Study of the reactions of 3-acetoacetyl-7-methyl-2H, 5H-pyrano[4,3-b]pyran-2,5-dione with aromatic amines

Article abstract of DOI:10.1002/jhet.5570380134

The reactions of 3-acetoacetyl-7-methyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione with aromatic amines afforded 3-(arylaminomethylene)-6-methylpyran-2,4-dione. Our results allowed the correction of the structures reported in the literature for the products of these reactions.

Full text of DOI:10.1002/jhet.5570380134

Jan-Feb 2001
Study of the Reactions of 3-Acetoacetyl-7-methyl-2H,5H-
pyrano[4,3-b]pyran-2,5-dione with Aromatic Amines
Baya Boutemeur-Kheddis and Maamar Hamdi*
227
Laboratoire des Composés Organiques Hétérocycliques, Institut de Chimie,
Université des Sciences et de la Technologie H. Boumédiène,
BP 32, El-Alia, 16111 Bab-Ezzouar, Alger, Algérie
Nicole Sellier
Laboratoire de Spectrométrie de Masse, (UMR 75-73) E.N.S.C.P, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Artur M. S. Silva
Department of Chemistry, University of Aveiro 3810-193 Aveiro, Portugal
Received May 2, 2000
Dedicated in the memory of Professor Raymond N. Castle for his important contribution
to heterocyclic chemistry and his devotion in serving the heterocyclic community.
The reactions of 3-acetoacetyl-7-methyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione with aromatic amines
afforded 3-(arylaminomethylene)-6-methylpyran-2,4-dione. Our results allowed the correction of the
structures reported in the literature for the products of these reactions.
J. Heterocyclic Chem., 38, 227 (2001).
Introduction.
However, this structure was not compatible with our X-ray
result [2], which agrees with the structure of the dione 3a
[3,4] (Scheme 1). Zaman et al. [5] have also studied this
reaction and proposed the structure 3b for the product. This
structure 3b is the enolic form of the dione 3a; in solution
there is an equilibrium between these two species (vide
experimental) (Scheme 1).
At the beginning of this decade we started a program of
research aiming to revisit the reaction of ethyl orthoformate
with triacetic acid lactone 1 (TAL) and the structure of the
product of this reaction. Structure 2 has been proposed by
Hirsch and Hoefgen [1] for the product they have isolated.

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B. Boutemeur-Kheddis, M. Hamdi, N. Sellier and A. M. S. Silva
Zaman et al. [5] have also studied the reactivity of 3
the pyrazole ring [6] and at the same time establishes that
the reaction of 3 with phenylhydrazine is regioselective.
Structure 8a was also described by Zaman et al. [5] but
with a lower melting point. A condensation also took place
between compounds 3 and hydroxylamine and hydrazine,
giving, regioselectively, the corresponding isoxazole 8b
and pyrazole 8c derivatives (Scheme 2).
The reaction of 3 with 2,4-dimethoxyaniline, in a 1:1
mixture of acetic acid and ethanol, gave two products, 9
and 10 (Scheme 2). The former is a Shiff base, formed by
attack of the amine at C-3' of 3, whereas the latter confirms
that the amino group can attack other sites in the molecule.
The mass spectrum of compound 10 presents a peak at m/z
towards aniline and phenylhydrazine. From the reaction of
3 with aniline they established the structure of the products
as a mixture of syn- and anti-4-benzimino-3-hydroxy-
methine-6-methylpyran-2-one, 4a and 4b, the pyridine
derivatives 5a and 5b and also the pyridinolactone
derivative 6. In the reaction of 3 with phenylhydrazine
they assigned phenylhydrazone 7 for the structure of the
product (Scheme 1).
We have studied the reaction of compounds 3 [6] with
aniline and phenylhydrazine and the results obtained [3,4]
are completely different from those of Zaman et al. [5]. In
order to confirm these results, we have revisited these
reactions under the experimental conditions reported by
Zaman et al. [5] and we present here our results. The
reaction mechanisms are also discussed.
289 and the elemental analysis indicate a molecular
1
formula of C H NO . The H nmr spectrum of this
15 15
5
compound presents two signals at δ 11.75 and 13.73 ppm,
in a proportion of 1:4, which disappear after shaking with
deuterium oxide. Two other doublets are observed at δ
Results and Discussion.
The reaction of compound 3 with phenylhydrazine, in
acidic medium, gave only one pure product. The analytical
data for this product indicate that a condensation reaction
took place with the loss of two water molecules, and the
structure still has the pyranopyran-2,5-dione skeleton 8a
(Scheme 2). The X-ray structure of this compound 8a
unequivocally proves the position of the phenyl moiety on

Jan-Feb 2001
229
3-Acetoacetyl-7-methyl-2H,5H-pyrano-[4,3-b]pyran-2,5-dione with Aromatic Amines
8.52 and 8.69 ppm, in the same ratio, which are assigned to
the proton resonances of the imino group. These analytical
data are only compatible with the structure of 3-(2,4-
dimethoxyanilinomethylene)-6-methylpyran-2,4-dione 10.
This compound can exist in E and Z configurations, which
explains the presence of two signals, in a 1:4 proportion,
for the resonance of each proton.
The unexpected formation of 10 was very interesting,
since we have recently reported the preparation of an
analogue 3-(anilinomethylene)-6-methylpyran-2,4-dione
13 from the reaction of compounds 11 and 12 with aniline
[7]. This analogue 13 was also obtained as a mixture of E
and Z diastereomers, in a 1:4 proportion (Scheme 2).
Compound 10 was also obtained from reaction of 2,4-
dimethoxyaniline with 11 and 12.
Aniline does not react with compound 3 in a cold ethanolic
solution, but under reflux we can observe by tlc the formation
of triacetic acid lactone 1 and a new product. The analytical
data of this new product indicate the presence of compound
13. This reaction was also carried out in ethanol with some
drops of acetic acid, as described by Zaman et al. [5], but we
have also obtained the products, 1 and 13 (Scheme 2), and not
those (4a,b, 5a,b and 6) reported by the authors (Scheme 1).
The treatment of compound 3 with phenylhydrazine in
ethanol gave 3-(phenylhydrazinomethylene)-6-
methylpyran-2,4-dione 14 (Scheme 3). This compound

230
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B. Boutemeur-Kheddis, M. Hamdi, N. Sellier and A. M. S. Silva
3-Methyl-5-(7-methyl-2,5-dioxopyrano[4,3-b]pyran-3-yl)-1-
phenylpyrazole 8a.
was also obtained from the reaction of 11 with phenyl-
hydrazine. The H nmr spectrum of 14 indicates that only
1
one diastereomer, E or Z, is present. The proton resonances
reported by Zaman et al. [5] for phenylhydrazone 7 are
very similar to those which we attributed to compound 14.
However, the melting points values of these two
compounds are very different (222-225 ºC for 7 and
197-198 °C for 14).
A solution of 3 (0.01 mole) and phenylhydrazine (0.01 mole)
in a mixture of ethanol-acetic acid (50 mL) was refluxed for
6 hours. After evaporation of the solvent, the residue was poured
into cooled water to afford a yellow solid, which was collected
and recrystallized from methanol yielding pyrazole 8a (2.7 g,
1
80%), mp 186 ºC; H nmr (deuteriochloroform): δ 2.23 (s, 3H,
7'-CH ), 2.37 (s, 3H, 3-CH ), 6.13 (s, 1H, H-8'), 6.51
3
3
The formation of compounds 10 and 13 from the
reaction of 3 with aromatic amines (Scheme 2) prompted
us to suggest the mechanism depicted in Scheme 4 for
these transformations. However, if we consider that a
retrocondensation can also occur under the experimental
conditions, an alternative mechanism can also be proposed
(Scheme 5). Our results support the first mechanism, but
the results of Castillo et al. [8] showing that compound 15
was obtained from the reaction of 1 with aniline, indicate
that the second mechanism is also possible. As our results
do not exclude the second mechanism, other trans-
formations are being carried out in order get more
information to prove or to eliminate this alternative
mechanism (Scheme 5).
(s, 1H, H-4'), 7.35 (s br, 5H, C H ), 7.64 (s, 1H, H-4); ms (EI):
6
5
+
m/z (relative intensity) 334 (M., 100), 306 (37), 305 (20), 291
(16), 276 (18), 222 (82), 85 (50), 83 (44), 77 (63), 69 (28), 63
(16), 51 (24), 43 (41).
Anal. Calcd. for C H N O : C, 68.26; H, 4.19; N, 8.38.
19 14
2 4
Found: C, 67.96; H, 3.96; N, 8.31.
3-Methyl-5-(7-methyl-2,5-dioxopyrano[4,3-b]pyran-3-yl)-
isoxazole 8b.
A solution of 3 (0.01 mole) and hydroxylamine (0.01 mole) in
a mixture of ethanol- acetic acid (50 mL) was refluxed for
4 hours. After cooling, the reaction mixture was filtered and the
solvent evaporated to dryness. The obtained residue was
recrystallized from toluene to give isoxazole 8b (2.2 g, 83%), mp
1
272 ºC; H nmr (deuteriochloroform): δ 2.35 (s, 3H, 7'-CH ),
3
In summary, we have shown that the reaction of
3-acetoacetyl-7-methyl-2H,5H-pyrano[4,3-b]pyran-2,5-
dione 3 with aniline derivatives and with phenylhydrazine
follows the same pathway, giving 3-(arylaminomethylene)-
4–oxo-6-methyl-2-pyrone derivatives 10 and 13 and
3-(phenylhydrazinomethylene)-4-oxo-6-methyl-2-pyrone
14, respectively. Although these transformations were
carried out under the experimental conditions reported by
Zaman et al. [5], our results are completely different. On the
other hand the reaction mechanism they propose does not
explain the formation of the products that we have obtained.
2.39 (s, 3H, 3-CH ), 6.25 (s, 1H, H-8'), 6.87 (s, 1H, H-4'), 8.50
(s, 1H, H-4); ms (EI): m/z (relative intensity) 259 (M., 100), 205
(18), 134 (13), 120 (17), 106 (16), 85 (47), 83 (63), 82 (46), 78
(17), 69 (21), 63 (16), 53 (17), 50 (17), 47 (14), 43 (68).
3
+
Anal. Calcd. for C H NO : C, 60.23; H, 3.47; N, 5.40. Found:
13
9
5
C, 60.43; H, 3.30; N, 5.20.
3-Methyl-5-(7-methyl-2,5-dioxopyrano[4,3-b]pyran-3-yl)-
pyrazole 8c.
A solution of 3 (0.01 mole) and hydrazine (0.01 mole) in a
mixture of ethanol and acetic acid (50 mL) was refluxed for 3
hours. After cooling, the solvents were evaporated to dryness and
the residue was recrystallized from toluene to yield pyrazole 8c
EXPERIMENTAL
1
(1.8 g, 70%), mp 230 °C; H nmr was not registered due to the
insolubility of 8c in common solvents; ms (EI): m/z (relative
+
intensity) 258 (M., 100), 230 (18), 109 (15), 106 (18), 105 (14),
Melting points were determined in an Electrothermal
1
13
89 (16), 85 (29), 83 (33), 77 (17), 69 (14), 63 (18), 55 (11), 43
apparatus. H nmr and C spectra were recorded on a Bruker AC
200 and an ARX Bruker WM 300 instruments; the chemical
shifts are expressed in δ (ppm) values relative to tetramethyl-
silane as an internal reference. Mass spectra were recorded on a
Nermag R10-10C quadrupole mass spectrometer.
(57), 39 (13).
Anal. Calcd. for C H N O : C, 60.46; H, 3.87; N, 10.85.
Found: C, 60.26; H, 4.02; N, 11.02.
13 10
2 4
Synthesis of Compounds 9 and 10.
3-Acetoacetyl-7-methyl-2H,5H-pyrano[4,3-b]pyran-2,5-dione
3a and its Enolic Form 3b.
A solution of 3 (0.01 mole) and 2,4-dimethoxyaniline
(0.01 mole) in a mixture of ethanol and acetic acid (50 mL) was
refluxed for 1 hour. After cooling, the mixture was filtered and
the solvent was evaporated. The obtained residue was washed
with hot ethanol giving a soluble fraction which corresponds to
pyranopyran-2,5-dione 9 (1.6 g, 40%), whereas the rest was
recrystallised in ethanol giving pyran-2,4-dione 10 (1.1 g, 38%).
3-[3-(2,4-Dimethoxyphenylimino)-1-oxobutan-1-yl]-7-methyl-
A solution of 4-hydroxy-6-methylpyran-2-one 1 (triacetic
lactone) (0.02 mole) and triethyl orthoformate (9 mL) in ethanol
(30 mL) was refluxed for 4 hours. The precipitate was collected
and recrystallized from ethanol or toluene to yield compounds 3
1
(1.8 g, 70%), mp 192-193 °C; H nmr (deuteriochloroform): δ
2.23 (s, 3H, 7-CH ), 2.40 (s, 3H, H-4'), 4.11 (s, 2H, H-2', dione),
3
1
2H,5H-pyrano[4,3-b] pyran-2,5-dione 9, mp 270 ºC; H nmr
6.23 (m, 1H, H-8), 6.61 (s, 1H, H-4), 8.76 (s, 1H, H-2', enol),
15.74 (s, 1H, OH, enol); ms (EI): m/z (relative intensity) 262
(deuteriochloroform): δ 2.06 (d, 3H, 7-CH ), 2.21 (s, 3H, 3'-CH ),
3
3
+
(M., 32), 247 (14), 219 (6), 205 (100), 150 (8), 95 (11), 84 (6), 69
3.75 (s, 3H, OCH ), 3.84 (s, 3H, OCH ), 6.19 (s, 1H, H-8), 6.56
3 3
(25), 67 (5), 57 (9).
Anal. Calcd. for C
59.55; H, 3.80.
(m, 2H, C H ), 6.85 (m, 1H, C H ), 7.00 (s, 1H, H-4), 8.92 (s, 1H,
6 3 6 3
2'-H); ms (EI): m/z (relative intensity) 397 (M., 100), 396 (29),
340 (18), 285 (17), 282 (30), 84 (27), 59 (12), 55 (13), 43 (28).
+
H
O : C, 59.54; H, 3.82. Found: C,
13 10
6

Jan-Feb 2001
231
3-Acetoacetyl-7-methyl-2H,5H-pyrano-[4,3-b]pyran-2,5-dione with Aromatic Amines
Anal. Calcd. for C
Found: C, 63.13; H, 4.80; N, 3.35.
H
NO : C, 63.47; H, 4.78, N, 3.52.
recrystallized from ethanol to give pyran-2,4-dione 14 (1.7 g,
68%), mp 197-198 ºC; 1H nmr (dimethyl sulfoxide-d6): δ 2.19
21 19
7
3-(2,4-Dimethoxyanilinomethylene)-6-methylpyran-2,4-dione
10, mp 229-230 ºC; H nmr (deuteriochloroform): δ 2.15 (d, 3H,
(s, 3H, 6-CH ), 6.14 (s, 1H, H-5), 6.91-6.94 (m, 3H, C H ),
3
6 5
1
7.23-7.29 (m, 2H, C H ), 8.11 (s, 1H, =CH-N, E or Z) 10.18 and
6
5
6-CH ), 3.80 (s, 3H, OCH ), 3.91 (s, 3H, OCH ), 5.72 (s, 1H,
13.19 (2s, 2H, 2x NH, E or Z); ms (EI): m/z (relative intensity)
3
3
3
H-5), 6.46-6.57 (m, 2H, C H ), 7.21-7.33 (m, 1H, C H ), 8.52
+
6
3
6 5
244 (M., 7), 229 (11), 187 (71), 186 (13), 160 (11), 153 (16), 105
and 8.69 (2d, 1H, =CH-N, E and Z), 11.75 and 13.73 (2d, 1H,
(14), 93 (48), 92 (27), 91 (21), 85 (46), 78 (12), 77 (72), 69 (64),
68 (12), 65 (59), 57 (11), 54 (17), 53 (22), 51 (22), 43 (100), 42
(16), 41 (35), 40 (16), 39 (57), 38 (12).
+
NH, E and Z); ms (EI): m/z (relative intensity) 289 (M., 100),
274 (16), 246 (9), 209 (14), 190 (42), 177 (14), 176 (14), 174
(31), 164 (13), 163 (12), 162 (22), 151 (31), (150 (21), 139 (42),
138 (31), 137 (15), 135 (12), 134 (17), 124 (14), 119 (13), 95
(11), 85(23), 83 (15), 77 (9), 69 (12), 53 (17), 43 (29), 39 (13).
Anal. Calcd. for C H N O : C, 63.93; H, 4.91; N, 11.48.
13 12
2 3
Found: C, 63.62; H, 4.75; N, 11.29.
Anal. Calcd. for C
Found: C, 62.35; H, 5.2; N, 4.76.
H NO : C, 62.28; H, 5.19; N, 4.84.
Acknowledgements.
15 15 5
The authors thank C. Keil for her participation in this work and
especially for running the mass spectra.
3-(Anilinomethylene)-6-methylpyran-2,4-dione 13.
A solution of 3 (0.01 mole) and aniline (0.01 mole) in
2-propanol (50 mL) was refluxed for 4 hours. After solvent
evaporation, the residue was washed with toluene to give two
products. The compound insoluble in toluene corresponds to
4-hydroxy-6-methyl-2-pyrone 1. The soluble fraction gave, after
solvent evaporation and recrystallization from 2-propanol, pyran-
REFERENCES AND NOTES
[1] B. Hirsch and N. Hoefgen, German (East) Patent 255,417
(1983); Chem. Abstr., 103, 123354w (1985).
[2] M. Hamdi, V. Speziale and J. Jaud, Z. Kristallogr., 209, 495
(1994).
1
2,4-dione 13 (1.6 g, 70%), mp 177 ºC; H nmr (deuterio-
chloroform): δ 2.23 (s, 3H, 6-CH ), 5.75 (s, 1H, H-5), 7.25-7.43
3
[3] B. Boutemeur-Kheddis, A. Bendaas, M. Hamdi, R.
Sakellariou and V. Speziale, OPPI. BRIEFS., 26, 278 (1994).
[4] G. Ellingsen, K. Vercruysse, V. Spesiale, M. Hamdi and S.
Fery-Fargues, Acta Chem. Scand., 51, 521 (1997).
[5] M. Rafiuddin, Z. Seddequi, A. Zaman, A. Ur-Raman and M.
Chowdhary, Indian J. Chem., 33B, 1023 (1994).
[6] Unpublished results.
[7] A. Bendaas, M. Hamdi, R. Sakellariou and V. Speziale, J.
Chem. Soc. Algeria, 6, 29 (1996).
[8] S. Castillo, H. Ouadahi and V. Herault, Bull. Chem. Soc.
France, 257 (1982).
(m, 5H, C H ), 8.82 and 8.98 (2d, 1H, =CH-N, E and Z), 11.62
6
5
and 13.62 (2d, 1H, NH, E and Z); ms (EI): m/z (relative intensity)
+
,
229 (M. 100), 205 (16), 186 (10), 144 (22), 117 (40), 98 (33), 93
(34), 55 (11), 53 (14), 51 (24), 43 (71), 39 (20).
Anal. Calcd. for C H NO : C, 68.11; H, 4.8; N, 6.11. Found:
13 11
3
C, 68.66; H, 4.7; N, 5.80.
3-(Phenylhydrazinomethylene)-6-methylpyran-2,4-dione 14.
A solution of 3 (0.01 mole) and phenylhydrazine (0.01 mole)
in ethanol (20 mL) was refluxed for 15 minutes. The reaction
mixture was cooled and filtered to give a precipitate which was