Methods for the synthesis of cinnolines (Review)

Abstract

This review analyses the principal approaches to the synthesis of the cinnoline nucleus, used as synthetic precursors of arenediazonium
salts, arylhydrazones, and arylhydrazines, and also reductive methods for the synthesis of polycondensed derivatives of cinnoline.
The mechanisms of the transformations and the possibilities and limitations of the various methods are discussed. Special
attention is paid to methods based on the cyclization of derivatives of arenediazonium salts, which have been developed substantially
in recent years.

Full text

Chemistry of Heterocyclic Compounds, Vol. 44, No. 5, 2008
METHODS FOR THE SYNTHESIS
OF CINNOLINES (REVIEW)*
O. V. Vinogradova and I. A. Balova
This review analyses the principal approaches to the synthesis of the cinnoline nucleus, used as
synthetic precursors of arenediazonium salts, arylhydrazones, and arylhydrazines, and also reductive
methods for the synthesis of polycondensed derivatives of cinnoline. The mechanisms of the
transformations and the possibilities and limitations of the various methods are discussed. Special
attention is paid to methods based on the cyclization of derivatives of arenediazonium salts, which have
been developed substantially in recent years.
Keywords: cinnolines, benzo[c]cinnolines, synthesis, cyclization, arylhydrazones, arenediazonium
salts, ortho-ethynylarenediazonium salts.
The chemistry of compounds of the cinnoline series is a vigorously developing branch of organic
chemistry in so far as the compounds exhibit a broad range of biological activity. In recent years a large number
of papers have appeared on research into the biological activity of compounds of the cinnoline series [1-6]. They
bear witness to the possibility of using them as anticancer [7-10], fungicidal, and bactericidal [11-15]
preparations. Compounds of the cinnoline series have antithrombocytic [16] and antituberculosis [17]
characteristics and also exhibit anesthetizing [18] and sedative [19] activity. Derivatives of cinnolines are also
used as agrochemicals [20].
Apart from their biological activity compounds containing a cinnoline fragment exhibit a series of
interesting physical characteristics. Thus, luminescence was detected in pyrrolo[1,2-b]cinnolines, where the
relative quantum yield amounted to 90% [21]. The possibility of using aryl-substituted cinnolines as materials
for nonlinear optics was demonstrated [22, 23].
The cinnoline ring was first synthesized by Richter during the diazotization of ortho-amino-
phenylpropionic acid and cyclization of the obtained arenediazonium salt [24]. Several reviews and monographs
on the synthesis and characteristics of cinnolines have now been published [25-30].
Among methods for the synthesis of cinnolines it is possible to identify three main approaches using
derivatives of arenediazonium salts, arylhydrazones, and arylhydrazines as precursors and also reductive
methods for the synthesis of polycondensed derivatives of cinnoline, among which a special position is occupied
by benzo[c]cinnolines in view of their biological activity [10, 31, 32].
_______
* In memory of A. A. Potekhin
__________________________________________________________________________________________
Chemical Faculty, St. Petersburg State University, St. Petersburg 198504, Russia; e-mail:
irinabalova@yandex.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 643-667, May,
2008. Original article submitted December 10, 2007.
0009-3122/08/4405-0501©2008 Springer Science+Business Media, Inc. 501

1. ARYLHYDRAZONES AND ARYLHYDRAZINES AS PRECURSORS OF CINNOLINES
This approach is the most universal since it makes it possible to obtain derivatives of cinnoline with
various types of substituents at various positions and includes methods in which the cinnoline system is formed
at various positions of the pyridazine ring. As a rule ring closure occurs during attack of the amino group at a
CC, CO, or CN multiple bond.
An example of the production of cinnoline through the formation of the N(2)–C(3) bond is the classical
method for the synthesis of 3-hydroxycinnolines–the Neber–Bossel method [33, 34]. During the diazotization of
(2-aminophenyl)hydroxyacetates and reduction of the diazonium salt the obtained hydrazine undergoes
cyclization to 3-hydroxycinnoline when boiled in HCl (Scheme 1). Substituents in the aromatic ring have an
appreciable effect on the course of cyclization, and in the case of the unsubstituted and 4-chloro-substituted ring
the yields of the desired compounds are 60 and 7% respectively.
Scheme 1
CO
2
OH
NH
2
X
OH
CO
2
H
N
2
X
OH
CO
2
H
N
H
NH
2
X
N
N
OH
X
–
Na
NaNO
2
, HCl
0°C
SnCl
2
, HCl
0°C
Cl
–
HCl
X = H, Cl
+
+
A similar approach was afterwards used by Gomaa’s group (Scheme 2) [35]. In this case the final
products were obtained with good yields (65-80%), irrespective of the electronic nature of the substituent in the
aromatic ring.
Scheme 2
N
N
NH
2
CN
R
O
CN
CN
R
NH
2
N
CN
CN
R
NH
2
NH
2
H
2
O
– H
2
O
R = Me,
, Hal, OH
.
Another example of the formation of the bond in this position of the cinnoline system is the cyclization
of 3-diethylamino-5-phenylethynyl-1,4-naphthoquinone [36]. 3-Benzyl-9-diethylaminobenzo[d,e]cinnolin-7-one
was obtained with a yield of 60% in the reaction of diethylamino-5-phenylethynyl-1,4-naphthoquinone with
hydrazine (Scheme 3). The reaction is sensitive to the nature of the substituent in the naphthoquinone ring. Thus
in the absence of the diethylamino group (X = H) the reaction of 5-ethynyl-substituted quinones with
502

N-nucleophiles leads to the formation of a seven-membered diazepine ring. In the case of 2,3-dimethyl-
substituted 5-phenylethynyl-1,4-naphthoquinone condensation with a molecule of hydrazine did not occur, and
the derivative underwent reductive cyclization with the formation of naphtho[1,8-bc]pyran. The authors found
no explanation for such dependence of the direction of the reaction on the nature of substitution.
Scheme 3
X
O
O
Ph
O
N
X
Ph
NH
2
N
N
CH
2
Ph
O
X
NH
2
NH
2
X = Et
2
N
For a long time the only example of the formation of a cinnoline ring through the construction of the
C
(3)
–C
(4)
was the reaction realized by Pfannstiel and Janecke [37, 38], as a result of which the hydrazone formed
by boiling 6-chloro-2-hydrazinobenzoic acid in benzaldehyde underwent cyclization to 5-chloro-4-hydroxy-
3-phenylcinnoline. However, the yield of cinnoline was low since the main direction of reaction was cyclization
of the initial hydrazine to 4-chloroindazolone (Scheme 4) [38].
Scheme 4
Cl
N
H
NH
2
CO
2
H
N
H
N
Cl
CO
2
H
Ph
N
N
Cl
OH
Ph
NH
N
H
Cl
O
PhCHO
∆
This approach found development as a result of work by Kiselev's group [39, 40]. While studying the
chemistry of the anion-activated CF
3
group they showed that the hydrazones obtained from ortho-
trifluoromethylarylhydrazines and benzaldehydes undergo cyclization by the action of a base, forming a
pyridazine ring (Scheme 5).
Scheme 5
CF
3
N
H
NH
2
CF
3
N
H
N
R
N
N
NH
2
R
RC
6
H
4
CHO
NaHMDS,
THF
R = H, F, Cl, Me, OMe, Pyr
503

The products in this case are 4-amino-3-arylcinnolines, and their yields amount to 60-90%. The authors
suggest that the deciding factor for cyclization is the presence of the CF
3
group, which promotes ionization of
the N–H bond in the hydrazone; at the same time the fluoride ions can act as leaving groups at the fourth carbon
atom, which is necessary to complete the cyclization. The cyclization mechanism proposed by the authors [40] is
presented in Scheme 6.
Scheme 6
CF
3
N
H
N
Ph
N
N
NH
2
Ph
CF
2
F
N
N
Ph
CF
2
N
N
Ph
CF
2
N
N
Ph
N
N
H
F
F
Ph
N
N
F
Ph
N
N
N
SiMe
3
Me
3
Si
Ph
B
– BH
–F
B
–BH, –F
B
–F
1
2
3
3a
4
5
6
7
–
–
–
–
–
–
–
The formation of the quinonemethylidene intermediate 3/3a had been postulated earlier in work by
Strekowski’s group [41] in a study of the mechanisms of similar transformations. Important for the progress of
the cyclization is the structure of hydrazone fragment; cyclization does not occur for the hydrazones obtained
from the ortho-substituted benzaldehydes, but the hydrazones containing a meta- and para-substituted phenyl
fragment readily undergo cyclization irrespective of the electronic and steric characteristics of the substituent.
The optimum conditions involve reaction in THF at -35 to -15°C in the presence of a four-fold excess of sodium
hexamethyldisilylamide (NaHMDS) as base. The formation of cinnoline is not observed if lithium
diisopropylamide (LDA) and also lithium morpholide and piperidide are used. However, cyclization is not
sensitive to the nature of the metal used as cation and takes place successfully with the lithium and also the
potassium derivative.
An example of the formation of the C(4)–C(4a) bond is the cyclization of the monoarylhydrazones
formed in the reaction of the esters and amides of 3-aminopropenoic acid with arenediazonium
tetrafluoroborates, studied by Kanner's group (Scheme 7) [42].
504

Scheme 7
H
Y
O
H
N
X
N
N
R
1
N
X
N
Y
O
NH
R
1
N
N
Y
O
R
1
N
BF
4
Y = OEt,
X = –, CH
2
, O
R
1
= H, OMe
BF
4
8
–
–
+
+
+
,
,
The substituent in the benzene ring has a strong effect on the course of the cyclization. In the case of
R
1
= H the cyclization of compound 8 takes place on boiling in acetonitrile for several days. If a methoxyl
substituent is introduced the hydrazone 8 undergoes spontaneous cyclization in the course of the reaction. There
is a general tendency for higher reactivity in the derivatives of the amides compared with the esters and also for
the derivatives of morpholine compared with those of pyrrolidine and piperidine. The authors proposed the
mechanism in Scheme 8 in order to explain this effect of the substituents.
The rate-determining stage is the formation of the bond between the imine carbon atom and the aromatic
ring, which can be regarded formally as an electrophilic substitution reaction. It is clear that this
Scheme 8
N
N
N
R
1
H
COY
N
H
N
N
R
1
COY
N
N
R
1
COY
N
N
H
N
H
R
1
N
H
N
COY
N
R
1
N
N
COY
N
Y = OEt, R
1
= H, OMe
–
–
+
+
;
505

process must be accelerated by electron-donating substituents in the aromatic ring. The decrease of the basicity
in the series pyrrolidine (pK
a
11.3) – piperidine (pK
a
11.2) – morpholine (pK
a
8.4) leads to an increase in the
electrophilicity of the imine carbon atom, which must increase its reactivity and accelerate the cyclization.
The significantly lower activity of the pyrrolidine derivatives compared with the activity of the
piperidine derivatives is explained by the nature of the five-membered ring, for which the configuration with the
exocyclic double bond is more stable. The difference in the behavior of the ester and amide derivatives was also
explained by the effect of the electronic effects of these groups on the cyclization reaction centers; both groups
increase the electrophilicity of the imine carbon atom and reduce the nucleophilicity of the benzene ring that is
in conjugation. Nevertheless the ester group, which has a large negative resonance effect, reduces the activity of
the corresponding derivatives in comparison with the amide.
Research by the Egyptian authors [43-47] was also directed toward methods for the synthesis of 3-aroyl-
substituted cinnolines in view of their supposed biological activity. By analogy with Kanner’s work 3-aryl-
2-arylhydrazono-3-oxopropanals 9 were used as starting compounds. The yields of the 3-aroylcinnolines
amounted to 35-65% (Scheme 9).
Cyclization was realized in the gas phase or by boiling the initial hydrazones in concentrated sulfuric
acid. In the case of compounds containing donating groups in the aromatic substituents of the hydrazone
fragment polyphosphoric acid was used. In spite of the fact that the initial compounds exist in the form of a
mixture of syn and anti isomers the cyclization takes place selectively with the formation of one of the possible
regioisomers.
Scheme 9
N
N
O
H
Ar
O
H
N
N
O
Ar
N
N
Ar
H
O
X
X
X
N
N
Ar
H
O
O
H
X
S
O
X = H, Cl, NO
2
, OMe; Ar = Ph, 4-ClC
6
H
4
, 4-MeOC
6
H
4
,
9
syn
anti
+
,
In order to investigate the mechanism of the transformation an investigation was carried out into the
kinetics of the reaction in the gas phase with variation of the nature of the substituents in the aromatic ring of the
hydrazone [44, 47]. Initially two possible reaction paths were proposed (Scheme 10). The first includes the
mechanism described in Kanner's papers, where the rate-determining stage involves attack by the carbonyl
carbon atom in the aromatic ring (mechanism A). According to the second mechanism, the cinnoline ring is
formed as a result of a 6-π-electrocyclic reaction, which precedes the thermal isomerization of 10 to 10′
(mechanism B).
A kinetic investigation of the cyclization at 550 K showed the absence of a significant effect from the
nature of the substituent on the rate of the reaction. Since the reaction by mechanism A must be accelerated by
electron-donating substituents while for the isomerization 9-10′ the presence of electron-accepting substituents
that increase the acidity of the nitrogen atom must lead to an increase in the rate, it was concluded on the basis
of the experimental data that the rate-determining stage of the reaction is the cyclization of compound 10′ to 10″
taking place through a quasiaromatic six-membered transition state.
506

Scheme 10
N
H
N
Ar
O
O
X
N
N
OH
O
Ar
X
N
N
Ar
O
HOH
X
C
N
N
O
H
Ar
O
H
N
N
Ar
O
H
HOH
N
N
Ar
O
X
X
X
–H
2
O
–H
2
O
9
10'
10"
A
B
+
–
The formation of a cinnoline ring with the participation of arylhydrazones through the construction of a
bond between the fourth carbon atom and the benzene ring can also be realized under the conditions of the
Friedel–Crafts reaction. This approach was first described in 1956 by Barber and co-workers [48, 49]. They
realized the cyclization of the phenylhydrazone of mesoxalyl chloride catalyzed by titanium salts, as a result of
which after alkaline hydrolysis they obtained 4-hydroxycinnoline-3-carboxylic acid (Scheme 11). In our days
this method has been used in the synthesis of polycondensed derivatives of cinnoline [50].
Scheme 11
N
H
N
Y
ClOC
X
N
N
OH
Y
X
TiCl
4
PhNO
2
, 100°C
11, 12 X = Me, OMe, NO
2
, Cl, Br, F11 Y = COCl, 12 Y = COOH;
11
12
2. SYNTHESIS OF BENZO[c]CINNOLINES
A powerful tool for the production of benzo[c]cinnolines is the reductive cyclization of 2,2′-dinitro-
biphenyls (Scheme 12) [51, 52].
Scheme 12
NO
2
O
2
N
N N
R
R
R
R
N N
O
R
R
[H]
+
+
–
507

In spite of the fact that this method has quite a large number of limitations associated with the
construction of the initial compounds it is practically the only method used for the synthesis of such structures in
contemporary chemistry. A wide range of reagents can be used as reducing agent [52], and the most frequently
employed are lithium aluminum hydride, sodium sulfide, and sodium amalgam; Zn (in the presence of CaCl
2
)
and Ni (in an alkaline medium); acetophenone can also be used as reducing agent. Often a mixture of cinnoline
and its oxide at one or two nitrogen atoms is formed in the reaction; reduction of the oxide can be achieved by
the addition of the reagent previously used for the reduction of the nitro groups. The method can be used to
obtain polycondensed compounds containing a cinnoline fragment in the presence of several structural
fragments capable of cyclization (Scheme 13) [53, 54].
Scheme 13
NO
2
NO
2
NO
2
NO
2
O
2
N
O
2
N
N
N
N
N
N
N
Raney Ni / NH
2
NH
2
H
2
O
.
The presence of substituents at positions 6 and 6′ hinders cyclization on account of steric factors; in this
situation the reaction only takes place by the path with reduction of the nitro groups and the formation of
nitroamino or diamino derivatives of biphenyl. In this case intermolecular azo coupling leading to azo
compounds can also occur.
A successful example of the synthesis of 1,10-substituted benzo[c]cinnolines is found in the papers by
Benin [55] (Scheme 14). By using metallic Zn or Ni in boiling ethanol as reducing system it was possible to
realize the cyclization of tetrasubstituted biphenyls 13. The corresponding benzocinnoline was obtained with an
80% yield.
Scheme 14
SPr
NH
NO
2
NO
2
ROC
SPrNH
ROC
NN
SPrNH
ROC
NN
O
Zn / CaCl
2
EtOH, ∆, N
2
Raney Ni
EtOH,
1% NaOH
Zn
EtOH
13
boiling
508

In the literature the mechanism proposed by Russell [56] is generally accepted as an explanation for the
formation of the N=N bond. It is assumed that, initially, reduction of the dinitrobiphenyls takes place with the
formation of 2-(2′-nitrosophenyl)phenylhydroxylamine 14 (Scheme 15). Intramolecular one-electron transfer
between the nitrogen functions of this intermediate leads to the generation of a bis(radical-anion), the
recombination of which and subsequent reduction of the obtained particle lead to the production of
benzo[c]cinnoline N-oxide as initial product.
Scheme 15
NO
2
O
2
N
O
2
N
N
O
N
N
O
O
NN
O
O
NN
O
NN
N
N
OH
H
O
[H]
:
[H]
[H]
14
+
+
––
–
––
The radical-ion character of the intermediate explains certain limitations that the reaction has with
respect to the structure of the initial compounds. Thus, the presence of –NH
2
, –CN, and –OH groups is
undesirable since they readily form radicals under the conditions of the oxidation–reduction process, leading to
resinification of the reaction mixture. In addition, the presence of aldehyde and primary alcohol groups can often
complicate the reaction as a result of the possibility of their oxidation to the corresponding carboxyl compounds.
Halogens in the aromatic ring are also unstable against the action of reducing agents, and they are substituted by
a hydrogen atom. However, the great variety of the employed reducing systems and the possibility of varying
the reaction conditions make it possible to find solutions to these problems in each specific case.
3. CYCLIZATION OF ARENEDIAZONIUM SALTS
This group of methods includes the first examples of the synthesis of the cinnoline system: Richter,
Widman–Stoermer, and Borsche–Herbert cyclizations. In spite of its long history the Richter reaction has only
attracted the attention of investigators in the last decade as a method for the synthesis of 4-halocinnolines. At the
same time the Widman–Stoermer and Borsche–Herbert reactions are already well-studied reactions and are
discussed in detail in the reviews [25-30].
The Widman–Stoermer reaction is a method for the production of cinnolines containing alkyl, aryl, of
heteroaryl substituents at position 4 (Scheme 16). The pyridazine ring is formed during diazotization of ortho-
vinylanilines followed by cyclization involving the diazonium cation and the double bond of the substituent.
509

The reaction takes place at room temperature and gives yields close to quantitative. An important restriction of
the method is the compulsory presence of a substituent at the α-carbon atom of the vinyl substituent, and the
reaction gives highest yields in the case of alkyl or aryl groups. The cinnolines are not formed in the presence of
strong accepting substituents (R
1
= COOH). In some cases the presence of a phenyl substituent at the β-carbon
atom of the double bond leads to the formation of phenanthrene, taking place by the Pschorr reaction, in
competition with the cyclization [25-30].
Scheme 16
R
1
R
2
N
N
N
N
C
+
R
1
H
R
2
N
N
R
1
R
2
–H
+
+
R
1
= Alk, XC
6
H
4
, 2-Py; R
2
= H, Alk, XC
6
H
4
, 2-Py
The Widman–Stoermer reaction is rarely used these days since the obtained 4-alkyl- and aryl(hetaryl)-
substituted cinnolines only find limited use in contemporary synthesis. In view of the substantial demands on the
nature of the substituents in the initial compound it is often more convenient to introduce the aryl fragment into
the already formed cinnoline ring. For this purpose it is possible to use the cross-coupling of halogenocinnolines
with acylboric acids (the Suzuki–Miyaura reaction) [22].
In the middle of the last century the Borsche and Herbert reaction was widely used as a method for the
production of 4-hydroxycinnolines. The method involves diazotization of ortho-aminoacetophenones followed
by cyclization of the obtained arenediazonium salt (Scheme 17) [25-30].
The reaction is fairly universal and makes it possible to obtain a wide range of cinnoline derivatives
containing substituents at various positions of the ring; the yields here amount to 70-90%. Diazotization is
carried out with NaNO
2
in hydrochloric, sulfuric, or formic acids.
Scheme 17
O
R
2
N
2
R
1
N
N
OH
R
2
R
1
OH
R
2
N
2
R
1
R
2
= H, Hal, Alk, Aryl
X
X
–
+
+
–
It is assumed that the cyclization takes place through the formation of the enolic form of the ketone and
is facilitated by the presence in the aminoacetophenones of accepting substituents, which increase the
electrophilic characteristics of the diazo group depending on the nature and position. In the absence of such
substituents the rate-determining stage is the acid-catalyzed enolization, and the reaction becomes sensitive to
the concentration of the acid. In this case it is expedient to conduct the diazotization in concentrated
hydrochloric acid [57-59]. The presence of donating substituents in the aromatic ring initiates the concurrent
process of hydrolysis of the arenediazonium salt and the formation of the corresponding ortho-acetyl derivatives
of phenol. In contrast to the Widman–Stoermer reaction, in the presence of a phenyl substituent in the acetyl
510

fragment of the initial compound the formation of 9-phenanthrol by the Pschorr reaction can be avoided, and in
this case 4-hydroxycinnoline is the only product [60]. The limited application of this method is due to the
difficulties involved in the synthesis of the initial substituted ortho-aminoacetophenones and to the side
reactions involving substitution in the benzene ring [25-30].
A modification of the Borsche–Herbert method was proposed in [61], where the phosphorus ylides of
ortho-aminoacetophenones 15 were used for cyclization (Scheme 18). As an advantage of the method the
authors mention the availability of the initial compounds, which can be obtained with good yields from the
corresponding ester derivatives. Also the yields of the 4-hydroxycinnolines obtained by the method are high.
Scheme 18
O
NH
2
PPh
3
X
N
N
O
PPh
3
X
N
N
OH
X
O
PPh
3
N
2
X
PhONO, HCl
0°C
10% NaOH
30% NaOH
X = H, Cl, Me, OCH
2
O
15
Cl
–
+
From the synthetic standpoint the cyclization of ortho-ethynylarenediazonium salts (the Richter
reaction) is becoming ever more important as a method for the synthesis of 4-halogenocinnolines. On account of
the reactivity of the halogen atom in electrophilic substitution reactions these compounds are convenient
building blocks for the production of biologically active compounds [25, 62, 63], including the 4-amino
derivatives of cinnoline and their salts [64]. On the other hand the development in recent decades of methods for
Pd-catalyzed cross coupling has made the initial ortho-ethynyl-substituted arenediazonium salts containing
various types of substituents in the aromatic ring accessible.
The reaction was discovered during the diazotization of ortho-aminophenylpropionic acid and
cyclization of the diazonium salt in aqueous solution at 70°C (Scheme 19). After decarboxylation of the
obtained 4-hydroxycinnoline-3-carboxylic acid 4-hydroxycinnoline was isolated with a quantitative yield [24].
However, attempts to repeat this synthesis by other investigators led to substantially lower yields [65, 66].
Scheme 19
OH
O
N
2
N
N
OH
OH
O
N
N
OH
Cl
70°C
H
2
O
260°C
– CO
2
+
–
The formation of the same product as in the Borsche–Herbert method as a result of the Richter
cyclization prompted the search for analogies in the mechanisms of these two reactions. In papers by Schofield
and Simpson it was suggested that hydration of the triple bond with the formation of the corresponding ortho-
aminobenzoylacetic acid occurs initially during the diazotization of ortho-aminophenylpropionic acids and
511

cyclization then takes place according to the mechanism of the Borsche–Herbert reaction through an enolic
intermediate [66-68]. In order to check this suggestion the diazotization and cyclization of (2-amino-
benzoyl)acetic acid (16), which according to the hypothesis must act as intermediate in the synthesis performed
by Richter, were carried out (Scheme 20).
Scheme 20
NH
2
OH
O
NH
2
O
OH
O
N
N
OH
OH
O
N
OH
OH
H
2
O, H
NO
16
+
+
However, all attempts to isolate the required acid or its diethyl ester in the individual state were
unsuccessful since during preparation it underwent spontaneous cyclization to 2,4-dihydroxyquinoline. A
similar problem was observed during the diazotization of 2-amino-3-methoxyacetophenone, which must act as
intermediate in the Richter reaction for 2-amino-3-methoxyphenylacetylene. In the presence of a donating
substituent the Borsche–Herbert reaction is realized when the concentrated acids are used, while diazotization of
2-amino-3-methoxyacetophenone under the conditions of the Richter reaction does not lead to the formation of
cinnoline [66-68]. At the same time 2-amino-3-methoxyphenylacetylene itself readily forms the corresponding
cinnoline. While refuting the hypothesis about the initial hydration of the triple bond in the course of the Richter
reaction, the authors put forward the alternative suggestion that the reaction begins with coordination of the
diazonium cation to the triple bond followed by the addition of a water molecule [67]. Later on during study of
the acidity constants and UV spectra of various hydroxycinnolines it was shown that 4-hydroxycinnolines exist
in the form of the other tautomeric form – 4-(1H)-cinnolinones [69, 70].
The investigations in this region continued in the work of Vasilevsky’s group [71-74]. There it was
shown that during the diazotization of 2-aminotolane in HCl medium 4-chlorocinnoline, isolated with a yield of
5%, is formed as a second product in addition to 4-cinnolinone. By realizing this reaction at room temperature it
was possible to increase the yield of the 4-chloro derivative to 41% [71]. This fact also indicated that the halide
anion acts as nucleophile participating in the cyclization. It was also suggested that the 4-cinnolinones are
formed at least partly as a result of hydrolysis of the corresponding 4-halocinnoline (Scheme 21).
Scheme 21
R
NH
2
R
OH
R
N
2
N
N
R
Hal
N
N
R
OH
Cl
Nu
NO
Nu = Hal
Nu = H
2
O
H
2
O, HCl
–
+
+
–
512

This possibility was refuted in Schofield’s papers on account of unsuccessful attempts to detect the
formation of the 4-halocinnoline even in the presence of donating substituents (–OMe) in the benzene ring,
which should increase the stability of the chlorine atom against hydrolysis reactions [67]. When 4-chloro-
cinnoline was boiled in dilute hydrochloric acid it changed completely into 4-cinnolinone; the reverse transition
from 4-cinnolinone to the halogen derivative was not observed [71]. The formation of the 4-halocinnoline is
promoted by decrease of the reaction temperature, increase in the nucleophilicity of the halogen atom, and the
presence of donating substituents. In the reaction at room temperature and with HBr instead of HCl it was
possible to increase the yields of 4-bromocinnolines from 11-54% to 56-93%. It was shown that the 4-cinnolines
are not formed during the cyclization of 5-amino-4-ethynylpyrazoles. On account of the π-electron excess of the
pyrazole ring the halogen atom in the formed pyrazolo[3,4-c]pyridazine is resistant to hydrolysis [74].
An important limitation of the Richter reaction is the presence of the acetylene fragment of the electron-
accepting substituent at the β-carbon atom. The 2-pyridyl- or diethylamino groups are protonated under the
reaction conditions, as a result of which cyclization does not occur; the only products are the corresponding
phenols. This fact is explained on the basis of the proposed Ad
E
mechanism of the reaction; electron-accepting
substituents reduce the electron density of the triple bond, preventing electrophilic addition of the diazonium
cation [71].
The effect of the nature of substituents in the aromatic ring and the reaction conditions on the
composition and yield of the products of the Richter reaction was studied in detail in the series of ortho-alka-
1,3-diynylarenediazonium salts produced during the diazotization of the respective arylamines. In the absence of
substituents in the aromatic ring and also in the presence of donating or weakly accepting substituents (Me, Br)
the only reaction products were 4-chloro-3-ethynylcinnolines, the yields of which amounted to 30-55%. In the
case of the ortho-alka-1,3-diynylarenediazonium salts containing electron-accepting substituents such as –NO
2
or –COOMe groups furo[3,2-c]cinnolines were isolated as the main products together with the 4-chloro-
3-ethynylcinnolines [75].
By spectrophotometric investigations it was possible to establish that the only products from the Richter
cyclization in the presence of electron-accepting substituents are 3-alk-1-ynyl-4-chlorocinnolines, which
undergo hydrolysis in the course of the reaction. The 3-alk-1-ynyl-4-hydroxycinnolines formed as a result of
hydrolysis undergo spontaneous cyclization, giving 2-alkylfuro[3,2-c]cinnolines (Scheme 22) [76].
Scheme 22
N
N
Y
R
Cl
X
N
N
O
R
X
Y
N
N
Y
R
OH
X
Y = COOMe, NO
2
R
Y
X
N
2
2
Y
X
NH
2
R
2
HCl
,
X = H;
Et
2
O, C
6
H
14
NO
+
Cl
–
+
+
-20°C
When the reaction was carried out in methanol saturated with HCl furo[3,2-c]cinnolines were obtained
with yields of 39-54% even during the diazotization of anilines not containing accepting substituents. On the
513

basis of the investigations it was established that a series of transformations take place in the MeOH medium.
The cyclization of ortho-alka-1,3-diynylarenediazonium salts also leads initially to the formation of 3-alk-
1-ynyl-4-chlorocinnolines, which soon undergo solvolysis in the course of the reaction, giving 4-methoxy-
cinnolines. It was possible to isolate 4-methoxycinnoline by treating the reaction mixture with anhydrous
triethylamine. The presence of water, released as a result of diazotization, in the reaction mixture leads to
subsequent hydrolysis of the 4-methoxycinnoline. On account of the further cyclization of 4-hydroxycinnoline
to furo[3,2-c]cinnoline the hydrolysis reaction is irreversible. The solvolysis and hydrolysis reactions are
promoted by protonation of the cyclization products in the anhydrous methanol saturated with HCl [76].
In papers by Fedenok’s group, concerning investigations of the cyclization of derivatives of 6-alkynyl-
1,4-naphthoquinone-5-diazonium salts [77-79], it was found that the reaction in this case leads to the formation
not only of the pyridazine but also the pyrazole ring depending on the conditions of cyclization. Cyclization of
the diazonium salt 17 with dilution of the reaction mixture with water leads to closure of the pyridazine ring and
the formation of compound 18. If the initial solution of the diazonium slat 17 is diluted with 20% NaCl, after
2 min compound 19, containing a pyrazole ring, is formed as the only reaction product (Scheme 23).
Scheme 23
O
O
Et
2
N
N
N
CH
2
R
1
O
O
Et
2
N
C
N
N
C
CH
2
R
1
Cl
O
O
Et
2
N
NH
N
CH
2
R
1
O
O
O
Et
2
N
N
H
N
CH
2
R
1
Cl
Cl
O
O
Et
2
N
N
H
N
CH
2
R
1
Cl
Cl
20% NaCl
H
2
O
19 (60%)
18% HCl
18 (25%)
17
20
18
19
2 h
21 (15%)
+
–
+
+
On the basis of quantum-chemical calculations of the energy profile of the reaction [80] it was
concluded that the cyclization of the arenediazonium salt with the formation of both a six-membered ring and a
five-membered ring is an energetically unfavorable process with a high activation energy. Moreover, attack by
the terminal nitrogen atom at the β-carbon atom of the triple bond is unlikely on account of the large distance
between them. In the opinion of the authors the reaction must begin with the addition of the halogen at the
second position of the triple bond, which according to the calculations has a small positive charge (+0.05). As a
result of change in the initial geometry of the system cyclization leads to the formation of a five-membered ring
containing an exocyclic double bond.
514

During the cyclization of the diazonium salt 17 3 min after dilution of the reaction mixture with water it
was possible to detect a compound to which structure 20 was assigned on the basis of the
1
H NMR spectrum and
also the data from mass-spectrometric analysis (Scheme 23). On treatment of a solution of compound 20 in
chloroform with a 20% solution of NaCl it was fully converted, and the product 19 was formed; on dilution with
18% HCl a mixture of products 18, 19, and 21 was formed. On the basis of the obtained data the authors
concluded that both the six- and the five-membered ring in the series of naphthoquinones is formed through the
single intermediate 20 in a multistage process. Ring enlargement takes place under conditions with
thermodynamic control, whereas the reactions with retention of the pyrazole ring are kinetically controlled
processes.
This is supported by the calculated data, according to which compound 19 is less stable than compound
18 [79]. The formation of naphthocinnolinone 18 was observed when there was a diethylamino group at position
3, which in the authors’ opinion reduces the electrophilicity of the exocyclic carbon atom at the double bond in
the intermediate 20 and prevents repeated attack of the chloride ions leading to the five-membered products.
Thus the formation of a six-membered ring was not observed in the reaction with ethynylnaphthoquinones
unsubstituted at position 3.
The same authors carried out investigations into the effect of the reaction conditions and the nature of
the substituent at the triple bond for the Richter reaction in the series of ortho-phenylethynylanilines [80, 81]. As
in the case of naphthoquinones the cyclization was carried out in three versions: with dilution of the reaction
mixture containing the diazonium salt with water and with concentrated solutions of NaCl and HCl. The
cyclizations conducted in water and NaCl solution were comparable in rate and finished in a few minutes,
whereas the reaction in HCl solution required 2 h. It was found that in this case the reaction conditions did not
affect the composition of the products, but the electronic nature of the substituents played an appreciable role.
The presence of donating groups in the phenyl substituent at the triple bond promoted the formation of the five-
membered products whereas the presence of accepting groups promoted the production of the six-membered
products (Scheme 24), which may favor the formation of a cationic intermediate in the course of the cyclization.
Scheme 24
X
N
N
N
H
N
O
X
N
N
Cl
X
X = NMe
2
, OMe
X = NO
2
+
Cl
–
An interesting modification of the Richter reaction is the use of ortho-ethynyl-substituted
phenyltriazenes, in which the triazine fragment acts as a masked diazonium cation, for cyclization [82, 83]. This
method of synthesis was used for the creation of combinatorial libraries [84]. An obvious advantage of this
approach for the Richter reaction is the possibility of separating the diazotization and cyclization stages, which
makes it possible to avoid side reactions.
Thus, Brase realized the synthesis of 4-halocinnolines during the treatment of alkynyl-substituted
triazines with solutions of hydrohalic acids (Scheme 25) [82, 83]. The reaction was conducted in a solid-phase
version on a polystyrene support, which significantly simplified the isolation and purification of the final
products. Good yields of 4-halocinnolines were obtained with HCl and HBr, where cyclization took place in
acetone under mild conditions.
515

Scheme 25
N
N
N
R
1
Ph
N
N
Cl(Br)
R
1
R
2
OBn
SiMe
3
R
2
HCl (HBr)
R
1
= SiMe
3
, C
5
H
11
,
R
2
= H, F,
acetone / H
2
O
,
The corresponding 4-cinnolinones were formed as side products, and their yields increased with increase
in the reaction time. When a more dilute hydrohalic acid was used the 4-cinnolinones were the main products.
Decomposition of the ethynyl-substituted triazines in HF and HI did not lead to the formation of the desired 4-
iodo- and 4-fluorocinnolines.
Another example of the cyclization of ortho-ethynyl-substituted triazines by heating the compounds in
ortho-dichlorobenzene was described in Kimball's papers [85-89]. Initially, on heating to 170°C a mixture of
products was obtained – the isoindazole 22 and cinnoline 23 in a ratio of 1:1 (Scheme 26). The authors chose
reaction conditions that made it possible to obtain each of the cyclization products selectively. Thus, increase of
the reaction temperature to 200°C led to the formation of the cinnoline with yields of 80-90%, while reaction in
the presence of CuCl at 50°C made it possible to obtain the isoindazole as the main product (yields 60-80%).
Scheme 26
N
N
NEt
2
H
R
N
N
NEt
2
CHO
R
N
N
R
170
o
C
CuCl, 50°C
R = F, Cl, Br, CN, Me, t-Bu
22
23
+
200°C
1,2-C
6
H
4
Cl
2
Substituents in the aromatic ring do not have a significant effect on the course of the reaction. According
to calculations, isoindazole is less stable, and its formation is characterized by a smaller activation energy
compared with cinnoline. It is clear that the formation of cinnoline is a thermodynamically controlled process
whereas under kinetic control the reaction is directed toward the isoindazole [87, 88].
It was shown that the isoindazole 22 is formed through the carbene intermediate 24 as a result of its
reaction with atmospheric oxygen. As evidence for the generation of the carbene the authors prepared its
dimerization product 25 and the adduct from the reaction of the carbene 24 with 2,4-dimethylbut-2-ene 26
(Scheme 27).
On the basis of quantum-chemical calculations and experimental data it was assumed that the cinnolines
are formed from the triazines through a zwitterionic intermediate, which has a small share of biradical character.
The proposed mechanism of transformation of the triazines into cinnolines is presented in scheme 28 [86].
516

Scheme 28
N
R
N
NEt
2
H
N
N
NEt
2
H
R
N
N
NEt
2
R
N
N
R
Et
2
N
N
N
NEt
2
R
Me
Me
Me
Me
Me
2
CCMe
2
..
MeI, 145
o
C
CuCl,
DCE
CuCl,
CH
2
Cl
2
R = CN, t-Bu
24
22
25
26
~20
o
C
Scheme 28
N
N
NRR
1
H
N
N
NRR
1
N
N
N
R
1
H(D)
N
N
N
R
1
H(D)
N
N
H(D)
N
R
1
R
N
N
NRR
1
H
N
N
NRR
1
H
N
N
N
R
1
H(D)
N
N
H(D)
N
R
1
R
+
+
1,3-1,3-zwitterion
Е = 0 kcal/mol
1,2-zwitterion
Е = -13.1 kcal/mol
–
–
–
–
–
–
+
+
+
++
+
517

During cyclization in benzhydrol deuterated at the O-H bond cinnolines containing the deuterium atom
at both at position 3 and at position 4 were obtained. In terms of the proposed mechanism this is explained by
rearrangement of the 1,3-zwitterionic intermediate into the 1,2-zwitterion. Such a rearrangement had already
been described in the literature for the case of pyridine systems; the 1,2-zwitterion is regarded as more stable
[90]. The diethylamino group leaves in the form of the imine, giving up a proton to the negatively charged
carbon atom.
Another approach to the synthesis of complex heterocyclic systems containing the cinnoline system
involves electrophilic reactions in the aromatic ring, which take place with the participation of the diazonium
cation. This method is not general, and there have not therefore been any systematic investigations in this
direction.
The possibility of such a reaction was first demonstrated by Hata's group [91], where the condensed
cinnoline 27 was isolated as side product as a result of the diazotization of 2,2′-diamino-4,4′-dimethoxybiphenyl
during an attempt to prepare 2,7-dimethoxyphenylene oxide (Scheme 29). Later Sandin and Cairns realized the
synthesis of benzo[c]cinnoline with a yield of 45% according to the same reaction scheme by using arsenic
oxide instead of copper sulfate [92]. This method was not developed further; at present the most convenient
method for the production of benzo[c]cinnolines is the reduction of 2,2′-dinitrobiphenyls mentioned earlier.
Scheme 29
N
2
N
2
OMe
MeO
O
OMe
MeO
N N
OMe
MeO
CuSO
4
Cl
Cl
27
–
–
+
+
+
Electrophilic attack by the diazonium ion on the furan ring leads to opening of the ring. The
electrophilic mechanism for the process is confirmed by the cis configuration of the substituent at position 3 of
the cinnoline ring (Scheme 30) [93].
Scheme 30
R
2
R
2
NH
2
O
O
R
1
R
1
R
2
R
2
O
O
R
1
R
1
N
N
O
N
N
R
2
R
2
O
R
1
R
1
H
N
N R
1
O
O
R
1
R
2
R
2
i-PrONO
Me
3
SiCl,
MeCN
R
1
= Alk, R
2
= H, OAlk
80-90%
+
+
518

An example of the use of such cyclization in the pyrrole series is the synthesis of derivatives of
indolo[3,2-c]cinnolines exhibiting biological activity against leukemia (Scheme 31) [94].
Scheme 31
NH
2
R
1
R
2
N
H
R
3
N
H
N
N
R
3
R
1
R
2
NaNO
2
AcOH, 0°C
R
1
= H, Cl; R
2
= H, Cl, Me; R
3
= H, Cl, Br, OMe, NO
2
The chief advantages of the method are the mild conditions, the high yields of the desired products, and
the tolerance of the reaction toward the nature of substitution. The last factor makes it possible to insert the
functional substituents required for selective bonding with DNA both into the indole fragment and into the
cinnoline fragment.
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