Comparative studies for selective deprotection of the N-arylideneamino moiety from heterocyclic amides: Kinetic and theoretical studies

Article abstract of DOI:10.1016/j.tet.2005.10.069

The kinetics, product analysis and theoretical studies for selective deprotection of N-arylideneamino pyridone, pyrimidinone and triazinone systems were carried out. Their reactivities were compared with each other and with related compounds previously studied. This reaction represents an efficient, clean and general synthetic procedure for the protection and selective synthesis of potential biologically active pyridines, pyrimidines and triazines and their derivatives.

Full text of DOI:10.1016/j.tet.2005.10.069

Tetrahedron 62 (2006) 1182–1192
Comparative studies for selective deprotection of the
N-arylideneamino moiety from heterocyclic amides:
kinetic and theoretical studies
Bobby J. George, Hicham H. Dib, Mariam R. Abdallah, Maher R. Ibrahim,
*
Nasser S. Khalil, Yehia A. Ibrahim and Nouria A. Al-Awadi
Chemistry Department, Kuwait University, PO Box 5969, Safat 13060, Kuwait
Received 21 June 2005; revised 11 October 2005; accepted 27 October 2005
Available online 28 November 2005
Abstract—The kinetics, product analysis and theoretical studies for selective deprotection of N-arylideneamino pyridone, pyrimidinone and
triazinone systems were carried out. Their reactivities were compared with each other and with related compounds previously studied. This
reaction represents an efficient, clean and general synthetic procedure for the protection and selective synthesis of potential biologically
active pyridines, pyrimidines and triazines and their derivatives.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ones 2 and their thio analogues 32 (Scheme 2). The kinetic
results and product analysis of these compounds lend
support to a reaction pathway involving a six-membered
transition state and the thiooxotriazoles 3 were found to be
103-fold more reactive than the corresponding oxotriazoles
2. In order to investigate further in this elimination
reaction, 4-arylideneamino-3(2H)-thioxo-1,2,4-triazin-
Gas-phase pyrolytic elimination of arylnitriles from
N-arylideneamino heterocyclic compounds were started with
the Schiff bases of 1-arylmethyleneamino-1,2-dihydro-4,
6-dimethyl-2-oxopyridine-3-carbonitrile 1a–e (Scheme 1).1
This was followed by a gas-phase study on the elimination
of arylnitriles from 4-arylideneamino-1,2,4-triazol-3(2H)-
5(4H)-ones
4
and 4-arylidieneamino-3-methylthio-
1,2,4-triazin-5(4H)-ones 5 were synthesized, and pyrolytic
Ar
Ar
Me
Me
N
C
O
Me
Me
N
C
O
Me
Ar
C
N
H
N
H
N
H
O
+
N
CN
CN
Me
CN
T.S.
1a-e
Ar
a 4-NO2C6H4
4-ClC6H4
C6H4
b
c
4-MeC6H4
4-MeOC6H4
d
e
Scheme 1.
Keywords: Arylideneamino; Pyrolysis; Kinetics; Mechanism.
*
Corresponding author. Tel.: C965 4985537; fax: C965 4816482; e-mail: nouria@kuc01.kuniv.edu.kw
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.069

B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
1183
In the present study we have extended the investigation to
include arylideneamino pyrimidinones 6–9, condensed
pyrimidinones 10, pyridone 11, and condensed triazinone
systems 12–14 (Scheme 5).
N
NH
Ar
N
NH
Ar
N NH
ArCN
N
N
X
H
N
N
X
H
N
H
X
2. Results and discussion
2.1. Product analysis
Ar = C6H5, 4-ClC6H4, 4-CH3C6H4, 4-CH3OC6H4
2, X = O
3, X = S
Substrates 6–14 were prepared and fully characterized by
NMR and MS, as described in the Experimental section. The
products of static as well as flash vacuum pyrolysis of each
substrate were analyzed and the constituents ofthe pyrolysates
from 6–11 were ascertained to be arylnitrile together with the
heterocyclic fragment, while FVP of 12–14 resulted in further
fragmentation of the heterocyclic product (Table 1).
Scheme 2.
deprotection of these substrates were carried out
(Scheme 4).3
Based on the product analysis together with kinetic results
and in the absence of theoretical studies two mechanistic
pathways were suggested (Scheme 3). Theoretical studies
showed that the carbonyl, and not the thione bond, attacks
the hydrogen atom of the arylidinimino groups.
2.2. Kinetic studies
For each substrate, first-order rate coefficients were obtained
at regular temperature intervals. Each rate constant is an
N
NH
Ar
N
NH
O
N
N
S
ArC
N
+
O
O
N
SH
H
N
NH
Ar
A
N
NH
NH
O
N
N
S
H
N
H
S
4
N
NH
N
N
ArC
N
O
N
N
S
+
HO
S
H
Ar
B
Scheme 3.
N
N
N
N
ArCN
+
O
N
N
SCH3
O
N
H
SCH3
H
Ph
5
Scheme 4.

1184
B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
N
O
Ph
N
S
Ph
N
N
H
H
H
H
O
O
N
H
O
O
N
H
6
7
OCH3
OCH3
N
O
N
S
N
N
N
H
N
H
8
9
CH3
CN
O
N
O
Ph
N
H3C
N
N
O
H
H
N
H
N(CH3)2
O
10
11
O
H3C
N
Ph
N
N
N
O
H
N
N
N
O
H
N
N
N
13
12
Ph
Ph
O
N
Ph
N
N
O
H
N
N
14
Ph
Scheme 5. Substrates under study.
average of at least three independent measurements in
agreement to within G2%. The reactions for which the
kinetic data were obtained have been ascertained to be
homogeneous, unimolecular, non-catalytic and non-radical
proceses.4,5 Arrhenius plots of the data using first-order rate
equation:
involved in the reaction pathway, whereas in 7, not
only the lone pair of electrons on N1 will be less
effectively delocalized onto the thione sulfur, but also
the lone pair of electrons of N3 will be delocalized
preferentially onto the carbonyl oxygen rather than
the thione sulfur, which results in decreasing the
protophilic character of the thione sulfur relative to
that of the carbonyl oxygen involved directly in the
reaction pathway. The enhanced protophilicity of
C]O over C]S moiety were reported not only in
the preferential involvement of C]O over C]S in
thioxotriazine 4 which was supported by theoretical
study, but also observed in the thermal elimination
reaction of N-acetylthiourea6 and N-acetyl-
N-phenylthiourea,7 where introducing a phenyl group
in N-acetyl-N0-phenylthiourea has influenced the proto-
philicity of C]S moiety to an extent that has restored the
H-bonding facility of the acetyl C]O group and have
further increased the acidity of the remaining hydrogen of
the amino group, thus enhancing its interaction with
C]O over C]S function.
K1
log k ðsK1Þ Z log AKEaðkJ molK1Þð2:303RTÞ
were strictly linear over R95% reaction with correlation
coefficient in the 0.99G0.005 range. The log A, Ea values
and the first-order rate constants of the nine compounds
under investigation are given in Table 2.
The main features of the kinetic results (Scheme 6) are as
follows:
† Compound 6 is 114 times more reactive than 7; this
can be attributed to the enhanced nucleophilicity
(protophilicity) of the carbonyl oxygen atom of 6 due
to the fact that the lone pair of electrons on N1 and
on N3 are delocalized onto the carbonyl oxygen atom

B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
1185
Table 1. Pyrolysis products and % yield of compounds 6–14 under static pyrolysis and FVP
Compound
% Yield (FVP/static)
NH
Ph–C^N
(85/58)
6
O
N
O
H
(16/39)
NH
Ph–C^N
(99/14)
7
8
9
O
N
H
(0/4)
S
N
Ph–C^N
(72/29)
O
N
H
(38/15)
OH
S
NH
Ph–C^N
(47/8)
O
N
H
(0/4)
O
Ph–C^N
(93/32)
NH
10
N
H
O
(37/15)
CH3
CN
NC–N(CH3)2
(81/72)
11
H3C
N
H
OH
(26/72)
O
O
N
H3C
O
N
N
N
HN
Ph–C^N
(87/65)
12
13
H3C–C^N (67/0)
H2N
N
O
(0/39)
O
Ph
O
N
Ph–C^N
(100/63)
N
HN
N
H
N
H2N
N
(11/0)
(0/59)
O
O
N
H
C
CN
C
Ph
N
N
HN
Ph
H
Ph–C^N
(52/24)
14
(48/0)
O
N
H
Ph
CN
H2N
N
C
C
(9/0)
(0/29)
H
H
(47/0)

1186
B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
Table 2. Rate coefficients (k/sK1), Arrhenius parameters of compounds 6–14
Compound
T/K
104 k/sK1
log A/sK1
Ea/kJ molK1
148.45G1.72
k500K /sK1
6
549.95
557.85
571.25
579.00
593.05
600.15
609.95
619.90
634.80
639.95
644.95
649.95
654.85
537.35
549.55
563.75
576.55
609.80
624.65
631.10
639.65
649.80
435.45
453.65
476.45
509.25
517.35
551.90
569.65
587.05
604.35
445.85
455.65
475.55
485.75
496.05
440.50
450.30
460.25
470.05
480.35
490.45
419.15
464.90
476.55
487.95
499.35
3.514
5.744
11.49
17.58
37.06
1.875
3.637
6.626
14.90
19.38
25.53
31.81
41.94
4.368
8.638
18.10
39.51
4.652
10.91
14.26
23.81
41.54
0.925
2.839
10.521
49.947
0.184
2.942
6.644
10.77
25.07
2.173
4.451
15.527
29.428
57.036
0.674
1.320
3.020
6.679
14.461
28.849
1.234
9.851
16.868
27.013
36.924
10.48G0.16
1.441!10K5
7
12.24G0.16
185.40G2.12
1.256!10K7
8
9
10.57G0.44
11.98G0.15
143.46G4.73
178.81G1.84
3.877!10K5
2.013!10K7
10
11
7.95G0.14
9.90G1.24
99.881G1.21
143.76G13.3
3.308!10K3
7.648!10K6
12
13
10.21G0.15
12.12G0.26
119.79G1.44
139.19G2.36
6.932!10K3
5.460!10K3
14
5.42G0.16
75.723G1.44
3.975!10K3
† Reactivity of compounds 8 and 9 parallels that of
compounds 6 and 7, respectively. Compound 8 is 192
times more reactive than 9 for the same reason used to
explain the reactivity of 6 over 7.
more difficult in the transition state suggested in the
mechanistic pathway for the elimination of NCN(Me)2
from compound 11.
† Two alternative pathways could be postulated for the
elimination of PhC^N from 12–14 (Schemes 7 and 8)
respectively, pathway (A) involves nucleophilic attack of
the C]O group on the hydrogen of the arylidene moiety
while pathway (B) involves nucleophilic attack of the
C]N on the same hydrogen atom. To make the choice
between (A) and (B), we have examined both pathways
theoretically for two compounds 12 and 13 as described in
Section 2.2 below.
† The relative reactivity of 230 of 10 over 6 could be
attributed to the fact that the lone pair of electrons on the
nitrogen atom of 10 is effectively delocalized by cross
conjugation onto the two carbonyl oxygens, while in 6 the
delocalization is limited to one carbonyl oxygen (Fig. 1),
this will result in greater polarity of N–N bond
(a) involved in the transition state for 10 over 6.
Consequently, this will facilitate breaking of this
particular bond and hence accelerate the reaction rate.
† The reactivity of compound 11 is best related to 1.
Compound 11 is ca. 11 less reactive than compound 1.
This decrease in reactivity of compound 11 could be
attributed to the fact that the N(Me)2 moiety has CM
effect which will result in the N–N bond of 11 having high
electron density (Fig. 2), thus render breaking this bond
Results are in good agreement with many reported studies
which favor the oxo forms of cyclic amides and vinylogous
amide over the hydroxyl forms. These studies involved
many experimental techniques (NMR, IR, UV, X-ray)8a,b as
well as theoretical calculation8b on some model compounds
mainly from the oxo-hydroxypyridine derivative.

B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
1187
krel.
N
O
Ph
N
S
Ph
N
N
H
H
O
N
O
N
H
H
7
6
k500K/s-1 1.44 x 10-5
1.26 x 10-7
114.3
OCH3
OCH3
N
N
N
N
H
N
H
O
N
O
O
N
S
H
H
8
9
k500K/s-1 3.88 x 10-5
O
2.01 x 10-7
193.0
N
O
Ph
N
N
Ph
H
H
N
H
O
N
O
H
10
6
k500K/s-1 3.31 x 10-3
1.44 x 10-5
229.9
CH3
CH3
CN
CN
H3C
N
N
O
H
H3C
N
N
O
H
Ph
N(CH3)2
1
11
7.65 x 10-6
k500K/s-1 8.54 x 10-5
11.2
Scheme 6. Relative reactivity of compounds 1 and 6–11 at 500 K.
(a)
2.3. Computational studies
O
Theoretical studies on the thermolysis of methyl and phenyl
substituted compounds 12 and 13, respectively, in the gas
phase were carried out using an ab initio SCF method.
Calculations were carried out to explore the nature of the
reaction mechanism of the unimolecular decomposition of
studied reaction. Two competitive reaction pathways for the
decomposition process have been studied (Schemes 7
and 8). All the calculations were performed with the
TITAN and SPARTAN computational packages.9,10
N
O
Ph
N
O
Ph
N
N
H
H
N
H
O
N
H
10
6
Figure 1.
CH3
CH3
The geometric parameters of the substrates, the transition
states, and the products of compounds 12 and 13 were fully
optimized at the HF/3-21G* level to obtain the energy
profile corresponding to the studied reaction. Each
stationary structure characterized by frequency calculations
was a minimum or saddle point of first-order. A scaling
factor of 0.9207 for the zero-point vibrational energies has
been used.11 The main distances of the optimized structure
of the two pathways of 12 and 13 is represented in Table 3.
CN
CN
H3C
N
N
O
H
H3C
N
N
O
H
Ph
N
H3C
CH3
1
11
Electronic energies, Zero-point vibrational energies, Enthal-
pies, and Entropies, evaluated at the HF/3-21G* level of
Figure 2.

1188
B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
O
O
X
N
X
N
N
N
C1
C7
C3
C1
C7
C3
O5
H6
N2
N4
O5
H6
N2
N4
N8
N8
Ph
Ph
12-14
(T.S.I)
N
C
N
C
O
O
X
N
X
N
N
N
+
+
C1
C3
C1
N2
C3
N2
N4
O5
H6
N4
O5
H6
Imidol (PI)
(T.S.III)
N
C
O
X
+
C1
C3
O5
N2
H6
N4
(Product)
X
CH3
Ph
12
13
14
Ph
Scheme 7. Pathway A involving the (C]O).
O
O
X
N
X
N
N
N
C1
C3
C1
C3
O5
N2
N8
N4
H6
O5
N2
N8
N4
H6
C7
C7
Ph
Ph
(T.S.II)
12-14
N
N
C
O
O
C
X
N
X
N
N
N
+
+
C1
C3
H6
C1
C3
O5
N2
N4
O5
N2
N4
H6
(TS-IV)
N
C
Vinylogous amide (PII)
O
X
N
N
+
C1
C3
O5
N2
H6
N4
(Product)
X
CH3
Ph
12
13
14
Ph
Scheme 8. Pathway B involving (C]N).

B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
1189
˚
Table 3. Main distances (A) of the reactants, T.S.I, T.S.II, T.S.III, T.S.IV, PI & PII of the two pathways of compounds 12 and 13 calculated at the HF/3-21G*
level
˚
Species
Distance (A)
N4–H6
C1–O5
N2–N8
C7–N8
N2–H6
C7–H6
O5–H6
12: XZCH3
Reactant 1
T.S.I
Imidol (PI)
T.S.III
Reactant 2
T.S.II
Vinylogous (PII)
T.S.IV
1.221
1.261
1.344
1.277
1.218
1.204
1.209
1.208
1.416
1.427
—
1.261
1.269
—
4.562
4.567
5.349
3.361
2.262
2.039
1.000
1.373
2.630
2.538
3.082
1.361
2.556
2.618
2.405
1.387
1.061
1.074
–
2.109
1.998
0.962
1.331
4.395
4.546
4.608
3.468
—
—
–
1.432
1.437
—
1.265
1.267
—
1.067
1.063
–
—
—
–
13: XZPh
Reactant 1
T.S.I
Imidol (PI)
T.S.III
Reactant 2
T.S.II
Vinylogous (PII)
T.S.IV
1.217
1.217
1.344
1.283
1.207
1.219
1.210
1.210
1.417
1.414
—
1.265
1.266
—
4.567
4.571
5.354
3.381
2.386
1.014
1.000
1.382
2.674
2.694
3.066
1.357
2.449
2.301
2.423
1.382
1.065
1.065
–
2.077
2.116
0.966
1.322
4.197
4.364
4.583
3.398
—
—
–
1.445
1.449
—
1.267
1.214
—
1.070
1.098
–
—
—
–
Table 4. Total energy, zero-point vibrational energy (ZPE) and thermal correction to enthalpy and entropy at HF/3-21G* and 500 K for the two pathways of
compounds 12 and 13
Species
Total energy (Hartre)
ZPE (kcal/mol)
Enthalpy (kcal/mol)
Entropy (cal/mol.K)
12: XZCH3
Reactant 1
T.S.I
Imidol (PI)
T.S.III
Reactant 2
T.S.II
Vinylogous (PII)
T.S.IV
K1104.909787
K1104.900687
K784.285847
K784.226210
K1104.908954
K1104.910063
K784.625786
K784.239056
194.208
193.848
123.977
121.517
193.858
194.178
125.280
121.694
204.922
204.541
131.290
128.681
204.791
204.844
132.52
135.016
134.866
106.541
106.202
136.186
134.156
106.748
105.597
128.816
13: XZPh
Reactant 1
T.S.I
Imidol (PI)
T.S.III
Reactant 2
T.S.II
Vinylogous (PII)
T.S.IV
K1294.354906
K1294.355928
K973.734854
K973.688665
K1294.354926
K1294.355625
K973.772406
K973.683739
230.740
230.665
160.530
158.304
230.814
230.739
162.001
158.328
243.644
243.552
169.474
167.047
243.732
243.590
170.898
167.133
155.725
155.323
121.283
120.155
157.658
154.782
122.255
121.910
Ph–C^N
Product (XZCH3)
Product (XZPh)
K320.638112
K784.333568
K973.780445
67.673
125.391
162.020
71.125
132.617
170.870
74.939
106.529
121.388
theory, for all the reactants, transition states and products
involved in the two pathways of the 12 and 13 are collected
in Table 4. The free energy profile for the decomposition
process of the 12 and 13 is presented in Figures 3 and 4,
respectively.
50
0
TS-I
TS-III
TS-IV
TS-II
Reactant
-50
For methyl substituted compound 12, it appears clear that
the formation of the PII is kinetically more favorable via
pathway B than PI via pathway A; T.S.I is higher than T.S.II
by 21.45 kJ/mol. The calculated activation energies are
22.742 and 1.294 kJ/mol for the reaction via the transition
states T.S.I and T.S.II, respectively. The overall process is
exergonic; with the reaction free energy equal to
K263.5 kJ/mol.
-100
-150
-200
-250
-300
P-I + Ph CN
P-II + PhCN
P + PhCN
Reaction Coordinates
Pathway A involving C=O
Pathway B involving C=N
For phenyl substituted compound 13, there are no large
differences between the two transition states of the two
pathways. The calculated activation energies are K2.199
and 3.612 kJ/mol for the reaction via the transition states
Figure 3. Free energy profile evaluated at the HF/3-21G* level for
compound 12.

1190
B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
3.2.2. 1-Benzylideneaminopyrimidine-2,4(1H,3H)-dione
50
0
6. Pale yellow crystals, mp 230 8C (lit.12 mp 219–220 8C),
yield 65%. IR (KBr): 3100, 3000, 2806, 1715, 1667, 1450,
1409, 1370, 1276, 1147, 1090, 957, 862, 824, 751, 690.
LCMS: m/zZ216 (MC1). 1H NMR (DMSO-d6): d 11.59 (s,
1H, NH), 9.06 (s, 1H, CH]N), 8.02 (d, 1H, JZ8.0 Hz),
7.83 (d, 2H, JZ7.6 Hz), 7.52–7.77 (m, 3H), 5.69 (d, 1H, JZ
8.0 Hz). Anal. Calcd for C11H9N3O2 (215.2): C 61.39, H
4.22, N 19.52. Found C 61.48, H 4.39, N 19.52.
TS-III
TS-IV
TS-II
Reac tant
TS-I
-50
-100
-150
-200
-250
-300
P-I + PhCN
P-II + PhCN
3.2.3. 1-Benzylideneamino-2-thioxo-2,3-dihydropyri-
midin-4(3H)-one 7. Yellow crystals, mp 212–214 8C
(lit.12 mp 219–220 8C), yield 70%. IR (KBr): 3027, 2924,
2853, 1671, 1625, 1559, 1380, 1274, 1153, 867, 809, 754,
P + PhCN
1
689. LCMS: m/zZ232 (MC1). H NMR (DMSO-d6): d
11.86 (s, 1H, NH), 8.40 (s, 1H, CH]N), 7.77–7.72 (m, 3H),
Reaction Coordinates
Pathway A involving C=O
Pathway B involving C=N
7.48–7.46 (m, 3H), 6.30 (d, 1H, JZ10.4 Hz).
Figure 4. Free energy profile evaluated at the HF/3-21G* level for
compound 13.
3.2.4.
1-p-Methoxybenzylideneaminopyrimidine-
2,4(1H,3H)-dione 8. Pale yellow crystals, mp 230 8C,
yield 1.10 g (45%). LCMS: m/zZ246 (MC1). IR: 3011,
2922, 2850, 1700 (br), 1606, 1514, 1372, 1256, 1175, 1027,
826. 1H NMR (DMSO-d6): d 11.54 (s, 1H, NH), 8.93 (s, 1H,
CH]N), 7.96 (d, 1H, JZ8.0 Hz), 7.78 (d, 2H, JZ8.4 Hz),
7.08 (d, 2H, JZ8.4 Hz), 5.66 (d, 1H, JZ8.0 Hz), 3.84 (s,
3H, OCH3). 13C NMR (DMSO-d6): d 56.1, 101.3, 115.1,
125.8, 130.8, 144.0, 149.1, 161.4, 162.9, 163.4. Anal. Calcd
for C12H11N3O3 (245.2): C 58.77, H 4.52, N 17.13. Found C
58.90, H 4.58, N 17.14.
T.S.I and T.S.II, respectively. But in this reaction the
formation of PII is more favored than the formation of PI.
The calculated activation energies are K235.1 and
K144.0 kJ/mol for PII and PI respectively. The overall
process is exergonic; with reaction free energy equal to
K255.0 kJ/mol. These results indicate that the formation of
the product is more favored via pathway B than pathway A.
3. Experimental
3.1. General
3.2.5. 1-p-Methoxybenzylideneamino-2-thioxo-2,3-di-
hydropyrimidin-4(3H)-one 9. Yellow crystals, mp
225 8C, yield 1.72 g (66%). LCMS: m/zZ262 (MC1). IR:
3143, 3070, 3025, 2938, 2832, 1685, 1620, 1574, 1509,
1371, 1305, 1347, 1165, 1024, 800. 1H NMR (DMSO-d6): d
11.31 (s, 1H, NH), 8.31 (s, 1H, CH]N), 7.71 (d, 2H, JZ
8.4 Hz), 7.70 (d, 1H, JZ10.5 Hz), 7.03 (d, 2H, JZ8.4 Hz),
6.26 (d, 1H, JZ10.5 Hz), 3.81 (s, 3H, OCH3), 13C NMR
(DMSO-d6): d 56.0, 114.3, 118.2, 127.4, 130.1, 139.2,
156.0, 157.4, 162.0, 162.6. Anal. Calcd for C12H11N3O2S
(261.3): C 55.16, H 4.24, N 16.08. Found C 55.22, H 4.34, N
15.91.
Melting points were determined on a Shimadzu-
Gallenkamp apparatus and are uncorrected. Elemental
analysis was by means of a LECO CHNS-932 Elemental
Analyzer. NMR spectra were measured using a Bruker DPX
400 MHz superconducting spectrometer, and FT-IR
measurements were from a Perkin–Elmer 2000 FT-IR
system. Mass spectrometric analysis was carried out on a
VG-Autospec-Q high performance tri-sector GC/MS/MS,
and the instrument for HPLC was an Agilent 1100 series
LC/MSD with an API-ES/APCI ionization mode.
3.2.6. 3-Benzylideneaminoquinazoline-2,4(1H,3H)-dione
10. White crystals, mp 249 8C (lit.13 mp 243 8C). IR (KBr):
3061, 3005, 2929, 1721, 1666, 1615, 1490, 1445, 1394,
1287, 1169, 935, 823, 755, 683. LCMS: m/zZ266 (MC1).
1H NMR (DMSO-d6): d 11.72 (s, 1H, NH), 8.74 (s, 1H,
CH]N), 7.98 (d, 1H, JZ7.8 Hz), 7.92 (d, 2H, JZ7.6 Hz),
7.70 (t, 1H, JZ7.8 Hz), 7.64 (t, 1H, JZ7.6 Hz), 7.58 (t, 2H,
JZ7.6 Hz), 7.25 (t, 1H, JZ8.0 Hz), 7.24 (d, 1H, JZ
8.0 Hz). 13C NMR (DMSO-d6) d 114.7, 116.0, 123.4, 128.2,
128.9, 129.3, 133.0, 133.3, 135.7, 139.4, 148.4, 159.5,
172.1. Anal. Calcd for C15H11N3O2 (265.3): C 67.92, H
4.18, N 15.84. Found C 67.80, H 4.27, N 15.84.
3.2. Synthesis
3.2.1. General procedure. Compounds 8, 9, 11 and 14 are
new compounds. Compound 8 and 9 were prepared as
described for the synthesis of 6 and 7,12 by reacting the
appropriate semicarbazone or thiosemicarbazone with
methyl 3,3-dimethoxypropanoate in dioxane and
sodium hydride. Compound 10 was prepared as reported.13
Compound 14 was prepared using the same
experimental procedure described for 12 and 13.14 Pyrolysis
1
products were identified by H NMR, LCMS and GC-MS
and compared with authentic samples: benzonitrile,15
uracil,16 2-thiouracil,16 quinazolinone-2,4(1H,3H)-dione,17
2-aminoquinazolin-4(3H)-one,18 dimethylcyanamide,19
acetonitrile,20 Z- and E-cinnamonitrile,21 3-methyl-2H-
[1,2,4]triazino[3,2-b]quinazoline-2,6(1H)-dione,22
3-phenyl-2H-[1,2,4]triazino[3,2-b]quinazoline-2,6(1H)-
dione,22 3-styryl-2H-[1,2,4]triazino[3,2-b]quinazoline-
2,6(1H)-dione.22
3.2.7. 1-Amino-4,6-dimethyl-2-oxo-1,2-dihydro-pyri-
dine-3-carbonitrile. A mixture of cyanoacetohydrazide
(0.99 g, 10 mmol) and acetylacetone (1.00 g, 10 mmol) in
ethanol (10 mL) in the presence of diethylamine (1 mL) was
heated under refluxed for 2 h. The solvent was removed in
vacuum and the residue was cooled to give a solid
precipitate, which was crystallized from ethanol, to give

B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
1191
1.29 g (79%) of pale yellow crystals; mp 173 8C. LCMS m/z
Z164 (MC1). 1H NMR (CDCl3): d 2.43 (s, 3H, CH3), 2.51
(s, 3H, CH3), 4.95 (br s, 2H, NH2), 6.09 (s, 1H, ArH). Anal.
Calcd for C11H14N4O (163.18): C 58.85; H 5.56; N 25.75.
Found: C 58.90; H 5.49; N 25.64.
3.3.2. Flash vacuum pyrolysis (FVP). The apparatus used
was similar to the one which has been described in our
recent publications.5,23 The sample was volatilized from a
tube in a Bu¨chi Kugelrohr oven through a 30!2.5 cm
horizontal fused quartz tube. This was heated externally by a
Carbolite Eurotherm tube furnace MTF-12/38A to a
temperature of 600 8C, the temperature being monitored
by a Pt/Pt-13%Rh thermocouple situated at the center of the
furnace. The products were collected in a U-shaped trap
cooled in liquid nitrogen. The whole system was maintained
at a pressure of 10K2 Torr by an Edwards Model E2M5 high
capacity rotary oil pump, the pressure being measured by a
Pirani gauge situated between the cold trap and the pump.
Under these conditions the contact time in the hot zone was
estimated to be y10 ms. The different zones of the products
3.2.8. N0-(3-Cyano-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-
N,N-dimethyl-formamidine 11. A mixture of 1-Amino-
4,6-dimethyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile
(1.63 g 10 mmol) and dimethylformamide dimethyl acetal
DMFDMA (1.19 g) in dioxane (10 mL) was heated under
refluxed for 4 h. The resulting solution was poured into
water and the reaction product was collected and crystal-
lized from DMF to give 1.57 g (72%) of yellowish brown
crystals; mp 196 8C. IR (KBr): 3069, 2923, 2212, 1656,
1623, 1581, 1545, 1436, 1418, 1371, 1214, 1122, 1091, 844,
762. MS m/zZ218 (MC). 1H NMR (CDCl3): d 2.35 (s, 3H,
CH3), 2.38 (s, 3H, CH3), 3.04 (s, 6H, 2CH3), 6.02 (s, 1H,
ArH), 7.82 (s, 1H, ArH). Anal. Calcd for C11H14N4O
(218.2): C 60.53; H 6.47; N 25.67. Found: C 60.61; H 6.44;
N 25.39.
1
collected in the U-shaped trap were analyzed by H NMR,
LCMS and GC-MS. Relative and percent yields were
determined from 1H NMR. Identity of compounds obtained
were confirmed by comparison of their H NMR with data
1
of products separated from preparative HPLC.
3.4. Kinetic runs and data analysis
3.2.9.
1-Benzylidineamino-3-methyl-2H-[1,2,4]tri-
azino[3,2-b]quinazoline-2,6(1H)-dione 12. Brown crys-
tals, mp 272–275 8C (lit.14 mp 270–273 8C). LCMSZ332
(MC1). 1H NMR (DMSO): d 8.78 (s, 1H), 8.20 (dd, 1H, JZ
7.8, 1.4 Hz), 8.01 (d, 2H, JZ7.4 Hz), 7.80 (dt, 1H, JZ8.4,
1.4 Hz), 7.70 (t, 1H, JZ7.4 Hz), 7.63 (t, 2H, JZ7.4 Hz),
7.49 (d, 1H, JZ8 Hz), 7.46 (t, 1H, JZ7.4 Hz), 2.43 (s, 3H).
A stock solution (7 mL) was prepared by dissolving
6–10 mg of the substrate in acetonitrile as solvent to give
a concentration of 1000–2000 ppm. An internal standard
was then added, the amount of which was adjusted to give
the desired peak area ratio of substrate to standard (2.5:1).
The solvent and the internal standard are selected because
both are stable under the conditions of pyrolysis, and
because they do not react with either substrate or product.
The internal standard used in this study is chlorobenzene,
1,3-dichlorobenzene or 1,2,4-trichlorobenzene. Each
solution was filtered to ensure that a homogeneous solution
is obtained. The weight ratio of the substrate with respect to
the internal standard was calculated from the ratio of the
substrate peak area to the peak area of the internal standard.
The kinetic rate was obtained by tracing the rate of
disappearance of the substrate with respect to the internal
standard as follows: An aliquot part (0.2 mL) of each
solution containing the substrate and the internal standard is
pipetted into the reaction tube, which is then placed in the
pyrolyzer for 6 min under non-thermal conditions. A sample
is then analyzed using a Waters HPLC probe (pump model
515, UV detector model 2487), or a Metrohm HPLC (pump
model 7091C, and SPD 10 AV Shimadzo UV detector) and
UV detector at wavelength of 256 nm, and the standardi-
zation value (Ao) was then calculated. Several HPLC
measurements were obtained with an accuracy of R2%.
HPLC columns used for the analysis were Supelco (25 cm
length, 4.6 mm ID) ABZC, LC-8 and LC-18. The
temperature of the pyrolysis (aluminium) block is then
raised and held for ca. 900 s to allow approximately 10%
pyrolysis to take place at this temperature. This procedure is
repeated after each 10–15 8C rise in the temperature of the
pyrolyzer until R90% pyrolysis takes place. The relative
ratios of the integration values of the sample and the internal
standard (A) at the pyrolysis temperature are then
calculated. A minimum of three kinetic runs were carried
out at each reaction temperature, following every 10–15 8C
rise in the temperature of the pyrolyzer, in order to ensure
reproducible values of (A). Treatment of the kinetic data has
been detailed elswhere.24,25
3.2.10. 1-Benzylidineamino-3-phenyl-2H-[1,2,4]tri-
azino[3,2-b]quinazoline-2,6(1H)-dione 13. Yellow crys-
tals, mp 250–253 8C, (lit.14 251–253 8C). LCMS m/zZ394
(MC1). 1H NMR (CDCl3): d 8.86 (s, 1H), 8.23 (dd, 1H, JZ
8.0, 1.0 Hz), 8.09–8.03 (m, 4H), 7.83 (dt, 1H, JZ8.0,
1.2 Hz), 7.70 (t, 1H, JZ7.4 Hz), 7.66–7.54 (m, 6H), 7.48
(t, 1H, JZ7.6 Hz).
3.2.11. 1-(Benzylidineamino)-3-styryl-2H-[1,2,4]tri-
azino[3,2-b]quinazoline-2,6(1H)-dione 14. Yellow crys-
tals, mp 255–257 8C, yellow crystales from DMF, yeild
1.68 g (40%). IR (KBr): 3062, 3024, 1720, 1689, 1587,
1475, 1411, 1336, 1273, 1153, 975, 764, 688. LCMS: m/zZ
420 (MC1). 1H NMR (DMSO-d6): d 8.84 (s, 1H), 8.23 (dd,
1H, JZ8, 1.2 Hz), 8.08 (d, 1H, JZ16.4 Hz), 8.04 (d, 2H,
JZ7.2 Hz), 7.84–7.78 (m, 3H), 7.72 (t, 1H, JZ7.2 Hz),
7.64 (t, 2H, JZ7.6 Hz), 7.53 (d, 1H, JZ8.0 Hz), 7.50–7.45
(m, 4H), 7.41 (d, 1H, JZ16.4 Hz). Anal. Calcd for
C25H17N5O2 (419.5): C 71.59; H 4.09; N 16.70. Found: C
71.32; H 3.96; N 16.50.
3.3. Pyrolysis
3.3.1. Static pyrolysis. Each of the substrates 6–14 (0.2 g)
was introduced into the reaction tube (1.5!12 cm Pyrex),
cooled in liquid nitrogen, sealed under vacuum (0.06 mbar)
and then placed in the pyrolyzer for 15 min at a temperature
deemed necessary for complete pyrolysis of the substrate.
The pyrolysate was then separated by preparative HPLC
using ABZC column and an eluent of suitable composition
(acetonitrile and water). The collected solutions of the
pyrolysate fractions were evaporated and each fraction was
1
subjected to H NMR and GCMS and LCMS analysis.

1192
B. J. George et al. / Tetrahedron 62 (2006) 1182–1192
Comprehensive Heterocyclic Chemistry II; Elsevier:
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