Synthesis of new mesomeric betaines containing a triazolopyridiniumolate system and their unexpected function as masked isocyanates

Article abstract of DOI:10.3987/com-99-8760

A series of mesomeric betaines containing 1-alkylated triazolopyridiniumolate system were synthesized and their cycloaddition with dimethyl acetylenedicarboxylate were examined. An unusual ring-opening reaction occurred to give pyridone derivatives indicating that these betaines act as masked isocyanates.

Full text of DOI:10.3987/com-99-8760

HETEROCYCLES, Vol. 53, No. 2, 2000, pp. 265 - 270, Received, 24th September, 1999
SYNTHESIS OF NEW MESOMERIC BETAINES CONTAINING
A TRIAZOLOPYRIDINIUMOLATE SYSTEM AND THEIR
UNEXPECTED FUNCTION AS MASKED ISOCYANATES
Norio Sakai, Makoto Funabashi, Satoshi Minakata, Ilhyong Ryu,
and Mitsuo Komatsu*
Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
Abstract-
A
series of mesomeric betaines containing 1-alkylated
triazolopyridiniumolate system were synthesized and their cycloaddition with
dimethyl acetylenedicarboxylate were examined. An unusual ring-opening reaction
occurred to give pyridone derivatives indicating that these betaines act as masked
isocyanates.
Mesomeric betaines are widely utilized as useful synthetic intermediates in the construction of a variety of
heteropolycycles involving natural products and biologically active compounds. Their utility derives from
the fact that most act as 1,3-dipoles and lead to heteropolycycles by one-step reactions with
dipolarophiles.1-3 Hence, the development of novel mesomeric betaines having different arrangements of
heteroatoms or different ring skeletons is of great importance from the stand point of synthetic and
pharmaceutical chemistry. While, fused pyridine derivatives, for example, [1,2,4]triazolo[4,3-
4
5
a]pyridines, are often found in various biologically active substances and functional materials, only a few
examples have been reported in which this unit is embedded into a mesomeric betaine structure.6 Further
applications of mesomeric betaines to reactions with dipolarophiles leading to heterocyclic compounds have
not been documented. We have already reported the development of a convenient preparation for
mesomeric betaines which contain a pyrrolotriaziniumolate system and their 1,3-dipolar cycloaddition with
dipolarophiles leading to ring-enlargement bicyclic products.7 In this paper, we wish to report facile
synthesis of novel mesomeric betaines which contain a triazolopyridiniumolate system and especially their
unexpected ring-opening reactions, which clearly show that these betaines function as masked isocyanates
in clear contrast with pyrrolotriaziniumolates.
Pyridinotriazol-3-one (3, a starting product) was produced from 2-hydrazinopyridine (2), which was, in
turn, prepared via the reaction of 2-bromopyridine (1) and hydrazine, with urea at 200 °C for 2 h in 57%
yield (Scheme 1).8 IR absorption (1710 cm ) indicative of a carbonyl group in 3 is consistent with the
cyclic urea form.9 Based on our earlier studies on mesomeric betaines, the quaternization of
pyridinotriazolone (3) with alkyl halides was carried, giving novel mesomeric betaines. These results are
summarized in Table 1. Pyridinotriazolone (3) was treated with benzyl bromide (10 equiv) in the presence
-1
7

Scheme 1
H N
2
O
NH NH2
H N
2
2
N
N
1
00 °C, 10 h
N
Br
N
200 °C, 2 h
57%
N
H
NHNH2
O
100%
1
2
3
of potassium carbonate (10 equiv) at 80 °C for 10 h in dioxane to give 1-benzyl[1,2,4]triazolo[4,3-
a]pyridinium-3-olate (4a) in 60% yield, along with 2-methyl[1,2,4]triazolo[4,3-a]pyridin-3-one (5a) in
3
2% yield (entry 1).10 The structure of compound (4a) was qualitatively deduced from spectral data and
unambiguously confirmed by X-Ray crystallographic analysis (Figure 1).11 The N(2)-C(3) and N(1)-
C(9) bond lengths (1.33 and 1.32 Å, respectively) indicate double-bond characteristics and the C(3)-N(4)
bond length (1.43 Å) is slightly shorter than that of a typical C-N single bond (1.45 Å). These results
strongly support the conclusion that 4a contains a five-membered triazolonium structure. The C=O bond
length of 1.24 Å in 4a was slightly longer than 1.20 Å which is the typical length of a C=O for mesoionic
compounds such as N-(p-bromophenyl)sydonone.12 A strong absorption at 1666 cm in the IR spectrum
was observed, which is atypical of a carbonyl group in five-membered cyclic ureas. Collectively, these
-1
1
data are indicative of a larger single-bond character for the C=O bond of 4a. The H-NMR spectrum
indicated that four protons on the pyridine ring in 4a were shifted to lower magnetic field than the
corresponding protons in the starting (3), reflecting the mesomeric effect of the cation in 4a. All the other
spectral data were fully consistent with the mesomeric betaine structure of 4a.
Table 1. Quaternization of Pyridinotriazolone (3) with Alkyl halides
RX (10 equiv) / K CO
2
3
+
N R
N
N
+
N
N
N
N
H
solvent / Δ / 10 h
N
N
-
O
O
O
R
3
4
4
a: R = PhCH2
b: R = Me
5a: R = PhCH2
5b: R = Me
a
yield (%)
entry
RX
solvent
temp. (℃)
4
5
3
1
2
3
4
PhCH Br
dioxane
dioxane
80
40
40
40
4a 60
4b 10
4b 19
5a 32
0
2
MeI
MeI
MeI
5b 20
65
45
0
CH Cl
5b
9
2
2
acetone
4b
0
5b 100
a
Isolated yields
The quaternization reaction of 3 with methyl iodide (10 equiv) also afforded a 1-methylated analog (4b),
along with a 2-methylated pyridin-3-one (5b) in 10% and 20% yields, respectively (entry 2). In the case
where CH Cl was used as a solvent, the yield of 4b was slightly increased to 19% and that of 5b reduced
2
2
mto 9% (entry 3). It is noteworthy that, when a polar solvent such as acetone was employed, only the 2-
alkylated product (5b) was obtained in quantitative yield (entry 4). The mesomeric structure of compound

C7
C9
C6
C8
C5
N1
N4
C3
N2
O
Figure 1. ORTEP view of betaine (4a)
(
4b) was also defined by spectral data and elemental analysis. In contrast, spectral data for (5a,b) are in
good agreement with the nonaromatic structure which is formed as a result of the alkylation of the nitrogen
on the 2-position.
It is quite important to clarify whether mesomeric betaines (4a,b) act as 1,3-dipoles or not. Thus, the
cycloaddition reaction of betaines (4) with a typical dipolarophile as dimethyl acetylenedicarboxylate
(
DMAD) was investigated. These results are listed in Table 2. When a solution of 4a and DMAD (2 equiv)
in benzene was heated at 140 °C for 5 h, no cycloaddition products were observed (entry 1). In an attempt
Table 2. The reactions of betaines (4) with DMAD in the presence of Lewis acids
leading to Pyridone derivatives (6) a
R
N
O
N
N
+
N R
N
DMAD, Lewis acid
C H , 140 h, 5 h
N
CO Me
2
-
6
6
O
MeO C
CO Me
2
2
4a, b
CO Me
2
6a, b
b
entry
R
DMAD (eq)
Lewis acld (0.1 eq)
—
yield (%)
1
2
3
4
5
6
7
8
4a PhCH2
4a PhCH2
4a PhCH2
4a PhCH2
4a PhCH2
4a PhCH2
4a PhCH2
2
2
0
5
MgBr ・6H O
2
2
MgBr ・6H O
4
2
2
27
42
15
31
38
51
MgBr ・6H O
10
10
10
10
10
2
2
MgBr ・6H O (1.0 eq)
2
2
AlCl3
ZnBr2
MgBr ・6H O
4b
Me
2
2
a
In sealed tubes. b Isolated yield.
to accelerate the cycloaddition reaction, the addition of a Lewis acid (0.1 equiv) such as MgBr •6H O was
2
2
then examined. Interestingly, an unexpected reaction occurred to afford a ring-opening adduct, 1-(N-2-
pyridylbenzylamino)-3,4,5,6-tetra(methoxycarbonyl)pyrid-2-one (6a) in 5% yield (entry 2).10
The
structure of 6a was confirmed by X-Ray crystallographic analysis as shown in Figure 2.13 When the
amount of DMAD was increased to 10 equiv, the yield of 6a was improved to 42% (entry 4). Other Lewis

acids, such as AlCl and ZnBr were also effective in improving the yield of 6a (entries 6, 7). Of the
3
2
reaction conditions examined to date, the reaction of 4b with DMAD provided the pyridone derivative (6b)
in the best yield (51%, entry 8).
N
N
O
O
N
O
O
O
O
O
O
Figure 2. ORTEP view of pyridone detivative (6a)
A plausible mechanism for the formation of the pyridone derivatives (6) is shown in Scheme 2. A
nucleophilic attack of the amido anion in 4 on DMAD, which is activated by a Lewis acid, would give rise
to an allenic intermediate (7) (path a). The thus formed intermediate (7) adds to another activated DMAD to
form a triazolopyridinone intermediate (8) (path b), followed by the intramolecular nucleophilic attack of the
terminal carbanion in 8 to the carbonyl carbon in the triazolone ring to give the pyridone (6) (path c). The
pyridone ring in the final product (6) would be formed by the 1 : 2 cycloaddition reaction of an isocyanate
with DMAD. Hence, these betaines act as masked isocyanates in the proposed mechanism.
Scheme 2. Plausible reaction mechanism of the reaction of betaine (4) with DMAD
leading to pyridone derivative (6). (LA: Lewis acid)
+
N
a
N
R
+
+
N
N
-
N
R
N
R
N
O
LA
O
N
N
-
-
O
O
MeO C
2
OMe
7
4
OMe
LA
MeO
MeO C
CO Me
2
2
O
LA
O
R
+
N
N
N
R
N
O
c
b
N
CO Me
N
CO Me
2
2
O
MeO
MeO C
CO Me
2
2
CO Me
2
-
CO Me
2
LA O
CO Me
2
6
8

Thus far, we have succeeded in the synthesis of novel mesomeric betaines, which consist of a
triazolopyridiniumolate system and found that the reaction of these types of betaines with DMAD
unexpectedly affords pyridone derivatives. This suggests that the betaines have a low degree of 1,3-dipolar
character and, function as masked isocyanates in these reactions. Further reactions with various
dipolarophiles and the development of related mesomeric betaines are under investigation.
ACKNOWLEDGMENT
We are grateful to Prof. Dr. Yasushi Kai and Dr. Nobuko Kanehisa for their support in performing the X-
Ray crystallographic analysis. This work was partially supported by a Grant-in-Aid for Scientific Research
from Ministry of Education, Science, Sports and Culture, Japan.
REFERENCES AND NOTES
1
2
.
.
For selected reviews on mesomeric betaines, see; W. D. Ollis and S. P. Stanforth, Tetrahedron,
985, 41, 2239; C. A. Ramsden, ‘Advances in Heterocyclic Chemistry,‘ Vol. 26, ed. by A. R.
1
Katritzky and A. J. Boulton, 1980, p. 1.
For selected reviews on 1,3-dipolar cycloadditions, see; A. Padwa, ‘1,3-Dipolar Cycloaddition
Chemistry,’ Vols. I and II, John Wiley & Sons, New York, 1984; B. M. Trost and I. Fleming,
‘Comprehensive Organic Synthesis, ‘ Vol. 4, Pergamon Press, New York. 1991, pp. 1069-1168.
3
4
.
.
J. S. Glas by, ‘Encyclopedia of the Alkaloids,’ Vols. I and II, Plenum Press, New York, 1975.
For selected reviews on [1,2,4]triazolo[4,3-a]pyridines, see; S. W. Schneller, ‘Comprehensive
Heterocyclic Chemistry I,’ Vol. 5, ed. by K. T. Potts, Pergamon Press, Oxford, 1984, pp. 847-903;
G Jones and D. R. Sliskovic, ‘Advances in Heterocyclic Chemistry,‘ Vol. 34, ed. by A. R.
Katritzky, 1983, pp. 80-143.
5
6
7
.
.
.
S. W. Schneller, ‘Comprehensive Heterocyclic Chemistry I,’ Vol. 5, ed. by K. T. Potts, Pergamon
Press, Oxford, 1984, pp. 903-904; D. R. Sliskovic, ‘Comprehensive Heterocyclic Chemistry II,’
Vol. 8, ed. by G. Jones, Pergamon Press, Oxford, 1996, pp. 385-388.
B. C. Bishop, H. Marley, K. J. McCullough, P. N. Preston, and S. H. B. Wright, J. Chem. Soc.,
Perkin Trans. 1, 1993, 705; I. Ya. Postovskii, S. K. Kotovskaya, and A. V. Polonyankin, Chem.
Abstr., 1980, 93, 46529; K. T. Potts and H. R. Burton, J. Org. Chem., 1966, 31, 251.
M. Komatsu, M. Kobayashi, S. Itoh, and Y. Ohshiro, J. Org. Chem., 1993, 58, 6620; N. Sakai,
M. Funabashi, T. Hamada, S. Minakata, I. Ryu, and M. Komatsu, Tetrahedron, 1999, 55, 13703.
K. T. Potts, H. R. Burton, and S. K. Roy, J. Org. Chem., 1966, 31, 265.
8
9
.
.
The compound (3) was detected in its enol form in a polar solvent such as DMSO (vide infra). Spectral
-
1
data for 3: mp 201 °C (colorless crystals from hex-CH Cl ); IR (KBr, cm ) 3400 (NH), 3203
2
2
1
(
NH), 1710 (C=O); H-NMR (270 MHz, DMSO-d ) δ 6.52-6.58 (m, 1H, H-7), 7.15-7.18 (m, 2H,
6
N
N
N
N
N
H
N
O
HO

1
3
H-6 and H-8), 7.77-7.8 (m, 1H, H-5), 12.43 (br s, 1H, OH); C-NMR (68 MHz, DMSO-d ) δ
6
+
1
1
10.4, 115.5, 123.7, 130.0, 142.5, 159.6; MS (EI) m/z 135 (M ); HR-MS. Calcd for C H N O:
6
5 3
35.0433 Found: 135.0428.
1
0. All new compounds are fully characterized. Data for selected compounds; 4a: mp 166-168 °C (colorless
-
1
1
crystals from hex-CH Cl ); IR (KBr, cm ) 1666; H-NMR (270 MHz, CDCl ) δ 5.30 (s, 2H,
2
2
3
CH ), 6.86 (t, 1H, J = 6.9 Hz, H-6), 7.19 (d, 1H, J = 9.2 Hz, H-8), 7.34-7.37 (m, 5H, Ph), 7.46
2
1
3
(
dd, 1H, J = 9.2 Hz, J = 6.9 Hz, H-7), 8.22 (d, 1H, J = 6.9 Hz, H-5); C-NMR (68 MHz, CDCl )
3
δ 52.6, 108.5, 112.5, 125.6, 127.7, 128.6, 129.0, 133.9, 134.1, 138.5, 154.1; MS (EI) m/z 225
+
+
(
M ) 91 (PhCH ); Anal. Calcd for C H N O 0.5H O: C, 66.65; H, 5.16; N, 17.94. Found: C,
•
2
13 11
3
2
-
1
ꢀ
66.51; H,5.19; N, 17.88. 5a: mp 145-147 °C (colorless crystals from hex-CH Cl ); IR (KBr, cm )
2 2
1
1
702 (C=O); H-NMR (270 MHz, CDCl ) δ 5.17 (s, 2H, CH ), 6.45 (t, 1H, J = 6.9 Hz, H-6), 7.06
3 2
(
d, 1H, J = 6.9 Hz, H-8), 7.09 (t, 1H, J = 6.9 Hz, H-7), 7.26-7.42 (m, 5H, aromatic), 7.77 (d, 1H,
1
3
J = 6.9 Hz, H-5); C-NMR (68 MHz, CDCl ) δ 49.7, 110.5, 115.4, 123.7, 128.0, 128.3, 128.7,
3
+
+
1
6
29.8, 135.8, 141.6, 148.9; MS (EI) m/z 225 (M ), 91(PhCH ); Anal. Calcd for C H N O: C,
2 13 11 3
9.32; H, 4.92; N, 18.65. Found: C, 69.18; H, 4.97; N, 18.77. 6a: mp 127-129 °C (colorless
-
1
1
crystals from hex-PhH); IR (KBr, cm ) 1722, 1684; H-NMR (270 MHz, CDCl ) δ 3.49 (s, 3H,
3
Me), 3.78 (s, 3H, Me), 3.87 (s, 3H, Me), 3.93 (s, 3H, Me), 4,51 (d, 1H, J = 16 Hz, PhCH ), 5.72
2
(
d, 1H, J = 16 Hz, PhCH ), 6.57 (d, 1H, J = 8.3 Hz), 6.93 (dd, 1H, J = 8.3 Hz, J = 5 Hz), 7.26-
2
7
.36 (m, 5H, Ph), 7.55 (dd, 1H, J = 8.3 Hz, J = 5 Hz), 8.29 (d, 1H, J = 5 Hz); 13C-NMR (68
MHz, CDCl ) δ 53.2, 53.3, 56.7, 104.6, 109.0, 118.0, 123.4, 127.6, 128.2, 128.4, 136.2, 137.9,
3
+
1
45.8, 147.8, 151.3, 156.4, 157.4, 159.9, 161.9, 163.4, 165.0; MS (CI) m/z 510 (M + 1); Anal.
Calcd for C H N O : C, 58.94; H, 4.55; N, 8.25. Found: C, 59.10; H, 4.46; N, 8.22.
2
5 23 3 9
1
4
1
1. X-Ray crystallographic data for 4a: C H N O, M = 225.09, colorless prismatic, orthorhombic,
13 11 3
space group Pccn (alt. setting No. 56), a = 12.356 (3) Å, b = 14.074 (3) Å, c = 13.102 (3) Å, α =
3
-1
9
0.00°, β = 90.00°, γ = 90.00°, V = 2278 (1) Å , Z = 4, Dc 0.71 g/cm , F(000) = 360.00, µ(Cu
-
1
Kα) = 5.03 cm , graphite monochromated CuKα (λ = 1.54178 Å), T = 14 °C. Final discrepancy
factor: R = 0.052 and Rw = 0.058.
1
1
2. H. Barnighausen, F. Jellinek, J. Munnik, and A. Vos, Acta. Crystallogr., 1963, 16, 471.
1
4
2. X-Ray crystallographic data for 6a: C H N O, M = 509.47, colorless plates, triclinic, space
2
5
23
3
group P1 (alt. setting No. 2), a = 10.362 (8) Å, b = 15.226 (9) Å, c = 8.615 (8) Å, α = 90.33 (6)°, β
3
-1
=
109.04 (6)°, γ = 75.49 (5)°, V = 1239 (1) Å , Z = 2, Dc 1.365 g/cm , F(000) = 820.00, µ(Mo
-
1
Kα) = 0.77 cm , graphite monochromated MoKα (λ = 0.71069 Å), T = 23 °C. Final discrepancy
factor: R = 0.110 and Rw = 0.116.
1
4. The structures of 4a and 6a were solved by the direct method (SHELEX-86).