Gas-phase pyrolysis in organic synthesis. Part 3: Novel cyclization of 2-arylhydrazonopropanals into cinnolines

Article abstract of DOI:10.1002/kin.1035

3-oxo-3-aryl-2-arylhydrazonopropanals (1) have been converted under thermal gas-phase conditions cleanly into cinnolines (2). A plausible mechanism is suggested to account for this transformation based on the kinetics and products of reaction.

Full text of DOI:10.1002/kin.1035

Gas-Phase Pyrolysis in
Organic Synthesis. Part 3:
Novel Cyclization of 2-
Arylhydrazonopropanals
1
into Cinnolines
AJITH KUMAR, NOURIA A. AL-AWADI, MOHAMED H. ELNAGDI, YEHIA A. IBRAHIM,
KAMINI KAUL
Chemistry Department, Kuwait University, P.O. Box 5969, 13060, Safat, Kuwait
Received 27 July 2000; accepted 14 March 2001
ABSTRACT: 3-oxo-3-aryl-2-arylhydrazonopropanals (1) have been converted under thermal
gas-phase conditions cleanly into cinnolines (2). A plausible mechanism is suggested to ac-
count for this transformation based on the kinetics and products of reaction. ᭧ John Wiley &
Sons, Inc. Int J Chem Kinet 33: 402–406, 2001
INTRODUCTION
moiety of the hydrazone on the formyl carbonyl car-
bon, followed by elimination of water to produce cin-
noline (2). Alternatively, one would assume initial
thermal isomerization of 1 into 1Ј, which will undergo
6-␲-electrocyclization process to produce 1Љ via a
quasi-aromatic six-membered transition state followed
by elimination of water to yield cinnoline (2). Ac-
cording to mechanism (A), electron-donating substit-
uent (X), which will increase the nucleophilicity of
the ring, should significantly accelerate the reaction
rate.
By contrast, mechanism (B) predicts that electron-
withdrawing substituent (X) should enhance the re-
action rate if the thermal isomerization of 1 to 1Ј is
the rate-controlling factor since this will increase the
acidity of the hydrogen atom of the hydrazono group
involved in the isomerization process of 1 to 1Ј. While
a negligible electronic effect of the substituent (X) on
the rate of reaction would be observed if the 6-␲-elec-
trocyclization of 1Ј into 1Љ is the rate-controlling fac-
tor.
This article describes an efficient synthesis of 3-aroyl-
cinnolines via cyclization of 2-arylhydrazonopropan-
ols under gas-phase conditions (Scheme I). Kinetic
data were used to suggest a mechanism for this cycli-
zation reaction based on the products of the reaction.
It is of value to report here that synthetic ap-
proaches to cinnolines are rather limited; cyclization
of the monophenylhydrazones of benzil and 4,6-di-
methyl-1,2-cyclohexanedione in sulfuric acid was re-
ported more than half century ago and no further report
for the application of this procedure to other deriva-
tives was reported [2].
Two possible pathways for the gas-phase cycliza-
tion of (1) to (2) could be postulated (Scheme II). The
first one involves a nucleophilic attack by the aromatic
Correspondence to: N. A. Al-Awadi (chesc@kuc01.kuniv.
edu.kw)
1
See [1].
᭧
2001 John Wiley & Sons, Inc.

GAS-PHASE PYROLYSIS IN ORGANIC SYNTHESIS. PART 3
403
O
Ar
O
H
N
N
X
H
N
Ar
O
H
⌬
(2)
N
Ar
O
X
X
X
N
N
1
(a–k)
(3)
No.
Ar
C H5
X
a
b
c
d
e
f
H
H
H
H
H
H
6
4-ClC H4
6
4-MeC H4
6
4-MeOC H
2-Furyl
2-Thienyl
6
4
g
h
i
C H5
4-OMe
4-NO2
4-Cl
6
C H5
6
C H5
6
j
k
C H5
4-OMe
3-Cl
6
C H5
6
Scheme I
EXPERIMENTAL
Kinetic Procedure and Product Analysis
standard were pipetted into the reaction tube, which
was then sealed under vacuum (0.28 mbar) and placed
inside the pyrolyzer for 600 s at a temperature at which
1
0–20% pyrolysis is deemed to occur. The contents
Experimental details of both kinetic and reaction prod-
uct analysis have been described in an earlier com-
munication [5].
of the tube were analyzed using the HPLC probe.
At least three kinetic runs were repeated for each
5
–10ЊC rise in temperature of the pyrolyzer and for
the same time interval until 90–95% pyrolysis was
achieved. The rates were followed over a temperature
range exceeding 55 K, and the rate coefficients were
calculated using the expression for a first-order reac-
Kinetic Studies.
Reaction Set-up. Preliminary kinetic results were
obtained on a system featuring a Eurotherm 093 py-
rolysis unit coupled to a Perkin Elmer Sigma 115 gas
chromatograph. The kinetic data reported are from a
reactor set-up including: (1) HPLC (Bio-rad Model
tion: kt ϭ ᐉna /a. The Arrhenius parameters were ob-
0
tained from a plot of log k vs. 1/T(K).
2
1
700) fitted with a UV/VIS detector (Bio-rad Model
740); HPLC: Column LC-8, 25 cm, 4.6 mm, 5 ␮m
(Supelco); and a CDS custom-made pyrolysis unit for
Product Analysis.
Flow Technique. Solutions of substrates in chloro-
benzene were passed down a 1-m reactor column
packed with helices. The column was heated to tem-
peratures comparable to those used in the kinetic in-
vestigations. The products of pyrolysis were swept
through the column using a stream of nitrogen gas,
and the effluents were trapped in a glass coil sur-
rounded by a jacket of dry ice. The material collected
the thermolysis reactions. The pyrolysis tube is jack-
eted by an insulating aluminium block fitted with a
platinum resistance thermometer and a thermocouple
connected to a Comark microprocessor thermometer.
Kinetic Runs and Data Analysis. Aliquot parts (0.2
ml) of very dilute solutions (ppm) of neat substrates
in acetonitrile as solvent and chlorobenzene as internal

4
04
KUMAR ET AL.
Ϫ
O
O
O
O
H
H
N
HO
H
N
X
X
X
Ar
Ar ϪH2O
Ar
N
ϩ
N
H
N
H
N
(2)
electrophilic
A) aromatic
substitution
(
O
C
O
X
H
Ar
ϪH O
2
H
N
N
H
thermal
isomerization
(1)
(B)
OH
O
O
H OH
X
X
H
Ar
Ar
6-p-electrocyclization
N
N
N
N
H
(1Љ)
(1)
Scheme II Pathways for the gas-phase cyclization of 2-arylhydrazonopropanals into cinnolines (2).
on the walls of the trap (glass coil) was crystallized
and analyzed by NMR spectroscopy.
The relative rate values at 550 K (Table II) for the
gas-phase cyclization of (1) to (2) show no significant
effect of the subsistent on the reaction rate, so mech-
anism (A) is improbable. We therefore suggest that the
cyclization reaction proceeds via mechanism (B),
which is initiated by a thermal isomerization of (1) to
RESULTS AND DISCUSSION
Kinetics
(1Ј) followed by a rate-determining step that involves
6
-␲-electrocyclization of (1Ј) into (1Љ). The latter then
Ϫ
1
The rate coefficients k/(s ) are used to determine the
dehydrates to produce cinnoline (2).
Ϫ
1
E (kJ mol ) values of compounds (Table I). Each rate
a
coefficient represents the mean from three kinetic runs
in agreement to within Ϯ2%. The reactions were as-
certained to be homogeneous, unimolecular, and free
of reactor surface effects. The Arrhenius plots were
linear up to Ն95% reaction. The homogeneous nature
of the reaction was tested by comparing rates using a
normal reactor with those obtained when the reactor
vessel is packed with helices. Absence of a free radical
pathway in the elimination reaction is confirmed using
established procedures [3,4]. The relative rates of gas-
phase pyrolysis of the substrates 1(a–k) are recorded
in Table II.
Product Analysis
The cyclization of compounds 1(a–k) into the corre-
sponding cinnolines upon pyrolysis in the gas phase
is remarkably straightforward. The product from this
cyclization may be formulated as 3-aroyl derivatives
(2) or the isomeric 3-carboxaldehyde derivatives (3)
(Scheme I). However, based on careful spectral anal-
ysis, the former were proved to be the sole reaction
product. Moreover, we found that the same cinnoline
derivatives (2) could be made by acid-catalyzed cy-
clization of the corresponding hydrazones 1.

GAS-PHASE PYROLYSIS IN ORGANIC SYNTHESIS. PART 3
405
Table I Kinetic Data for Gas-Phase Cyclization of
O
H
N
Ar
O
H
N
X
Ϫ
1
Ϫ1
Cpd.(1)
Ar
X
H
T(k)
438.3
k(s )
E (kJ mol )
a
(a)
C H5
6
0.29
0.79
2.73
3.50
6.14
11.25
0.27
0.80
2.34
3.01
3.73
6.33
9.36
0.33
1.06
1.53
2.04
5.37
6.75
0.42
0.62
2.29
3.19
4.56
6.88
8.10
1.40
1.78
2.56
3.67
5.09
6.83
0.61
0.99
3.25
5.00
7.24
6.47
8.53
13.56
30.09
3.60
4.80
9.65
15.90
19.91
22.10
61.26 Ϯ 0.76
4
5
5
5
5
63.3
02.9
13.5
34.3
58.3
(
b)
4-ClC H4
H
434.8
53.79 Ϯ 2.87
6
4
4
5
5
5
5
62.8
93.8
08.5
22.5
44.4
64.8
(
c)
d)
4-MeC H4
H
H
440.7
45.18 Ϯ 1.34
54.94 Ϯ 0.95
6
4
4
5
5
5
69.1
86.3
01.4
48.8
58.2
(
4-MeOC H4
446.3
6
4
5
5
5
5
5
59.7
00.6
16.3
32.3
51.4
59.6
(
e)
f)
2-Furyl
H
H
496.05
62.60 Ϯ 1.72
43.00 Ϯ 1.11
5
5
5
5
5
05.95
18.95
32.05
43.85
53.65
(
2-Thienyl
443.85
4
5
5
5
60.25
22.55
43.45
63.25
(
g)
h)
C H5
6
4-OMe
4-NO2
517.5
63.19 Ϯ 0.48
31.38 Ϯ 0.67
5
5
5
33.25
48.45
79.35
(
C H5
6
434.75
4
4
5
5
5
46.95
85.15
24.15
37.05
48.25
(continues)

4
06
KUMAR ET AL.
Table I Continued
Ϫ
1
Ϫ1
Cpd.(1)
Ar
X
T(k)
k(s )
E (kJ mol )
a
(
i)
C H5
4-Cl
518.45
1.98
4.90
7.12
12.53
1.83
2.38
74.94 Ϯ 4.40
6
5
5
5
48.35
63.55
78.35
(j)
C H5
6
3-OMe
3-Cl
526.75
84.96 Ϯ 3.41
5
5
5
6
40.85
54.95
83.35
05.05
4.08
11.10
18.93
4.63
(k)
C H5
6
539.95
74.93 Ϯ 7.27
5
5
5
5
52.25
64.05
76.55
88.25
7.01
10.96
12.1
19.6
In this communication, the mechanism of the gas-
substrates (propanals) and a detailed n.m.r. and m.s.
spectra analysis of the formed cinnoline, is a subject
of another publication.
phase pyrolysis of (1) as an interesting route toward
cinnoline derivatives is described. Kinetic and mech-
anistic study of acid-catalyzed synthesis of (2) from
(1), together with a detailed synthetic procedure of the
The support of Kuwait University through research grant
No. SC 091 and use of the facilities of ANALAB and SAF
is gratefully acknowledged.
Table II Rate Coefficients and Relative Rates at 550 K
for Gas-Phase Cyclization of 2-Arylhydrazonopropanals
(1a–K)
4
Ϫ1
Compound (1)
10 k(s ) 550 K
krel.
a
b
c
d
e
f
g
h
i
9.37
7.48
5.59
6.83
5.99
5.90
14.45
23.03
5.22
3.57
6.49
1
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0.8
0.6
0.7
0.6
0.6
1.5
2.4
0.5
0.4
0.7
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j
k