Study of cyclyzation of o-(1-Alkynyl)- and o-(1,3-Butadiynyl)aryltriazenes under the action of acids

Article abstract of DOI:10.1134/S1070428012110048

The investigation of Richter cyclization of o-(1-alkynyl)- and o-(1,3-butadiynyl)arenediazonium salts generated by acid cleavage of triazenes was carried out by the methods of NMR and ESI MS (Electrospray Ionization Mass Spectrometry). The effect was show

Full text of DOI:10.1134/S1070428012110048

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 11, pp. 1424−1434. © Pleiades Publishing, Ltd., 2012.
Original English Text © N.A. Danilkina, E.G. Gorbunova, V.N. Sorokoumov, I.A. Balova, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48,
No. 11, pp. 1428−1439.
Study of Cyclyzation of o-(1-Alkynyl)-
and o-(1,3-Butadiynyl)aryltriazenes
under the Action of Acids
N. A. Danilkina, E. G. Gorbunova, V. N. Sorokoumov, and I. A. Balova
St. Petersburg State University, St. Petersburg, 198504 Russia
e-mail: balova.irina@chem.spbu.ru
Received June 14, 2012
Abstract—The investigation of Richter cyclization of o-(1-alkynyl)- and o-(1,3-butadiynyl)arenediazonium
salts generated by acid cleavage of triazenes was carried out by the methods of NMR and ESI MS (Electrospray
Ionization Mass Spectrometry). The effect was shown of the substituents at the carbon atom of the triple bond and
in the aromatic ring, of the solvent, temperature, and the reagents ratio on the rate of the cyclization and the yield of
its products, 4-bromo-3-alkyl- and 4-bromo-3-ethynylcinnolines; the conditions of their synthesis were optimized.
The possibility to use 4-bromo-3-ethynylcinnolines as substrates of electrophilic cyclization was demonstrated.
DOI: 10.1134/S1070428012110048
In the last decade the chemistry of cinnoline and its
derivatives has been essentially developed since these
compounds possess diverse kinds of biological activity
[1–7] and interesting optoelectronic characteristics [8, 9].
Among the methods of the synthesis of these compounds
the main procedures should be mentioned applying as pre-
cursors the derivatives of arenediazonium salts (Richter,
Widman–Stoermer, and Borsche–Herbert cyclizations),
arylhydrazones and arylhydrazines, and nitro derivatives
were also used for the synthesis of polyfused cinnolines
by reductive methods [10–12].
amines [13, 14] Bräse et al. for the first time obtained
4-bromo-(chloro)cinnolines by the cyclization of ortho-
ethynylarylaryltriaz-1-enes under the acid cleavage [18].
Depending on the structure of the starting substrates
and the reaction conditions in both cases the process
may occur by the endo-dig type with the formation of
4-halocinnolines and the side products of their hydrolysis,
cinnolin-4-ones [14, 18, 19], as well as by the exo-dig
type leading to indazoles [19–23].
Based on the cyclization of o-buta-1,3-diynylaryl-
triazenes under the action of HBr and HCl we formerly
developed an approach to the synthesis of 4-bromo-
(chloro)-3-ethynylcinnolines [24]. This approach is more
advantageous than the diazotization of the diacetylene
derivatives of arylamines [25, 26] for it makes it possible
to avoid the side processes and provides better yields of
the target products. However it was found that the cy-
clization rate of the o-buta-1,3-diynylaryltriazenes was
affected by the concentration of the acid and the character
of the substitutents in the aromatic ring. In the presence
of the acceptor methoxycarbonyl substituent the side hy-
drolysis products were formed, and the yield of the target
3-alkynyl-4-bromocinnoline did not exceed 41% [26].
Although the synthesis of the cinnoline core was first
performed by the diazotization of o-aminophenylpro-
pionic acid followed by the cyclization of the obtained
salt [13] only to the end of the previous century the at-
tention of researchers was turned to Richter reaction as
the method of the synthesis of 4-halocinnolines [14].
Owing to the reactivity of the halogen atom in the nu-
cleophilic substitution these compounds are convenient
building blocks for the preparation of biologically active
substances [15, 16], in particular, cinnoline 4-amino
derivatives and their salts [17]. Also the development of
the Pd-catalyzed cross-coupling made accessible starting
ortho-ethynyl-substituted arenediazonium salts contain-
ing in the aromatic ring substituents of versatile character.
Since as the 4-bromo-3-ethynylcinnolines are of inter-
est as building-blocks for the preparation of polyfused
heterocycles and endiyne systems [24, 27] we have
Along with the classic diazotization of o-ethynylaryl-
1424

STUDY OF CYCLYZATION
1425
investigated in this work the effect of the reaction condi-
tions and the triazene structure on the course of Richter
cyclization aiming at the optimization of the synthesis of
4-bromocinnolines.
aromatic ring on the rate of triazene I cyclization with the
use of 1H NMR spectroscopy. The cyclization of 0.1 M
solutions of triazenes Ib, Ic in acetone-d6 in the presence
of 20-fold molar excess of 48% HBr was carried out in
the NMR tubes (Scheme 2).
We have chosen as the objects of the study the deriva-
tives of o-(ethynyl)- and o-(1,3-butadiynyl)aryltriazenes
Ia–Ii containing diverse substituents both in the aromatic
ring in the para-position to the triazene function and at
the triple bond. These compounds were synthesized by
Sonogashira reaction [28] of 2-iodoaryltriazenes with the
terminal mono- and diacetylenes [29] (Scheme 1).
1
It turned out that in the H NMR spectra of the
mixtures obtained 3 min after the addition of HBr only
the signals of cyclization products 4-bromocinnolines
IIIb, IIIc and of N-ethylaniline were observed. Besides
1
in the H NMR spectrum of the sample of the formed
cinnoline IIIc registered 15 min later signals of its
hydrolysis product, 6-nitrocinnolin-4-one (IVc) were
appeared. The spectrum of this sample obtained after
2 days contained only the signals of cinnolinone IVc.
4-Bromo-6-nitrocinnoline IIIc also easily hydrolyzed at
storage and even under the conditions of the registration
of ESI MS (Electrospray Ionization Mass Spectrometry)
spectra where a strong peak was observed belonging to
the 6-nitrocinnolin-4-one. Thus the presence of a strong
electron-acceptor substituent resulted in the substitution
of bromine in the position 4 of the cinnoline skeleton for
the hydroxy group. The acceleration of the nucleophilic
substitution of halogens in the position 4 of cinnolines in
strong acidic media we found earlier [26].
We first studied the effect of the substituents in the
Scheme 1.
Et
N
N
N
H
(
)
R2
n
I
+
R1
Et
1
Although the H NMR spectroscopy proved to be
N
N
useful for establishing the fast proceeding of Richter
cyclization of monoacetylene triazene derivatives Ib, Ic,
this method possessed significant drawbacks. The pres-
ence of excess HBr not only complicated the assignment
of the signals in the spectra of the reaction mixtures but
also led to the broadening of the signals from the formed
4,6-dibromocinnoline IIIb due to the partial precipitation
of its hydrobromide .
N
R2
Pd(PPh3)4, PPh3, CuI
Et3N
)n
(
R1
Ia_Ii
n = 1, R2 = C4H9, R1= CH3 (a), Br (b), NO2 (c), COOMe
(d); n = 2, R2 = C8H17, R1= CH3 (e), Br (f), COOMe (g);
n = 2, R2 = Ph, R1= Br (h), COOMe (i).
We have decided to use in the monitoring of the reac-
tions ESI MS which now becomes a frequent tool in the
Scheme 2.
Et
Ph
N
N
N
C4H9
O
Br
N
R1
C4H9
O2N
C4H9
HBr
H2O
PhNHEt
+
R1 = NO2
N
N
N
H
R1
Ib, Ic
IIIb, IIIc
R1 = Br (b), NO2 (c).
IVc
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

DANILKINA et al.
1426
Et
Scheme 3.
_R2
Br
N
OMe
)
n 1
R1
(
Br
C4H9
N
N
_
N
R2
N
N
N+ Br
R2
N
N
)
n
)
n
(
(
HBr
_HNEtPh
IIIb, IIIe, IIIg
VIb
R1
IIb, IIe, IIg
R1
C+
R2
R2
)
n
(
)
(
n
Ib, Ie, Ig
R1
R1
IVb, IVe, IVg
Vb, Vg
n =0 (IIb), 1 (IIe, IIg, IIIb, IVb), 2 (IIIe, IIIg, IVe, IVg).
study of mechanisms of organic reactions [30, 31]. The
spectra of triazene solutions after mixing with HBr solu-
tions were registered on-line during continuous spraying
of the reaction mixture. The spectra were registered in 40
s, 3, 6, or 8 min after the addition of the hydrobromic acid
solution. The obtained data are presented in Schemes 3,
4 and in Tables 1, 2.
It was found that in the acetone medium Richter
cyclization of triazene Ie (10–4 mol l−1) with 48% HBr
(10–1 mol l−1) and the subsequent hydrolysis of 4-bromo-
cinnoline IIIe proceeded so fast that already in the first
spectrum of the reaction mixture only the signal with
m/z 297.1958 [M + H]+ was observed corresponding to
the hydrolysis product 6-methyl-3-(1,3-decadiyn-1-yl)
cinnolin-4-one (M + H 297.1967), or to the product
of its further cyclization, furocinnoline [26, 29]. Test
experiments demonstrated that the replacement of ac-
etone by methanol provided the possibility to detect the
intermediate reaction products, therefore all subsequent
experiments were carried out in methanol.
The spectrum of the reaction mixture of triazene Ib
with HBr already after 40 s lacked the peaks correspond-
ing to the protonated form of the starting compound Ib
and only signals belonging to the diazonium cation IIb
and the products of its transformations were observed
(Scheme 3, Table 1).
In the spectrum of diacetylene triazene Ig containing
an electron-withdrawing methoxycarbonyl substituent
(Scheme 3, Table 2) after 40 s the protonated form of the
starting triazene was detected whose peak already in 3 min
disappeared. The reaction mixture like that of the mono-
acetylene triazene Ib after 3 min contained the signals of
Table 2. ESI MS spectra of the reaction mixture of triazene
Ig with HBra
Table 1. Data of ESI MS spectra of the reaction mixture of
triazene Ib with HBra
Time of the spectrum
registration from the
Time of the spectrum
Compound
m/z [M + H]+
registration from the
moment of HBr
addition
moment of HBr
addition
m/z [M + H]+
Compound
Calculated
Found
40 s 3 min 6 min
Calculated
384.1075
Found
40 s 3 min 8 min
Ig
444.2651 444.2641
323.1760 323.1758
403.1021 403.1009
122.0970 122.0978
295.1698 295.1700
297.1855 297.1864
+
–
–
–
–
–
–
+
+
+
+
+
–
+
+
+
+
+
Ib
–
+
+
+
–
–
–
+
+
+
+
+
–
+
+
+
+
+
IIg
IIb
263.0184 263.0195
342.9445 342.9454
122.0970 122.0987
235.0122 235.0130
295.0446 295.0452
IIIg
PhNNEt
IVg
IIIb
PhNHEt
Vb
VIb
Vg
a Concentrations: Ib 10–5 mol l−1, HBr 10–2 mol l−1.
a Concentrations: Ig 10–5 mol l−1, HBr 10–2 mol l−1.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

STUDY OF CYCLYZATION
1427
the diazonium cation and of its transformation products.
transformations. It was also found that the cyclization rate
is affected by the nature of the solvent, and under equal
conditions the conversion of alkynylaryltriazene Ib pro-
ceeded faster than that of alkadiynylaryltriazenes Ie, Ig.
According to the data of mass spectrometry the main
path of the transformation of diazonium cations IIb, IIg
was the cyclization resulting in 4-bromocinnolines IIIb,
IIIg. Besides it was possible to detect by ESI MS the
ions corresponding to aryl cations IVb–IVg formed due
to the reductive deamination of the diazonium cations.
This transformation product Vg appeared in the mass
spectra under the ESI conditions only in the case of the
methoxycarbonyl derivative Ig.
On the second stage of the research we estimated
the effect of substituents at the carbon atom of the triple
bond and in the benzene ring on the cyclization rate of
triazenes using the NMR spectroscopy. The cyclization of
aryltriazenes Ib, Id, If–Ii under the treatment of concn.
HBr was carried out in acetone (Scheme 4). After 3 min
from the beginning of the reaction the water solution
of triethylamine was added. After the treatment of the
reaction mixtures the relative content of products was
determined by 1H NMR spectra. The results obtained are
presented in Scheme 4 and Table 3. The relative content
of compounds I, III, V was estimated by the comparison
of the intensity of signals in the 1H NMR spectra: of the
protons of the aromatic ring H5 (Ib), H3 (Id, If, Ig, Ii), H2
(Vg), of the CH2 group adjacent to the triple bond (Ih),
and of atom H7 of cinnolines III.
The registration of a series of spectra of the reaction
mixture of triazenes Ie, Ig (10–5 mol l−1) with 48% HBr
(10–1 mol l−1) in the presence of an internal reference,
p-toluidine (10–5 mol l−1), for 10 min every ~20 s per-
mitted the establishment of the parallel changes in the
concentrations of the diazonium cation and the aryl cation
indicating that the arenediazonium cation decomposed
with the formation of the aryl cataion mainly directly in
the spray chamber of the spectrometer after the spraying
and desolvation processes.
In the mass spectra of the reaction mixture of the
bromoderivative Ib with HBr also a weak signal was
observed corresponding to 4-methoxycinnoline VIb. The
formation of 4-methoxycinnolines along with 4-chloro-
cinnolines was formerly observed at the diazotization
and cyclization of diacetylene derivatives of arylamines
in methanol saturated with HCl [26]. However in the
spectra of the reaction mixtures of diacetylene deriva-
tives Ie, Ig in methanol we did not find either signals of
4-methoxycinnolines, or 4-cinnolinones, or the products
of cyclization of the latter, furocinnolines.
The cyclization of alkynylaryltriazenes Ib, Id
(Table 3, runs nos. 1, 2) proceeded considerably faster
than that of ortho-(1,3-butadiynyl)aryltriazenes If–Ii
(Table 3, runs nos. 3–6), and after 3 min the reaction
mixtures contained only cinnolines IIIb, IIId. With the
diacetylene derivatives of aryltriazenes the conversion
within 3 min was incomplete, and in the mixtures the
signals appeared of starting compounds I alongside the
signals of cinnolines III. The replacement in the aromatic
ring of the substituent COOMe (Ig, Ii) by the weaker
electron-acceptor bromine atom (If, Ih) resulted in an
insignificant acceleration of the cyclization (cf. runs nos.
3 and 4, 5 and 6). At the same time the replacement of
the alkyl substituent at the conjugated system of triple
bonds in the triazenes If, Ig by the phenyl group in Ih, Ii
Therefore the application of the ESI MS method to the
monitoring of Richter reaction made it possible to detect
the diazonium cations formed at the triazenes decompo-
sition under the action of HBr, and the products of their
Scheme 4.
Et
N
N
Br
R2
n−1
)
R2
R1
(
N
HBr
)
+
n
C8H17
(
N
N
MeOOC
R1
Ib, Id, If_Ii
IIIb, IIId, IIIf_IIIi
Vg
III, n = 1, R2 = C4H9, R1= Br (b), COOMe (d); n = 2, R2 = C8H17, R1= Br (f), COOMe (g); R2 = Ph, R1= Br (h), COOMe (i).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

DANILKINA et al.
1428
Table 4. Richter cyclization of triazene Ib
Table 3. Richter cyclization of o-(1-hexynyl)aryltriazenes Ib,
Id and ortho-(1,3-butadiynyl)aryltriazenes If–Ii at the action
of HBr
Main
Molar
ratio
Reaction reaction
Run
no.
Molar ratio
triazene–acid triazene–
Et4NBr
Acid
time,
product
min (1H NMR
data)
Content of
Concentra-
compounds
tion of
(by the data of
Run Compd.
Molar ratio
I–conc. HBr
compound
I,
mol l−1
1H NMR
a
no.a
no.
1
2
3
4
H2SO4
H2SO4
H2SO4
HCl
1 : 2
3
Ib
spectrum), %
1 : 2
1 : 20
1 : 2
1 : 20
1 : 20
1 : 2
60
15
1.5
IIIb
IIIb
IIIjb
III
I
V
1
2
Ib
Id
Ig
If
0.1
0.1
1 : 20
1 : 20
1 : 20
1 : 20
1 : 20
1 : 20
1 : 20
1 : 10
1 : 40
1 : 20
1 : 20
100
100
32
37
50
59
67
28
24
59
7
–
–
–
–
a
Without addition of Et4NBr. bThe reaction mixture contained only
4-chlorocinnoline IIIj.
3
0.1
68
63
50
41
20
56
71
29
71
–
4
0.1
–
reductive deamination Vg.
5
Ii
0.1
–
The variations in the cyclization rate in the runs
nos. 9–11 may be ascribed to the influence of the solva-
tion effects on the cyclization of the diazonium cations
suggesting that tight ion pairs are involved in the cycli-
zation [26]. The increase in the excess of 48% HBr in
the run no. 9 was accompanied also with the increased
molar fraction of water in the reaction mixture; this fact
same as the use of methanol (run no. 11) might destroy
the tight ion pairs. The dilution of the reaction mixture
with acetone, a polar aprotic solvent, results in reduc-
ing the molar part of water, and this is favorable for the
formation of tight ion pairs and results in the increase in
the reaction rate (run no. 10).
6
Ih
Ig
Ig
Ig
Ig
Ig
0.1
–
7
0.1
13
16
5
8
0.1
9
0.1
10
11
0.005
0.04
12
22
a
Runs nos. 1–10 were carried out in acetone, run no. 11, in a mixture
MeOH–CH2Cl2, 5:1, at 20°C, run no. 7, at 30°C.
resulted in a considerable acceleration of the cyclization
(cf. runs nos. 3 and 5, 4 and 6).
The influence of the acid and its concentration was
investigated in the second set of experiments. The de-
composition of 0.1 m solutions of triazene Ib in acetone
was performed by the action of sulfuric and hydrochlo-
ric acids. After 3 min to the reaction mixture a solution
of tetraethylammonium bromide in aqueous acetone
(acetone–water 20:1 v/v) was added. The completeness
of the reaction was monitored by TLC. On the comple-
tion of cyclization the reaction mixture was diluted with
triethylamine water solution and after the treatment the
1H NMR spectra of mixtures obtained were registered.
The results are listed in Table 4.
The influence on the cyclization rate of the tempera-
ture, molar ratio triazene–HBr, triazene concentration
and the solvent character was studied by an example of
compound Ig (runs nos. 7–11). Raising the temperature
by 10°C resulted in an increased reaction rate and a
greater fraction of the cyclization product IIIg (runs nos.
3, 7), but therewith formed the product of the reductive
deamination Vg. The formation of this side product was
also observed at the 2-fold decrease in the acid excess
up to 10 equiv (run no. 8); therewith the ratio of the
cyclization product IIIg and the starting triazene did not
change as compared with the run no. 3. The increase in
the HBr excess to 40 equiv (run no. 9) in contrast to the
expectations resulted in a considerable deceleration of
the cyclization, and the dilution of the reaction mixture
with acetone (run no. 10) led to the increased rate of the
cyclization (runs nos. 3, 10). The replacement in the run
no. 11 of the aprotic solvent by a protic one (methanol)
significantly decelerated the reaction (runs nos. 3, 11)
and led to the formation of the fraction of the product of
Unlike the reaction with HBr the treatment of 0.1 M
solution of triazene Ib in acetone with 2 equiv of sulfu-
ric acid did not result in the formation of the cyclization
products, and after processing the reaction mixture with
triethylamine the starting triazene was recovered (Table 4,
run no. 1). If after 3 min this reaction mixture was diluted
with the Et4NBr solution the formation of compound IIIb
was observed, and in 1 h the triazene completely con-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

STUDY OF CYCLYZATION
1429
verted into bromocinnoline IIIb (run no. 2). The reaction
rate grew with the increased excess of sulfuric acid (run
no. 3), but still the cyclization proceeded slower than in
HBr (Table 3, run no. 1). At the action on triazene Ib of
2 equiv of HCl with the subsequent addition to the reac-
tion mixture of 2 equiv of tetraethylammonium bromide
(run no. 4) the only cyclization product according to the
NMR and mass spectra was 4-chlorocinnoline IIIj.
cation because of the appearance of the nodal plane and
this would decrease the rate of the allowed electrocyclic
reaction. Besides a strong effect on the cyclization rate
of o-(1-butadiyn-1-yl)triazenes produces the character
of the substituent at the conjugated system of the triple
bonds whereas the cyclization rate is weakly affected by
the properties of the substituents in the aromatic ring.
The data obtained have underlain the optimization of
the procedures for the preparation of 4-bromocinnolines
[18] and 4-bromo-3-ethynylcinnolines [24]. The reduction
of the cyclization time of triazenes Ia–Id to 3 min made it
possible to obtain bromocinnolines IIIa–IIId in 71–82%
yields. The cyclization of the diacetylene derivatives If–Ii
was carried out for 15 min, and 4-bromo-3-ethynylcinno-
lines IIIf–IIIi were isolated in 58–74% yields. Therewith
even in the event of triazene Ig containing the methoxy-
carbonyl substituent no hydrolysis product cinnolin-4-one
nor the furocinnoline was found (Scheme 5).
Thus the data obtained confirm that the cyclization
of o-ethynyl- and o-buta-1,3-diynylaryltriazenes at the
acid treatment proceeds through the stage of formation
of arenediazonium cations whose cyclization into the
cinnolines occurs in the tight ion pair with the counter ion.
The shift of the equilibrium in the first stage is favored by
the increased acid concentration, but at the use of the acid
with an anion of low nucleophilicity the cyclization of the
formed diazonium salt into the cinnoline does not occur.
At introducing into the system of an alien nucleophilic
anion the anion exchange takes place, and the diazonium
cation II is completely converted into bromocinnoline III.
We formerly showed that 4-bromo-3-ethynylcinnolines
could be used for the preparation of thienocinnolines,
pyrrolocinnolines in the tandem reactions of the
nucleophilic substitution-cyclization [24]. The
replacement of the halogen by an ethynyl fragment in
the cross-coupling reactions makes it possible to obtain
endiyne systems fused with the cinnoline framework [27].
The strongest effect on the cyclization rate produces
the character of the substituent at the triple bond involved
in the cyclization. The monoacetylene derivatives
are essentially more reactive in Richter cyclization
than 1,3-butadiynyltriazenes that may indicate the
electrophilic character of the addition which has been
regarded previously as the most probable reaction
mechanism [14], for the conjugated system of two
triple bonds is less reactive toward the electrophiles. Yet
the electrocyclization mechanism of Richter reaction
also cannot be excluded. The concerted mechanism is
consistent with the fact that the replacement of the alkyl
substituent at the triple bond by the ethynyl moiety would
essentially decrease the contribution of the atomic orbitals
of the sp-carbon atom into the HOMO of the diazonium
Theadditionalopportunitiesofthe synthetic application
of 4-bromo-3-ethynylcinnolines in the electrophilic
cyclization previously unknown for cinnolines [32] were
demonstrated by the example of 4-bromocinnoline IIIg
whose reaction with sodium methylsulfide led to the
formation of 4-methylsulfanyl-3-(1-octynyl)cinnoline
(VII). The sybsequent electrophilic cyclization of
compound VII under the action of iodine in acetonitrile
afforded iodothienocinnoline IX (Scheme 6).
Thus the separation of the stages of the nucleophilic
Scheme 5.
Et
Ph
(
N
N
Br
N
R2
n-1
R2
)
R1
(
N
20 equiv. 48% HBr
)
n
20oC, 3_15 min,
_HNEtPh
N
IIIа_IIId, IIIf_IIIi
R1
Iа_Id, If_Ii
III, n = 1, R2 = C4H9, R1= CH3 (a), Br (b), NO2 (c), COOMe (d); n = 1, R2 = C8H17, R1 = Br (f), COOMe (g); R2 = Ph,
R1 = Br (h), COOMe (i).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

DANILKINA et al.
1430
Scheme 6.
C8H17
I
Br
N
R2
R2
R3
)
OMe
n
S
R1
(
)
n
R1
(
2 equiv. I2
Nu
O
N
MeCN
MeCN
for VII
N
N
N
N
IIIc, IIIg
VII, VIII
IX
n = 1, R1 = COOMe, R2 = C8H17, R3 = NEt2 (VII); n = 0, R1 = NO2, R2 = C4H9, R3 = SMe (VIII); Nu = Et2NH (IIIc),
MeSNa (IIIg).
substitution and the heterocyclization provided a
possibility to easily introduce into the arising thiophene
fragment the iodine atom, an important functional group
for the modification of compounds obtained under the
conditions of the Pd-catalyzed cross-coupling.
30% formic acid, ionization potential 70 V, voltage on the
capillary 4500 V, drying gas temperature 180°C).
Study of Richter cyclization of triazenes Ib,Ic by
1H NMR spectroscopy. To a solution of 0.07 mmol of
triazene in 0.7 ml of acetone-d6 in an NMR tube was
fast added 1.4 mmol (0.16 ml) of 48% HBr, the tube
On 4-bromo-6-nitrocinnoline (IIIc) prone to
hydrolysis we demonstrated the possibility to perform
the nucleophilic substitution of bromine for diethylamino
group without preliminary isolation of cinnoline IIIc.
Thus from triazene Ic 3-butyl-4-diethylamino-6-
nitrocinnoline (VIII) was obtained in an overall yield
of 52%.
1
was thoroughly shaken, and the H NMR spectra were
registered. The first spectrum was registered 3 min after
the addition of HBr, the subsequent spectra, with 2–3 min
interval. The overall time of the experiment was 15 min.
Study of Richter cyclization of triazenes Ib,Id, Ig by
ESI MS method. To a solution of triazene Ib (Table 1),
Ig (Table 2), or a mixture of triazenes Ie, Ig and p-tolu-
idine in methanol was added a solution of concn. HBr in
methanol. The time from HBr addition to the registration
of the first spectrum was ~40 s. The time of observation
in the continuous mode was 6–8 min (the admission of
the sample flow into the spectrometer by a syringe pump
at a rate 180 μl h−1).
Hence we have demonstrated that along with the NMR
spectroscopy the ESI MS method can be successfully used
for the monitoring of Richter reaction. The application
of the latter method provided valuable information on
the intermediates formed in the course of the reaction.
Based on the performed research we found optimal
conditions of the synthesis of 4-bromo-3-ethynyl- and
-3-alkylcinnolines containing both electron-donor and
electron-acceptor substituents in the aromatic ring.
We demonstrated the synthetic potential of 4-bromo-
3-ethynylcinnolines as substrates for the electrophilic
cyclization aiming at the preparation of iodine-containing
polyheterocycles.
Study of Richter cyclization of triazenes Ib,If by
1H NMR spectroscopy. To a solution of 0.05 mmol of
triazene in an appropriate volume of the solvent was
quickly added at vigorous stirring a calculated quantity of
concn. hydrobromic acid (Table 3). The reaction mixture
was stirred at a controlled temperature for 3 min and was
poured into 10 ml of water solution of Et3N (equivalent
to the amount of HBr), the product was extracted into
dichloromethane, the extract was washed with a saturated
solution of NH4Cl and with water, the organic layer was
separated, dried with anhydrous sodium sulfate, the
solvent was removed in a vacuum, the residue was dis-
EXPERIMENTAL
The elemental analysis was carried out on an in-
1
strument EuroVector 3000. H (300.13 MHz) and
13C (75.5 MHz) NMR spectra were registered on
a spectrometer Bruker DPX 300. The chemical shifts
were measured with respect to the residual signals of the
solvent CDCl3 (δH 7.26, δC 77.00 ppm). High resolution
mass spectra with electrospray ionization were recorded
on a spectrometer Bruker MicroTOF in the mode of posi-
tive ions registration (solvent methanol, ionizing additive
1
solved in 0.6 ml of CDCl3, and the H NMR spectrum
was registered.
ortho-(1-Hexyn-1-yl)aryltriazenes Ia–Id and ortho-
(dodeca-1,3-diynyl)aryltriazenes Ie–Ig. General pro-
cedure. To a solution of 1.5 mmol of 1-(2-iodophenyl)-
3-phenyl-3-ethyltriaz-1-ene [33, 34] in 15 ml of Et3N
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

STUDY OF CYCLYZATION
1431
and 5 ml of dichloromethane were added in succession
2.25 mmol of an appropriate terminal alkyne or diyne
[29], 0.075 mmol (0.087 g) of Pd(PPh3)4, and 0.15 mmol
(0.039 g) of PPh3. For 5 min the reaction mixture was
flushed with argon, then 0.225 mmol (0.043 g) of CuI
was added, and the stirring in an argon flow at 50°C (for
compounds Ia–Id) or at 40°C (for compounds Ie–Ig)
was continued till the complete conversion of the starting
iodotriazenes (1– 24 h). The reaction mixture was poured
into a saturated solution of NH4Cl (~50 ml), extracted
with dichloromethane (3 × 15 ml), the organic layer was
washed with the saturated solution of NH4Cl (2 × 20 ml)
and water (30 ml), dried with Na2SO4, dichloromethane
was removed in a vacuum. The reaction products were
isolated by column chromatography on silica gel.
2.50 t (2H, CH2, J 7.3 Hz), 4.43 q (2H, CH2, J 7.3 Hz),
7.20–7.24 m (1Harom), 7.40–7.52 m (4Harom), 7.61 d [1H,
H6, 3J (H6–H5) 8.8 Hz], 8.10 d.d [1H, H5, 3J(H5–H6) 8.8,
4
4J(H5–H3) 2.4 Hz], 8.33 d [1H, H3, J(H3–H5) 2.4 Hz].
13C NMR spectrum, δ, ppm: 10.9, 13.6, 19.4, 22.0, 30.7,
41.4 (Bu, Et), 76.8 (Csp), 97.3 (Csp), 117.6, 117.9, 120.8,
123.3, 124.9, 128.7, 129.4, 143.6, 145.1, 156.0 (Carom).
Found, %: C 68.32; H 3.38; N 16.00. [M + H]+ 351.1851.
C20H22N4O2. Calculated, %: C 68.55; H 6.33; N 15.99.
(M + H) 351.1821.
Methyl 3-(1-hexynyl)-4-[(3-phenyl-3-ethyl)triazen-
1-yl]benzoate (Id). Yield 86%, orange crystals (eluent
petroleum ether–ethyl acetate, 20:1, then 10:1), mp
44–45°C. 1H NMR spectrum, δ, ppm: 0.97 t (3H, CH3,
J 7.3 Hz), 1.40 t (3H, CH3, J 7.3 Hz), 1.49–1.66 m (4H,
2CH2), 2.50 t (2H, CH2, J 7.3 Hz), 3.93 s (3H, OCH3),
4.42 q (2H, CH2, J 7.3 Hz), 7.18 t (1Harom, J 7.3 Hz),
7.40–7.58 m (5Harom), 7.94 d.d [1H, H5, 3J(H5–H6) 8.7,
1-[2-(1-Hexynyl)-4-methylphenyl]-3-phenyl-3-
ethyltriaz-1-ene (Ia). Yield 31% (eluent petroleum
ether–ethyl acetate, 40:1), bright-orange oily substance.
1H NMR spectrum, δ, ppm: 0.96 t (3H, CH3, J 7.3 Hz),
1.37 t (3H, CH3, J 7.3 Hz), 1.46–1.67 m (4H, 2CH2),
2.34 s (3H, CH3), 2.49 t (2H, CH2, J 7.3 Hz), 4.36 q (2H,
4
4J(H5–H3) 1.5 Hz], 8.18 d [1H, H3, J(H3–H4) 1.5 Hz].
13C NMR spectrum, δ, ppm: 11.3, 14.1, 19.8, 22.4, 31.3,
41.2 (Bu, Et), 52.5 (OMe), 78.1 (Csp), 96.1 (Csp), 117.6,
118.0, 120.5, 124.6, 127.8, 129.72, 129.74, 135.3, 144.3,
155.1, 166.9 (COOMe). Found, %: C 72.81; H 6.86;
N 11.62. [M + Na]+ 386.1840. C22H25N3O2. Calculated,
%: C 72.70; H 6.93; N 11.56. (M + Na) 386.1844.
CH2, J 7.3 Hz), 7.09–7.11 m (2Harom), 7.31 d (1Harom
,
J 1.5 Hz), 7.36–7.51 m (5Harom). 13C NMR spectrum,
δ, ppm: 10.9, 13.7, 19.4, 20.8, 22.0, 30.9, 39.9 (Bu, Et,
Me), 78.5 (Csp), 94.5 (Csp), 116.5, 117.5, 119.8, 123.1,
129.1, 129.2, 133.4, 135.8, 144.3, 149.2 (Carom). Found:
m/z 320.2088 [M + H]+. C21H25N3. Calculated (M + H)
320.2127.
1-[2-(Dodeca-1,3-diynyl)-4-methylphenyl]-3-
phenyl-3-ethyltriazene (Ie). Yield 19%, orange oily
substance (eluent petroleum ether–ethyl acetate, 40:1).
1H NMR spectrum, δ, ppm: 0.90 t (3H, CH3, J 7.3 Hz),
1.29–1.40 m [13H, (CH2)5, CH3], 1.53–1.60 m (2H, CH2),
2.33–2.39 m (5H, CH2, CH3), 4.37 q (2H, CH2, J 7.3 Hz),
7.10–7.15 m (2Harom), 7.35–7.50 m (6Harom). 13C NMR
spectrum, δ, ppm: 10.8, 14.1, 19.7, 20.8, 22.6, 28.3,
28.8, 29.06, 29.15, 31.8, 40.4 (C8H17, C2H5, CH3), 65.5,
73.2, 78.3, 85.0 (Csp), 116.7, 117.7, 117.8, 123.4, 129.17,
129.22, 130.3, 134.1, 135.8, 150.8. Found: m/z 400.2759
[M + H]+. C27H34N3. Calculated: (M + H) 400.2759.
1-[4-Bromo-2-(1-hexyn-1-yl)phenyl]-3-phenyl-
3-ethyltriaz-1-ene (Ib). Yield 80% (eluent petroleum
ether–ethyl acetate, 20:1), bright-orange oily substance.
1H NMR spectrum [(CD3)2CO], δ, ppm: 0.94 t (3H, CH3,
J 7.3 Hz), 1.37 t (3H, CH3, J 7.3 Hz), 1.47–1.63 m (4H,
2CH2), 2.50 t (2H, CH2, J 7.3 Hz), 4.44 q (2H, CH2,
J 7.3 Hz), 7.15–7.20 m (1Harom), 7.41–7.50 m (4Harom),
7.58–7.59 m (3Harom). 13C NMR spectrum, δ, ppm:
10.58, 13.63, 18.87, 19.40, 21.99, 30.77 (Bu, Et), 76.50
(Csp), 96.28 (Csp), 116.88, 118.94, 119.01, 121.81,
123.73, 129.25, 131.16, 135.47, 144.03, 150.41 (Carom).
Found, %: C 62.67; H 5.89; N 11.00. [M + H]+ 384.1079.
C20H22BrN3. Calculated, %: C 62.50; H 5.77; N 10.93.
(M + H) 384.1074.
1-[2-(Dodeca-1,3-diynyl)-4-bromophenyl]-3-phenyl-
3-ethyltriazene (If) and methyl 3-(dodeca-1,3-diynyl)-
4-[(3-phenyl-3-ethyl)triazene-1-yl]benzoate (Ig) were
obtained as described in [24], yields 69 and 90% respec-
tively.
1-[2-(1-Hexynyl)-4-nitrophenyl]-3-phenyl-3-
ethyltriazene (Ic). After the chromatographic isolation
(eluent petroleum ether–ethyl acetate, 20:1) the product
was crystallized from hexane. Yield 71%, mp 49–51°C.
1H NMR spectrum, δ, ppm: 0.96 t (3H, CH3, J 7.3 Hz),
1.40 t (3H, CH3, J 7.3 Hz), 1.47–1.67 m (4H, 2CH2),
1-[2-(4-Phenylbuta-1,3-diynyl)-4-bromophenyl]-3-
phenyl-3-ethyltriaz-1-ene (Ih). The phenyldiacetylene
was obtained from 2.0 mmol (0.368 g) of 2-methyl-
6-phenylhexa-3,5-diyn-2-ol in 10 ml of toluene [35],
the obtained toluene solution was added at stirring to a
mixture of 1 mmol (0.351 g) of 1-(4-bromophenyl)-3-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

DANILKINA et al.
1432
phenyl-3-ethyltriaz-1-ene, 0.1 mmol (0.026 g) of PPh3,
and 0.05 mmol (0.058 g) of Pd(PPh3)4. For 5 min the
reaction mixture was flushed with argon, then 0.15 mmol
(0.028 g) of CuI was added, and the stirring in an argon
flow at 40°C was continued for 23 h. The reaction mixture
was poured into a saturated solution of NH4Cl (~40 ml),
extracted with dichloromethane (3 × 15 ml), the organic
layer was washed with the saturated solution of NH4Cl
(2 × 20 ml) and water (30 ml), dried with Na2SO4, di-
chloromethane was removed in a vacuum. The residue
was subjected to column chromatography on silica gel
(eluent petroleum ether–ethyl acetate, 50:1). Yield 55%,
bright-orange oily substance. 1H NMR spectrum, δ, ppm:
1.40 t (3H, CH3, J 7.3 Hz), 4.39 q (2H, CH2, J 7.3 Hz),
7.14–7.19 m (1Harom), 7.34–7.55 m (11Harom), 7.70 s
(1Harom). 13C NMR spectrum, δ, ppm: 10.8 (CH3), 41.0
(CH2), 74.1 (Csp), 78.5 (Csp), 79.2 (Csp), 82.7 (Csp), 117.2,
118.9, 119.3, 119.5, 121.8, 124.1, 128.4, 129.2, 129.3,
134.5, 132.8, 136.0, 143.9, 152.1. Found, %: C 67.61;
H 4.35; N 9.53. [M + H]+ 428.0748. C24H18BrN3. Cal-
culated, %: C 67.30; H 4.24; N 9.87. (M + H) 428.0762.
and water, dried with Na2SO4, the solvent was removed
in a vacuum. The residue was subjected to column chro-
matography on silica gel (eluent petroleum ether– ethyl
acetate 20:1, then 10:1).
4-Bromo-3-butyl-6-methylcinnoline (IIIa). Yield
80%, orange oily substance. 1H NMR spectrum, δ, ppm:
0.99 t (3H, CH3, J 7.3 Hz), 1.50 sextet (2H, CH2,J 7.3 Hz),
1.88 m (2H, CH2), 2.62 s (3H, CH3), 3.39 t (2H, CH2,
3
4
J 8.0 Hz), 7.62 d.d [1H, H7, J(H7–H8) 8.7, J(H7–H5)
2.2 Hz], 7.87 C (1H, H5), 8.36 d [1H, H8, J(H8–H7)
3
8.7 Hz]. 13C NMR spectrum, δ, ppm: 13.9, 22.3, 22.6,
31.2, 36.0 (Me, Bu), 124.2, 126.3, 126.9, 129.7, 132.6,
143.1 148.7, 157.2. Found: m/z 279.0556 [M + H]+.
C13H15BrN2. Calculated: (M + H) 279.0497.
3-Butyl-4,6-dibromocinnoline (IIIb). Yield 82%, mp
59–61°C. 1H NMR spectrum, δ, ppm: 0.99 t (3H, CH3,
J 7.3 Hz), 1.50 sextet (2H, CH2, J 7.3 Hz), 1.83–1.93 m
(2H, CH2), 3.41 t (2H, CH2, J 8.0 Hz), 7.88 d.d [1H,
3
4
H7, J(H7–H8) 8.7, J(H7–H5) 1.5 Hz], 8.32 d [1H, H5,
4J(H5–H7) 1.5 Hz], 8.36 d [1H, H8, J(H8–H7) 8.7 Hz].
3
13C NMR spectrum, δ, ppm: 13.9, 22.6, 31.1, 36.0 (Bu),
125.5, 127.7, 127.9, 128.1, 131.6, 134.1, 148.0, 158.0.
Found, %: C 42.11; H 3.79; N 8.09. [M + H]+ 342.9419.
C12H12Br2N2. Calculated, %: C 41.89; H 3.52; N 8.14.
(M + H) 342.9445.
Methyl 3-(phenylbuta-1,3-diynyl)-4-(3-ethyl-3-
phenyltriaz-1-ene-1-yl)benzoate (Ii) was obtained
similarly from 1 mmol (0.409 g) of methyl 3-iodo-
4-(3-ethyl-3-phenyltriaz-1-ene-1-yl)benzoate. Yield
71%, bright-yellow oily substance (eluent petroleum
3-Butyl-4,6-dibromocinnoline hydrobromide
(IIIb). Yield 39%, mp 137–140°C. 1H NMR spectrum,
δ, ppm: 0.99 t (3H, CH3, J 7.3 Hz), 1.53 sextet (2H,
CH2, J 7.3 Hz), 1.85–1.95 m (2H, CH2), 3.64 t (2H,
CH2, J 8.0 Hz), 7.22 d.d (1Harom, J 8.7 Hz), 8.55 s (1H,
H5), 8.84 d (1Harom, J 8.7 Hz), 11.61 br.s (1H, HBr).
13C NMR spectrum, δ, ppm: 13.6, 22.4, 30.8, 33.6
(Bu), 128.4, 128.6, 132.0, 133.7, 134.5, 139.4, 143.5,
157.5 (Carom). Found, %: C 33.72; H 3.23; N 6.32.
[M + H]+ 342.9397. C12H12Br2N2. Calculated, %:
C 33.92; H 3.08; N 6.59. (M + H) 342.9445.
1
ether–ethyl acetate, 20:1). H NMR spectrum, δ, ppm:
1.43 t (3H, CH3, J 7.3 Hz), 3.93 s (3H, OCH3), 4.43 q
(2H, CH2, J 7.3 Hz), 7.15–7.21 m (1Harom), 7.32–7.44 m
(5H arom), 7.51–7.55 m (4Harom), 7.60 d [1H, H6,
3
3J(H6–H5) 8.7 Hz], 8.00 d.d [1H, H5, J(H5–H6) 8.7,
4
4J(H5–H3) 2.2 Hz], 8.27 d [1H, H3, J(H3–H5) 2.2 Hz].
13C NMR spectrum, δ, ppm: 10.8 (CH3), 41.3 (CH2), 52.2
(OCH3), 74.2 (Csp), 78.6 (Csp), 79.2 (Csp), 82.2 (Csp),
117.4, 117.5, 117.9, 121.9, 124.5, 127.4, 128.4, 129.1,
129.3, 130.8, 132.5, 135.6, 143.7, 156.1, 166.1 (COOMe).
Found: m/z 408.1682 [M + H]+. C26H21N3O2. Calculated:
(M + H) 408.1712.
4-Bromo-3-butyl-6-nitrocinnoline (IIIc). Yield 71%,
1
mp 75–77°C. H NMR spectrum, δ, ppm: 1.01 t (3H,
CH3, J 7.3 Hz), 1.46–1.58 m (2H, CH2), 1.86–1.97 m
(2H, CH2), 3.48 t (2H, CH2, J 8.0 Hz), 8.54 d.d [1H,
4-Bromocinnolines IIIa–IIId, IIIg–IIIi. General
procedure. To a solution of (0.25 mmol) of triazene in
2.5 ml of acetone at vigorous stirring was quickly added
5 mmol (0.843 g, 0.57 ml) of 48% HBr. The reaction
mixture was stirred at 20°C for 3 min in the case of
triazenes Ia–Id or for 15 min in the case of triazenes
Ig–Ii, the mixture was poured into 10 ml of water solu-
tion containing 5 mmol (0.505 g, 0.70 ml) of Et3N, the
product was extracted into dihloromethane (3 × 10 ml),
the extract was washed with saturated solution of NH4Cl
3
4
H7, J(H7–H8) 8.7, J(H7–H5) 2.2 Hz], 8.71 d [1H, H8,
4
3J(H8–H7) 8.7 Hz], 9.07 d [1H, H5, J(H5–H7) 2.2 Hz].
13C NMR spectrum, δ, ppm: 13.8, 22.6, 31.0, 36.1 (Bu),
123.4, 123.5, 126.4, 128.2, 132.7, 149.0, 149.5, 159.3
(Carom).
3-Butyl-6-nitrocinnoline-4-one (IVc) was obtained
after treating the reaction mixture in the course of the
study of triazene Ic cyclization by 1H NMR spectroscopy.
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STUDY OF CYCLYZATION
1433
1H NMR spectrum, δ, ppm: 0.95 t (3H, CH3, J 7.3 Hz),
1.36–1.48 m (2H, CH2), 1.64–1.72 m (2H, CH2), 2.85 t
(2H, CH2, J 8.0 Hz), 8.63 d [1H, H8, 3J(H8–H7) 8.7 Hz],
8.46 d.d [1H, H7, 3J(H7–H8) 8.7, 4J(H7–H5) 2.2 Hz], 9.2 d
[1H, H5, 4J(H5–H7) 2.2 Hz]. Found, %: C 57.92; H 5.07;
N 17.21. [M + H]+ 248.1117. C12H14N2O3. Calculated,
%: C 58.29; H 5.30; N 16.99. (M + H) 248.1035.
trile at 0°C was added 0.010 g (0.147 mmol) of NaSCH3.
The reaction mixture was stirred at 0°C for 2 h and then
0.5 h at room temperature. The solvent was removed at
a reduced pressure, the residue was chromatographed on
silica gel (eluent petroleum ether–ethyl acetate, 10 : 1,
then 7:1). Yield 73%, mp 44–46°C. 1H NMR spectrum,
δ, ppm: 0.87 t (3H, CH3, J 7.5 Hz), 1.24–1.30 m (8H,
4CH2), 1.48–1.57 m (2H, CH2), 1.74 quintet (2H, CH2,
J 7.3 Hz), 2.64 t (2H, CH2, J 7.3 Hz), 2.74 c (3H, SCH3),
Methyl 4-bromo-3-butyl-6-cinnolinecarboxylate
(IIId). Yield 52%, mp 104–106°C. 1H NMR spectrum,
δ, ppm: 1.00 t (3H, CH3, J 7.3 Hz), 1.51 sextet (2H,
CH2, J 7.3 Hz), 1.85–1.95 m (2H, CH2), 3.44 t (2H, CH2,
J 8.0 Hz), 4.04 s (3H, OCH3), 8.34 d.d [1H, H7, 3J(H7–
3
4.02 s (3H, OCH3), 8.34 d.d [1H, H7, J(H7–H8) 8.7,
3
4J(H7–H5) 1.5 Hz], 8.55 d [1H, H8, J(H8–H7) 8.7 Hz],
9.13 d [1H, H5, 4J(H5–H7) 1.5 Hz]. 13C NMR spectrum,
δ, ppm: 14.0, 18.0, 20.0, 22.6, 28.2, 29.0, 29.07, 29.15,
31.8, 52.8 (OCH3), 78.2 (Csp), 101.1 (Csp), 126.4, 127.7,
129.8, 130.8, 132.4, 138.5, 144.3, 148.2, 165.7 (COOMe).
Found: m/z 371.1790 [M + H]+. C21H26N2O2S. Calculated:
(M + H) 371.1793.
4
3
H8) 7.3, J(H5–H3) 2.2 Hz], 8.54 d [1H, H8, J(H8–H7)
7.3 Hz], 8.34 d [1H, H5, J(H5–H7) 2.2 Hz]. 13C NMR
4
spectrum, δ, ppm: 13.8, 22.6, 31.1, 36.0 (Bu), 52.9 (OMe),
126.2, 128.1, 129.1, 130.5, 133.0, 150.1 (one signal over-
lapped with the others) (Carom), 158.3 (COOMe). Found:
m/z 323.0374 [M + H]+. C14H15BrN2O2. Calculated: (M +
H) 323.0395. 4,6-Dibromo-3-(dec-1-yn-1-yl)cinnoline
(IIIf) [24]. Yield 66%.
3-Butyl-4-N,N-diethylamino-6-nitrocinnoline
(VIII). To a solution in 2 ml of acetonitrile of 4-bromo-5-
nitrocinnoline obtained by the above described procedure
0.123 mmol (0.07 g) of triazene Ic not subjected to the
chromatography was added 1.84 mmol (0.135 g, 0.2 ml)
of diethylamine. The reaction mixture was heated at
50°C over 48 h, poured into 10 ml of water, the product
was extracted into dichloromethane (3 × 7 ml), the com-
bined organic solutions were washed with the saturated
solution of NH4Cl, with water till pH 7, the extract
was dried with Na2SO4, the solvent was removed in a
vacuum, the residue was subjected to chromatography
(eluent petroleum ether–ethyl acetate, 5 : 1). Yield 52%,
mp 204–206°C. 1H NMR spectrum, δ, ppm: 1.00 t (3H,
CH3, J 7.3 Hz), 1.14 t (6H, 2CH3, J 7.3 Hz), 1.51 sextet
(2H, CH2, J 7.3 Hz), 1.90–2.00 m (2H, CH2), 3.19 t (2H,
CH2, J 8.0 Hz), 3.47 q (4H, 2CH2, J 7.3 Hz), 8.40 d.d [1H,
Methyl 4-bromo-3-(dec-1-yn-1-yl)-6-cinnolinecar-
boxylate (IIIg) [24]. Yield 74%.
4,6-Dibromo-3-(phenylethynyl)cinnoline (IIIh).
Yield 52%, mp 206–209°C. 1H NMR spectrum, δ, ppm:
7.40–7.45 m (3Harom), 7.71–7.74 m (2Harom), 7.94 d.d
[1H, H7, 3J(H7–H8) 8.7, 4J(H7–H5) 2.2 Hz], 8.34 d [1H,
H5, 4J(H5–H7) 2.2 Hz], 8.41 d [1H, H8, 3J(H8–H7) 8.7 Hz].
13C NMR spectrum, δ, ppm: 86.0 (Csp), 98.1 (Csp), 121.6,
127.0, 127.7, 128.3, 128.4, 128.6, 129.8, 132.0, 132.3,
135.1, 143.4 147.0. Found: m/z 386.9126 [M + H]+.
C16H8Br2N2. Calculated: (M + H) 386.9132.
Methyl 4-bromo-3-(2-phenylethynyl)-6-cinnolin-
ecarboxylate (IIIi). After chromatographing (eluent
petroleum ether–ethyl acetate, 10:1, then 5:1) the product
was crystallized from acetonitrile. Yield 58%, mp 157–
158°C. 1H NMR spectrum, δ, ppm: 4.04 s (3H, OCH3),
7.42–7.44 m (3Harom), 7.71–7.74 m (2Harom), 8.42 d.d
[1H, H7, 3J(H7–H8) 8.7, 4J(H7–H5) 1.5 Hz], 8.61 d [1H,
H8, 3J(H8–H7) 8.7 Hz], 8.85 d [1H, H5, 4J(H5–H7) 1.5 Hz].
13C NMR spectrum, δ, ppm: 53.0 (OCH3), 85.9 (Csp),
98.1 (Csp), 121.5, 125.5, 128.5, 128.98, 129.1, 129.8,
130.7, 130.9, 132.2, 133.7, 143.6, 149.0 (two overlapping
signals), 165.2 (COOMe). Found, %: C 59.05; H 2.82;
N 7.54. [M + H]+ 367.0092. C18H11BrN2O2. Calculated,
%: C 58.88; H 3.02; N 7.63. (M + H) 367.0082.
3
4
H7, J(H7–H8) 9.5, J(H7–H5) 2.2 Hz], 8.58 d [1H, H8,
3J(H8–H7) 9.5 Hz], 9.02 d [1H, H5, J(H5–H7) 2.2 Hz].
4
13C NMR spectrum, δ, ppm: 14.0, 14.1, 23.1, 31.6,
32.9, 47.9 (2Et, Bu) 121.7, 122.3, 125.7, 132.3, 144.1,
147.2, 150.5, 157.5. Found: m/z 303.1739 [M + H]+.
C16H22N2O4. Calculated: (M + H) 303.1821.
Methyl 3-iodo-2-octylthieno[3,2-C]cinnoline-8-
carboxylate (IX). To a solution of 0.068 mmol (0.025 g)
of 4-methylsulfanylcinnoline VII in 1.5 ml of acetonitrile
was added at stirring 0.136 mmol (0.034 g) of iodine
preliminary thoroughly ground in a mortar. The reaction
mixture was stirred for 15 h at room temperature, the
formed precipitate was filtered off and washed with ace-
tonitrile, with 5% solution of sodium sulfite, with water
Methyl 3-(dec-1-yn-1-yl)-4-(methylsulfanyl)
cinnoline-6-carboxylate (VII). To a solution of 0.060 g
(0.148 mmol) of bromocinnoline IIId in 2 ml of acetoni-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 11 2012

DANILKINA et al.
1434
and Dembofsky, B.T., US Patent 20070142328, 2007.
Chem. Abstr., 2007, vol. 147, 95686.
and again with acetonitrile. The filtrate was diluted with
water (20 ml), extracted with dichloromethane, washed
with water, and the extract was dried with anhydrous
sodium sulfate. The solvent was removed at a reduced
pressure, the residue was combined with the previously
obtained precipitate and recrystallized from acetonitrile.
Yield 70%, mp 134–136°C. 1H NMR spectrum, δ, ppm:
0.89 t (3H, CH3, J 6.6 Hz), 1.29–1.48 m (10H, 5CH2),
1.80–1.89 m (2H, CH2), 3.14 t (2H, CH2, J 7.3 Hz),
6. Aston, N.M., Robinson, J.E., and Trivedi, N., WO Patent
2007045861, 2007; Chem. Abstr., 2007, vol. 146, 462274.
7. Lunniss, C., Eldred, C., Aston, N., Craven, A., Gohil, K.,
Judkins, B., Keeling, S., Ranshaw, L., Robinson, E.,
Shipley, T.,and Trivedi, N., Bioorg. Med. Chem. Lett.,
2010, vol. 20, p. 137
8. Busch, A., Turck, A., Nowicka, K., Barsella, A., An-
draud, C., and Ple, N., Heterocycles, 2007, vol. 71, p. 1723.
9. Kok, G.B., Leung, B.K.Y., Gautier, E.C.L., and Barn-
ham, K.J., WO Patent 2004031161, 2004; Chem. Abstr.,
2004, vol. 140, 332510.
10. Haider, N. and Holzer, W., Product Class 9: Cinnolines
Science of Synthesis, 2004, vol. 16, p. 251.
11. Brown, D.J., Cinnolines and Phthalazines Supplement, II,
New York: J. Wiley & Sons, Inc., 2005, p. 64.
12. Vinogradova, O.V. and Balova, I.A., Khim. Geterotsikl.
Soedin., 2008, p. 643.
3
4.05 s (3H, OCH3), 8.39 d.d [1H, H7, J(H7–H6) 8.6,
4J(H7–H9) 1.3 Hz], 8.74–8.78 m (2H, H6, H9). 13C NMR
spectrum, δ, ppm: 14.1, 22.6, 29.07, 29.14, 29.3, 30.4,
31.8, 32.9 (C8H17), 52.9 (OCH3), 82.9 (CI) 120.9, 125.2,
128.7, 131.6, 132.3, 132.8, 146.7, 147.9, 154.1 (Carom),
165.7 (COOMe). Found: m/z 483.0566 [M + H]+.
C20H24IN2O2S. Calculated: (M + H) 483.0603.
ACKNOWLEDGMENTS
13. Richter, V. Ber. Deutsch. Chem. Ges. 1883, vol. 16, p. 677.
14. Vasilevsky, S.F. and Tretyakov, E.V., Lieb. Ann., 1995,
p. 775.
15. Le, Fur, N., Mojovic, L., Turck,A., Ple, N., Queguiner, G.,
Reboul, V., Perrio, S., and Metzner, P., Tetrahedron, 2004,
vol. 60, p. 7983.
16. Turck, A., Pie, N., and Queguiner, G., Tetrahedron., 1995,
vol. 51, p. 13045.
17. Hodgetts, K.J., US Patent PCT/US2005/011904, 2005.
Chem. Abstr., 2005, vol. 143, 416271.
The authors express their gratitude to Prof. R.R. Kos-
tikov for discussing the work and for valuable remarks.
The study was carried out under a financial sup-
port of the St. Petersburg State University (grants nos.
12.38.14.2011, 12.37.128.2011) and of the grant of the
President of the Russian Federation for young Candidates
of Sciences (MK-504.2011.3).
18. Brdse, S., Dahmen, S., and Heutus, J., Terahedron Lett.,
1999, vol. 40, p. 6201.
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