ꢀ(arylcarbamoyl)imidꢀ
azoleꢀ5ꢀdiazonium tetrafluoroborates 4a—e are very rapꢀ
idly transformed into 3ꢀarylimidazotriazinꢀ4ꢀones 3a—e.
It should be noted that solid 5ꢀimidazolyldiazonium
salts 4a—e and diazo compounds 2a—e are also very unꢀ
stable on storage in the dark at room temperature. After
one month, they undergo cyclization to imidazotriꢀ
azinones in quantitative yields. In the IR spectra of the
diazonium salts and diazo compounds recorded within
14 days after their preparation, the intensities of the
stretching absorption bands of the diazonium and diazo
groups decreased and a new absorption band appeared at
1700—1715 cm–1, which corresponds to the C=O bond
of the triazinone structure. After one month, the absorpꢀ
tion bands of the diazonium or diazo group as well as of
the amide carbonyl group at 1660—1680 cm–1 completely
disappeared.
νNN = 2290 cm–1) rather than 2ꢀdiazoimidazoleꢀ4,5ꢀ
dicarbonitrile (2m; νNN = 2250 cm–1), as has been reꢀ
ported earlier.13 Recrystallization of salt 4m from dry
acetonitrile or its storage in the solid state in the dark at
room temperature for 2—3 days gave diazo compound 2m
(Scheme 2). In our opinion, this transformation accounts
for some differences in the reactivity, which have been
observed earlier by other research groups.14,15
To summarize, under the conditions used for diazotiꢀ
zation, the diazonium salts and diazo compounds were
isolated in individual form.
Experimental
Spectroscopic studies were carried out with the use of anaꢀ
lytically and chromatographically pure samples. The IR spectra
were recorded on a Specord IRꢀ75 instrument (in KBr pelꢀ
lets and CaF2 cells). The UV spectra were measured on a
Beckmanꢀ26 spectrophotometer. The 1H NMR spectra were
recorded on a Brucker WRꢀ250 instrument (250 MHz) (δ scale,
Me4Si as the internal standard). The course of the reactions and
purities of the compounds were monitored by TLC on Silufol
UVꢀ254 and Sorbifil UVꢀ254 plates (silica gel CTХꢀ1A as
the sorbent) in the BunOH—AcOH—H2O (4 : 1 : 1) and
CHCl3—EtOH (3 : 1 and 10 : 1) solvent systems.
The results of elemental analysis of the compounds for C, H,
N, and Cl are consistent with the calculated data. The melting
points (Table 2) were not corrected. The spectroscopic characꢀ
teristics of the compounds are given in Table 1.
The starting 5ꢀaminoimidazoleꢀ4ꢀcarboxamide16 (1j),
5ꢀaminoimidazoleꢀ4ꢀ(Nꢀmethyl)carboxamide17,18
5ꢀaminoimidazoleꢀ4ꢀ(Nꢀaryl)carboxamides19
(1i),
1a—e,
5ꢀaminoimidazoleꢀ4ꢀ(Nꢀcycloalkyl)carboxamides19 1f—h,
5ꢀaminoꢀ4ꢀnitroimidazole20 (1l), and ethyl 5ꢀaminoimidazoleꢀ
4ꢀcarboxylate21 (1k) were synthesized according to procedures
described earlier. 2ꢀAminoꢀ4,5ꢀdicyanoimidazole (1m) was comꢀ
mercially available.
Unexpectedly, elemental analysis and IR spectroscopy
demonstrated that diazotization of 2ꢀaminoimidazoleꢀ4,5ꢀ
dicarbonitrile (1m) with sodium nitrite in dilute HCl
afforded 4,5ꢀdicyanoimidazoleꢀ2ꢀdiazonium salt (4m;
5ꢀDiazoimidazoleꢀ4ꢀ[Nꢀ(pꢀtolyl)]carboxamide (2a), 5ꢀdiꢀ
azoimidazoleꢀ4ꢀ[Nꢀ(oꢀtolyl)]carboxamide (2b), 5ꢀdiazoimidazoleꢀ
4ꢀ[Nꢀ(pꢀmethoxyphenyl)]carboxamide (2c), and 4ꢀ[Nꢀ(pꢀchloroꢀ
phenyl)]ꢀ5ꢀdiazoimidazolecarboxamide (2d) (general procedure).
A cooled solution of NaNO2 (0.08 g, 1.2 mmol) in water (2 mL)
was added portionwise with vigorous stirring to a suspension
of 5ꢀaminoimidazoleꢀ4ꢀ(Nꢀaryl)carboxamide hydrochloride
1a—d (1 mmol) in 1 N HCl (6 mL, 2 mmol) at 0 °C. The
reaction mixture was stirred at this temperature for 5—10 min.
The precipitate that formed was filtered off, washed with Et2O,
and dried in vacuo.
Scheme 2
5ꢀDiazoimidazoleꢀ4ꢀ[Nꢀ(pꢀethoxycarbonylphenyl)]carboxꢀ
amide (2e). Ethyl nitrite (0.4 mL, 4.8 mmol) was added to a
mixture of 5ꢀaminoimidazoleꢀ4ꢀ[Nꢀ(pꢀethoxycarbonylpheꢀ
nyl)]carboxamide (1e) (1 g, 3.2 mmol) and dry dioxane (50 mL)
saturated with HCl and cooled to 0 °C. The reaction mixture
was stirred with cooling for 2 h. The precipitate that formed was
filtered off. The filtrate was concentrated in vacuo. The residue
was suspended in Et2O (5 mL), filtered off, and dried in vacuo.
4ꢀ(NꢀCyclohexyl)ꢀ5ꢀdiazoimidazolecarboxamide
(2f).
A cooled solution of NaNO2 (0.34 g, 4.9 mmol) in water (3 mL)
was added portionwise with vigorous stirring to a solution of

1604
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
Sadchikova and Mokrushin
Table 2. Yields, melting points, retention factors, and elemental analysis data for the compounds synthesized
Comꢀ
pound
Yield
(%)
M.p.
/°C
Rf
(eluent)
Found
Calculated
Molecular
formula
(%)
C
H
N
Cl
—
2a
2b
2c
2d
2e
2f
89
80
84
75
17
77
82
81
85—86
94—95
0.71 (a)
0.66 (a)
0.70 (a)
0.68 (a)
0.57 (a)
0.80 (a)
0.59 (a)
0.62 (a)
0.56 (b)
0.47 (a)
0.43 (a)
0.63 (b)
0.70 (b)
0.46 (b)
0.55 (c)
0.78 (c)
0.82 (c)
0.64 (c)
0.75 (c)
0.82 (a)
57.88
58.15
57.95
58.15
54.04
54.32
48.12
48.50
54.62
54.74
54.51
54.78
46.17
46.38
52.76
52.68
58.11
58.15
58.03
58.15
54.24
54.32
48.62
48.50
54.65
54.74
54.85
54.78
41.48
41.94
41.54
41.94
39.58
39.91
35.35
35.81
41.54
41.85
33.35
33.26
4.32
3.99
4.36
3.99
3.94
3.73
2.67
2.44
3.94
3.89
6.35
5.98
4.42
4.38
5.42
5.40
4.02
3.99
4.07
3.99
3.76
3.73
2.51
2.44
3.93
3.89
6.03
5.98
3.02
3.20
3.11
3.20
3.33
3.04
2.44
2.10
3.37
3.24
0.58
0.56
30.34
30.82
30.51
30.82
28.47
28.79
27.94
28.28
24.67
24.55
31.72
31.94
33.73
33.80
34.05
34.13
30.88
30.82
30.67
30.82
28.92
28.79
28.14
28.28
24.61
24.55
32.02
31.94
22.00
22.23
21.93
22.23
20.77
21.16
20.51
20.88
18.30
18.77
46.23
46.55
C11H9N5O
—
—
C11H9N5O
97—99
C11H9N5O2
140—142
67—69
14.53
14.32
—
C10H6ClN5O
C13H11N5O3
C10H13N5O
76—77
—
—
—
—
—
—
2g
2h
3a
3b
3c
3d
3e
3f
64—65
C8H9N5O2
55—56
C9H11N5O
83 (A)
87 (B)
88 (A)
80 (B)
79 (A)
82 (B)
84 (A)
80 (B)
79 (A)
75 (B)
71
213—215
207—209
201—205
219—221
218—220
187—189
77—79
C11H9N5O
C11H9N5O
C11H9N5O2
14.53
14.32
—
C10H6ClN5O
C13H11N5O3
C10H13N5O
—
—
—
—
4a
4b
4c
4d
4e
4m
98
92
91
89
91
96
C11H10N5O•BF4
C11H10N5O•BF4
C11H10N5O2•BF4
C10H7СlN5O•BF4
C13H12N5O3•BF4
C5HN6Cl
94—96
128—130
65—66
10.12
10.57
—
60—61
148—150
19.47
19.64
* The following solvent systems were used: a, CHCl3—EtOH (3 : 1); b, CHCl3—EtOH (10 : 1); c, BunOH—AcOH—H2O
(4 : 1 : 1).
5ꢀaminoimidazoleꢀ4ꢀ(Nꢀcyclohexyl)carboxamide hydrochloride
(1f) (1 g, 4.1 mmol) in 1 N HCl (23 mL, 8.2 mmol) at 0 °C. The
reaction mixture was stirred at this temperature for 15—20 min
and then extracted with chloroform. The extract was concenꢀ
trated in vacuo and the oily residue was triturated with tertꢀbutyl
methyl ether to form a brightꢀyellow precipitate.
5ꢀDiazoimidazoleꢀ4ꢀcarboxylic acid morpholide (2g) and
5ꢀdiazoimidazoleꢀ4ꢀcarboxylic acid piperidide (2h) (general proꢀ
cedure). A cooled solution of NaNO2 (0.36 g, 5.2 mmol) in
water (3 mL) was added portionwise with vigorous stirring to a
solution of amine 1g,h (1 g, 4.3 mmol) in 1 N HCl (24 mL,
8.6 mmol) at 0 °C. The reaction mixture was stirred at this
temperature for 15—20 min. The yellow precipitate that formed
was filtered off, washed with Et2O, and dried in vacuo. An addiꢀ
tional amount of the diazo compound was extracted from an
acidic filtrate in CHCl3 and the extract was concentrated
in vacuo.
3ꢀ(pꢀTolyl)ꢀ3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ1,2,3ꢀtriazinꢀ4ꢀone
(3a), 3ꢀ(oꢀtolyl)ꢀ3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ1,2,3ꢀtriazinꢀ4ꢀone
(3b), 3ꢀ(pꢀmethoxyphenyl)ꢀ3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ1,2,3ꢀ

Synthesis of 5ꢀdiazoimidazoles and their salts
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1605
triazinꢀ4ꢀone (3c), and 3ꢀ(pꢀchlorophenyl)ꢀ3,7ꢀdihydroimidꢀ
azo[4,5ꢀd]ꢀ1,2,3ꢀtriazinꢀ4ꢀone (3d) (general procedure). 4ꢀArylꢀ
carbamoylimidazoleꢀ5ꢀdiazonium tetrafluoroborate (4a—d,
method A) or 5ꢀdiazoimidazoleꢀ4ꢀ(Nꢀaryl)carboxamide (2a—d,
method B) (1 g) was suspended in water (15 mL). The reaction
mixture was kept at 30 min. The precipitate that formed was
filtered off, crystallized from EtOH, and dried.
3ꢀ(pꢀEthoxycarbonylphenyl)ꢀ3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ
1,2,3ꢀtriazinꢀ4ꢀone (3e). A. 4ꢀ(pꢀEthoxycarbonylphenyl)carbꢀ
amoylimidazoleꢀ5ꢀdiazonium tetrafluoroborate (4e) (1 g,
2.68 mmol) was suspended in water (15 mL). The reaction mixꢀ
ture was kept for 30 min. The precipitate that formed was filꢀ
tered off, crystallized from EtOH, and dried.
B. A cooled solution of NaNO2 (0.27 g, 3.9 mmol) in water
(3 mL) was added portionwise with vigorous stirring to a suspenꢀ
sion of 5ꢀaminoimidazoleꢀ4ꢀ[Nꢀ(pꢀethoxycarbonylphenyl)]carbꢀ
oxamide hydrochloride (1e) (1 g, 3.2 mmol) in 1 N HCl (18 mL,
6.4 mmol) at 0 °C. The reaction mixture was kept for 5 min, The
precipitate that formed was filtered off, crystallized from EtOH,
and dried in vacuo.
3ꢀCyclohexylꢀ3,7ꢀdihydroimidazo[4,5ꢀd]ꢀ1,2,3ꢀtriazinꢀ4ꢀone
(3f). 5ꢀDiazoimidazoleꢀ4ꢀ(Nꢀcyclohexyl)carboxamide (2f) (1 g,
4.6 mmol) was suspended in a 1 N NH3 solution (5 mL). The
reaction mixture was kept for 1 h and then the solution was
cleared with activated carbon. The precipitate that formed was
filtered off and the filtrate was concentrated in vacuo. The resiꢀ
due was crystallized from EtOH and dried.
2. E. S. Newlands, M. F. G. Stevens, S. Wedge, R. T.
Wheelhouse, and C. Brock, Cancer Treatment Rev.,
1997, 23, 35.
3. H. Neunhoeffer, Chem. Heterocycl. Compd., 1978, 33, 3.
4. R. N. Butler, Chem. Rev., 1975, 75, 241.
5. M. Tishler and B. Stanovnik, Khim. Geterotsikl. Soedin.,
1980, 579 [Chem. Heterocycl. Compd., 1980, 16 (Engl.
Transl.)].
6. K. L. Kirk and L. A. Cohen, J. Am. Chem. Soc., 1973,
95, 4619.
7. G. U. Baig, M. F. G. Stevens, R. Stone, and E. Lunt,
J. Chem. Soc., Perkin Trans. 1, 1982, 8, 1811.
8. G. Cirrincione, A. M. Almerico, E. Aiello, and G. Dattolo,
Adv. Heterocycl. Chem., 1990, 48, 65.
9. H. Gehlen and J. Dost, Ann., 1963, 665, 144.
10. Y. F. Shealy, R. F. Struck, L. B. Holum, and J. A.
Montgomery, J. Org. Chem., 1961, 26, 2396.
11. V. S. Mokrushin, I. S. Selezneva, T. A. Pospelova, and V. K.
Usova, Khim. Geterotsikl. Soedin., 1997, 1245 [Chem.
Heterocycl. Compd., 1997, 33, 1086 (Engl. Transl.)].
12. E. V. Sadchikova, V. S. Mokrushin, T. A. Pospelova, and
I. S. Selezneva, Khim. Geterotsikl. Soedin., 1999, 199 [Chem.
Heterocycl. Compd., 1999, 35, 176 (Engl. Transl.)].
13. W. A. Sheppard and O. W. Webster, J. Am. Chem. Soc., 1973,
95, 2695.
14. A. Padwa and M. Tohidi, J. Chem. Soc., Chem. Commun.,
1984, 295.
4ꢀ[Nꢀ(pꢀTolyl)carbamoyl]imidazoleꢀ5ꢀdiazonium
4ꢀ[Nꢀ(oꢀtolyl)carbamoyl]imidazoleꢀ5ꢀdiazonium
(4a),
(4b),
15. M. Cabré, J. Farrás, J. F. Sanz, and J. Vilarrasa, J. Chem.
Soc., Perkin Trans. 2, 1990, 11, 1943.
4ꢀ[Nꢀ(pꢀmethoxyphenyl)carbamoyl]imidazoleꢀ5ꢀdiazonium (4c),
4ꢀ[Nꢀ(pꢀchlorophenyl)carbamoyl]imidazoleꢀ5ꢀdiazonium (4d),
and 4ꢀ[Nꢀ(pꢀethoxycarbonylphenyl)carbamoyl]imidazoleꢀ5ꢀdiazoꢀ
nium (4e) tetrafluoroborates (general procedure). Crystalline
NaNO2 (2.4 mmol) was added with stirring to a suspension of
5ꢀaminoimidazoleꢀ4ꢀ(Nꢀaryl)carboxamide hydrochloride 1a—e
(1 mmol) in 50% HBF4 (ρ = 1.41 g cm–3) (5 mL) at –5 °C. The
reaction mixture was kept for 3—5 min. The precipitate that
formed was filtered off and dried in vacuo.
16. E. Shaw and D. W. Woolley, J. Biol. Chem., 1949, 181, 89.
17. V. S. Mokrushin, V. I. Ofitserov, T. V. Rapakova,
A. G. Tsaur, and Z. V. Pushkareva, Khim. Geterotsikl. Soedin.,
1976, 556 [Chem. Heterocycl. Compd., 1976, 12 (Engl.
Transl.)].
18. V. S. Mokrushin, V. I. Nifontov, Z. V. Pushkareva, and V. I.
Ofitserov, Khim. Geterotsikl. Soedin., 1971, 1421 [Chem.
Heterocycl. Compd., 1971, 7 (Engl. Transl.)].
19. E. V. Sadchikova, O. V. Gul´kova, M. A. Bezmaternykh,
and V. S. Mokrushin, in Dostizheniya v organicheskom sinteze
[Advances in Organic Synthesis], UrO RAN, Ekaterinburg,
2003, 144 (in Russian).
20. V. S. Mokrushin, N. A. Belyaev, M. Yu. Kolobov, and A. N.
Fedotov, Khim. Geterotsikl. Soedin., 1983, 808 [Chem.
Heterocycl. Compd., 1983, 19 (Engl. Transl.)].
21. B. Robinson and D. M. Sheperd, J. Pharm. Pharmacol.,
1962, 14, 9.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
96433a) and the US Civilian Research and Development
Foundation (Grants RC1ꢀ2393ꢀEKꢀ02 and REC 005).
References
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M. Zanini, L. Devizzi, F. Soncini, and P. Valagussa, J. Clin.
Oncol., 1996, 14, 1421.
Received December 25, 2002;
in revised form April 3, 2003