Synthesis of 2,4-dimethyl-6-oxo-2,4-heptadienoic acid derivatives from 2,4,6-trimethylpyrylium salts

Article abstract of DOI:10.1016/S0040-4020(03)00484-8

Reaction 2,4,6-trimethylpyrylium salts with sodium cyanide in boiling water yielded the bicyclic lactone 1,3,5-trimethyl-6,8-dioxabicyclo[3.2.1]oct-2-en-7-one (6) along with a series of stereoisomers of 2,4-dimethyl-6-oxo-2,4-heptadienonitrile (5), which were the sole products when the reaction was carried out at room temperature. Compound 6, along with 3,5-dimethylphenol (7), was also obtained by refluxing 5 briefly in aqueous sodium hydroxide. However, when 5 was refluxed for a prolonged period in aqueous sodium acetate, 3,5-dimethyl-5-(2-oxopropyl)-furan-2-one (8), along with some 7, was generated instead. Compound 8 could also be produced from 6 on prolonged refluxing with aqueous sodium acetate, indicating that 6 was the kinetically-controlled and 8 the thermodynamically-controlled product.

Full text of DOI:10.1016/S0040-4020(03)00484-8

Tetrahedron 59 (2003) 3291–3295
Synthesis of 2,4-dimethyl-6-oxo-2,4-heptadienoic acid derivatives
from 2,4,6-trimethylpyrylium salts
b
b
Alexandru T. Balaban,a Adriana Tudose and Miron T. Caproiu
,
*
aTexas A&M University at Galveston, 5007 Avenue U, Galveston, TX 77553, USA
bCenter of Organic Chemistry, ‘C.D. Nenitzescu’ of the Romanian Academy, Spl. Independentei 202B, 71141 Bucharest, Romania
Received 25 July 2002; revised 14 March 2003; accepted 14 March 2003
Abstract—Reaction 2,4,6-trimethylpyrylium salts with sodium cyanide in boiling water yielded the bicyclic lactone 1,3,5-trimethyl-6,8-
dioxabicyclo[3.2.1]oct-2-en-7-one (6) along with a series of stereoisomers of 2,4-dimethyl-6-oxo-2,4-heptadienonitrile (5), which were the
sole products when the reaction was carried out at room temperature. Compound 6, along with 3,5-dimethylphenol (7), was also obtained by
refluxing 5 briefly in aqueous sodium hydroxide. However, when 5 was refluxed for a prolonged period in aqueous sodium acetate, 3,5-
dimethyl-5-(2-oxopropyl)-furan-2-one (8), along with some 7, was generated instead. Compound 8 could also be produced from 6 on
prolonged refluxing with aqueous sodium acetate, indicating that 6 was the kinetically-controlled and 8 the thermodynamically-controlled
product. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
ring opening leading to the acyclic valence tautomer 2,
which may undergo further intramolecular cyclization
involving the carbonyl group and either the nucleophile or
a methyl(ene) side chain of the initial pyrylium salt. The
literature is rich in papers describing the isolated 2H- or 4H-
pyranic forms obtained in reaction of pyrylium salts with the
methoxy anion,4 – 13 secondary amines,14,15 hydride
anion,16,17 organometallic reagents,18,19 or 1,3-dike-
tones.20–21 In several cases the final reaction products are
open-chain compounds, e.g. in the reaction of some
pyrylium salts with primary amines22,23 or the hydroxyl
anion (yielding products depending on the substitution
pattern of the cation, e.g. stable pseudobases from 2,4,6-
triarylpyrylium salts),24–26 or with sodium cyanide.27–28
Since pyrylium salts are readily obtained from simple
starting materials, the study of their reactions is of
continuous interest. In the present paper we report two
interesting isomers of the reaction product of 2,4,6-
trimethylpyrylium cation with sodium cyanide followed
by hydrolysis of the nitrile group.
The tautomerism and valence isomerism of heterocyclic
compounds is well documented.1 In all formulas, primed or
double-primed numbers will denote valence isomeric
intermediates that were not detected experimentally.
In the reaction of pyrylium salts (1) with anionic
nucleophiles (Nu2), the first reaction step is the nucleophilic
addition of t0he reactant to the substrate leading either to a
2H-pyran (2 ) or, less often, to a 4H-pyran structure, 3.2,3
(Scheme 1).
2. Results
Recently, we reinvestigated the reaction of pyrylium salts
with the cyanide anion.27,29 As shown in Scheme 2, we
obtained in the reaction of 2,4,6-trimethylpyrylium cation 1
The 2H-pyranic form (20) undergoes a thermally-allowed
Scheme 1.
Keywords: stereoisomers; 2,4,6-trimethylpyrylium salts; aqueous sodium acetate; lactones.
*
Corresponding author. Tel.: þ1-409-740-4706; fax: þ1-409-740-4787; e-mail: balabana@tamug.tamu.edu
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00484-8

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A. T. Balaban et al. / Tetrahedron 59 (2003) 3291–3295
Scheme 2.
(R¼Me) with sodium cyanide in water at 1008C for a short
reaction time (5 min), the bicyclic lactone 6 (1,3,5-
trimethyl-6,8-dioxa-bicyclo[3.2.1]oct-2-en-7-one) along
with the two stereoisomeric 4-Z-2,4-dimethyl-6-oxo-2,4-
heptadienonitriles (5), reported earlier29 with both E/Z
geometries at the double bond (C2–C3). On performing the
same reaction at room temperature or at 08C, no trace of
compound 6 was observed by H NMR: the crude reaction
product contained only 4-Z-2,4-dimethyl-6-oxo-2,4-hepta-
dienonitriles.
product.28 On the other hand, 2-benzopyrylium salts react
with sodium cyanide leading only to 2H-pyranic products,
in this case the ring opening being disfavored.30,31
We performed hydrolysis studies of cyanodienones 5. With
aqueous sodium hydroxide (molar ratio 5/NaOH¼2:1) for
short reaction times (5 min) in boiling water, compound 6
was obtained along with a substantial amount of 3,5-
dimethylphenol 7. On performing the same reaction with an
aqueous solution of sodium acetate at reflux for 3 h, the
reaction products were the 3,5-dimethylphenol (7) and
another lactonic product, 3,5-dimethyl-5-(2-oxopropyl)-5H-
furan-2-one, 8. The structure of this latter compound was
1
The initial compounds 5 can be isomerized into two other
stereoisomers involving the other double bond between C4
and C5 by concentrated hydrochloric acid.27,29 The
structures of the products obtained in reactions performed
at room temperature were described earlier,27 and the
stereochemistry of all possible stereoisomers was
1
unambiguously established by H and 13C NMR spectral
data and elemental analysis.
1
unambiguously established by H NMR techniques.29 The
structure of compound 6 was determined on the basis of 1H
and 13C NMR spectra (COSY and HETCOR), mass
spectrometry, and elemental analysis.
It is easily observed that the structure of compound 6
originates in the hydrolyzed product of the cyano group. In
the literature no case of isolation of pyranic products in the
reaction of 2,4,6-trisubstituted27 or 2,6-disubstituted28
pyrylium cations with sodium cyanide was described. In
the reaction with sodium borohydride in acetic acid, 2,6-
diphenyl-4-methylpyrylium perchlorate give as major
product the corresponding 4H-pyranic compound,17 but in
the reaction with cyanide anion 2,6-di-tert-butylpyrylium
perchlorate led only to the corresponding cyanodienone
3. Discussion of the results
We explain the formation of both compounds 6 and 8 by
reactions outlined in Scheme 3.
The first reaction step affords the a-cyanopyran 50. At room
temperature or at 08C the second reaction step is the ring-
opening to the valence tautomeric cyanodienone 5. At
1008C the hydrolysis of the nitrile group competes with the
Scheme 3.

A. T. Balaban et al. / Tetrahedron 59 (2003) 3291–3295
3293
Scheme 4.
ring opening. The fact that only at short reaction times could
the compound 6 be isolated suggests two facts: (i) in the
reaction of pyrylium salt 1 with sodium cyanide, the elusive
pyranic form 50 is the kinetically controlled product, while
the isolated cyanodienone is the thermodynamically stable
product; (ii) in the hydrolysis, the isomerizations 5–50 or
60 –600 –6 occurred, the compound 6 being the kinetically
controlled product, while the compound 8 is the thermo-
dynamically stable product. The reversibility of the
reactions in Scheme 3 was proved by heating the bicyclic
compound 6 with an aqueous solution of sodium acetate
when the sole product was the lactone 8 (see Section 5). This
explains the absence of compound 6 in the reaction of 5 with
sodium acetate. We presume that the reaction pathway is
6–60 –600 –8, but no detectable amounts of intermediates 60
formation involves an intramolecular condensation of the
pseudobase.2
4. Conclusions
Brief refluxing of 2,4,6-trimethylpyrylium salts (perchlorate
or the less dangerous tetrafluoroborate) with aqueous
sodium cyanide affords (along with the two previously
reported diastereomeric 4-Z-4-methyl-6-oxo-2,4-hepta-
dienonitriles) the bicyclic acetal-lactone 6 (1,3,5-tri-
methyl-6,8-dioxa-bicyclo[3.2.1]oct-2-en-7-one) isomeric
with the carboxylic acids formed by hydrolysis of the
above nitriles. Longer refluxing with aqueous sodium
acetate converts compound 6 into another lactone under
thermodynamic control, namely 3,5-dimethyl-5-(2-oxo-
propyl)-furan-2(5H)-one, 8. To the best of our knowledge,
this is the first example for the formation of lactone products
starting from pyrylium salts.
00
1
or 6 could be identified by H NMR in the crude reaction
product. The formation of 6 from the acid 60 –600 or its anion
9 may proceed either from 60 with a preformed pyranic ring,
or from the ring-opened form 600 simultaneously with the
electrocyclic ring closure.
The cyclization to the lactone 8 occurs by an intramolecular
1,4-addition of the carboxylate anion (9) of 600, to the
C4–C5 activated double bond (Scheme 4). On work-up,
protonation occurs forming the lactone 8.
5. Experimental
5.1. Instrumentation
Melting points were determined in a capillary tube with a
hot stage and are uncorrected. The NMR spectra were
recorded at 300 MHz for 1H, and at 75 MHz for 13C. The d
values are given in ppm from internal TMS, and the
coupling constants J in Hz. The 1H and 13C NMR chemical
shifts were determined from 1D (1H, 13C) and 2D
(HETCOR, COLOC) experiments, as well as from COSY
data.
The difference between the two lactones 6 and 8 is not only
in the mono/bicyclic structure, but also in the fact that 8 is
the intramolecular lactonization product of the carboxylic
acid 600 involving the C4–C5 double bond, whereas 6 is
formally derived from the 1,4-addition product of water to
the butadienic system of 600, placing a hydroxyl group at C2;
this hypothetical alcohol intermediate becomes then
dehydrated intramolecularly forming the acetal-lactone 6.
The potential lactone ring-opening hydrolysis products of 6
and 8 are isomeric allylic alcohols, namely with the
hydroxyl either at C2 (from 6), or at C4 (from 8).
5.2. Reagents, solvents
For preparative column chromatography, silica gel 60
was used. The elution solvents were petroleum ether (bp
35–458C) and diethyl ether freshly distilled on lithium
aluminum hydride. The 2,4,6-trimethylpyrylium perch-
lorate 132 or the fluoroborate33 were prepared as described
previously.
The 3,5-dimethylphenol (7) may be formed either by
decarboxylation of 600 or by elimination of hydrogen cyanide
from 50 followed by the formation of 4-methyl-2,5-
heptenedione (pseudobase of the pyrylium salt 1) which
recyclizes to 3,5-dimethylphenol, 7. This compound 7 is the
usual reaction product when 2,4,6-trimethylpyrylium salts
(1) are boiled with aqueous sodium hydroxide, and its
The cyanodienones 5 undergo isomerization and decompo-
sition on standing for a few days at room temperature, but

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A. T. Balaban et al. / Tetrahedron 59 (2003) 3291–3295
keeping the compounds in the refrigerator substantially
reduces the rate of this process.
was isolated by extraction with chloroform (21.8 mg, 91%
yield, lactone 8).
5.3. Reaction of 2,4,6-trimethylpyrylium salts
(perchlorate or fluoroborate) with sodium cyanide at
1008C
5.5.1. 3,5-Dimethyl-5-(2-oxopropyl)-5H-furan-2-one (8).
Oil, purified by column chromatography on silica gel. Anal.
calcd for C9H12O3: C, 64.27; H, 7.19. Found C, 64.45; H,
7.02%. IR (CCl4): 1712, 1750 cm21 for the ketonic and
lactonic groups, respectively. 1H NMR: 7.31 (CH, q,
J¼1.7 Hz), 3.07 (CHAHB, d, J¼16.6 Hz), 2.72 (CHAHB,
d, J¼16.6 Hz), 1.89 (COCH3, s), 1.50 (3-CH3, d, J¼1.7 Hz),
2.19 (5-CH3, s). 13C NMR: 204.8 (CO), 173.0 (2-CO), 152.5
(CH), 128.6 (3-C), 83.8 (5-C), 51.9 (CHAHB), 31.1 (CH3-
CO), 23.8 (5-CH3), 10.4 (3-CH3).
Sodium cyanide (0.11 g, 2.25 mmol) and 2,4,6-trimethyl-
pyrylium perchlorate 1 (0.5 g, 2.25 mmol) were added into
7 mL of boiling water. The mixture was maintained at reflux
with magnetic stirring for 5 min. The cooled reaction
mixture was extracted with diethyl ether, then hydrochloric
acid was added in the aqueous layer to pH about 2 and the
liquid was extracted with chloroform. The ethereal layer
was washed with brine, dried over anhydrous sodium
sulfate, and the solvent was evaporated under reduced
pressure (282 mg of residue, 87% yield of cyanodienones
5). From the chloroform layer, the bicyclic compound 6
was isolated after evaporation of the solvent (51.3 mg,
13% yield in the crude product). An analytically pure
sample of 6 was obtained by column chromatography on
silica gel with elution using diethyl ether/petroleum ether
1/20 (v/v).
Acknowledgements
Thanks are due to Dr Cornelia Uncuta for her outstanding
contribution to the results described in the present paper.
References
5.3.1. 1,3,5-Trimethyl-6,8-dioxabicyclo[3.2.1]oct-2-en-7-
one (6). Colorless crystals, mp 45–68C. IR (CCl4):
1790 cm21 (sharp). EI-MS: 168 [Mþ]; 123 [Mþ–CO2–
H]; 109 [Mþ2CO2–CH3]. Anal. calcd for C9H12O3: C,
1. Minkin, V. I.; Garnovskii, A. D.; Elguero, J.; Katritzky, A. R.;
Denisko, O. V. Adv. Heterocyl. Chem. 2000, 76, 1–276.
2. Balaban, A. T.; Dinculescu, A.; Dorofeenko, G. N.; Fischer,
G. W.; Koblik, A. V.; Mezheritskii, V. V.; Schroth, W.
Pyrylium Salts. Synthesis, Reactions and Physical Properties.
Adv. Heterocycl. Chem.; Academic: New York, 1982; Suppl.
Vol. 2.
1
64.27; H, 7.19. Found C, 64.08; H, 7.19%. H NMR in
CDCl3: 5.61 (2-CH, q, J¼1.6 Hz), 2.43 (CHAHB, dq, J¼18,
0.8 Hz), 2.21 (CHAHB, dq, J¼18, 0.8 Hz), 1.73 (3-CH3, m,
J¼1.6, 0.8 Hz), 1.66 (5-CH3, s), 1.54 (1-CH3, s). 13C NMR
in CDCl3: 174.0 (CO), 137.3 (3-C), 107.3 (5-C), 76.2 (1-C),
122.6 (2-CH), 38.7 (4-CHAHB), 23.8 (5-CH3), 21.8 (3-CH3),
18.0 (1-CH3).
3. (a) Balaban, A. T. In New Trends in Heterocyclic Chemistry;
Mitra, R. B., Ayyangar, N. R., Gogte, V. N., Acheson, R. M.,
Cromwell, N., Eds.; Elsevier: Amsterdam, 1979; pp 79–111.
(b) Balaban, A. T. In Organic Synthesis: Modern Trends.
Proceedings of Sixth IUPAC International Symposium on
Organic Synthesis, Moscow; Chizov, O., Ed.; Blackwell:
Oxford, 1987; pp 263–274. (c) Balaban, A. T. Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley:
New York, 1996; Vol. 7, pp 5224–5227 Vol. 8, pp 5407–
5411. (d) Schroth, W.; Balaban, A. T. In Methoden der
Organischen Chemie (Houben-Weyl). Hetarene II (Teil 2);
Kreher, R. P., Ed.; Thieme: Stuttgart, 1992; Vol. E7b,
pp 755–963. (e) Balaban, T. S.; Balaban, A. T. Science of
Synthesis. Houben-Weyl Methods of Molecular Transform-
ations; Thieme: Stuttgart, 2003; Vol. 14.
5.4. Reaction of 5 with sodium hydroxide
Cyanodienone 5 (150 mg) was heated in 20 mL water under
magnetic stirring. When the temperature reached 1008C,
20 mg of sodium hydroxide was added. After 5 min the
heating and the magnetic stirring were stopped. The solution
was acidified with aqueous hydrochloric acid and the
organic products were extracted with chloroform. The crude
reaction mixture (136 mg), consisting of 3,5-dimethyl-
phenol, 7 (128 mg) and 8 mg of the lactone 6, was identified
by 1H NMR. 3,5-Dimethylphenol (7) mp 648C (lit. mp¼65–
668C).34,35
4. Bersani, S.; Doddi, G.; Fornarini, S.; Stegel, F. J. Org. Chem.
1978, 43, 4112–4115.
5.5. Reaction of 5 with an aqueous solution of sodium
acetate
5. Doddi, G.; Fornarini, S.; Illuminati, G.; Stegel, F. J. Org.
Chem. 1979, 44, 4496–4500.
6. Doddi, G.; Ercolani, G. J. Chem. Soc., Perkin Trans. 2 1986,
271–275.
The cyanodienone 5 (330 mg, 2.21 mmol) and 300 mg
sodium acetate trihydrate (2.21 mmol) were refluxed in
15 mL water for 3 h. The crude reaction mixture was
isolated by repeated extractions with chloroform, obtaining
270 mg of lactone 8 and 93 mg of 3,5-dimethylphenol (7).
The composition of the mixture was established by 1H
NMR.
7. Doddi, G.; Ercolani, G. J. Org. Chem. 1986, 51, 4385–4390.
8. Doddi, G.; Ercolani, G.; Mencarelli, P. J. Org. Chem. 1992,
57, 4431–4434.
9. Raffaele, A.; Doddi, G.; Normano, I.; Stegel, F. J. Org. Chem.
1980, 45, 5160–5163.
10. Doddi, G.; Ercolani, G. J. Org. Chem. 1988, 53, 1729–1733.
11. Fischer, G. W.; Zimmermann, T.; Weissenfels, M. Z. Chem.
1981, 21, 260–261.
Alternatively, the bicyclic lactone 6 (24 mg, 0.143 mmol)
was refluxed under magnetic stirring for 2 h with 2%
aqueous solution of sodium acetate. The reaction product
12. Fischer, G. W.; Zimmermann, T.; Weissenfels, M. J. Prakt.
Chem. 1983, 325, 729–741.

A. T. Balaban et al. / Tetrahedron 59 (2003) 3291–3295
3295
13. Zimmermann, T.; Fischer, G. W. J. Prakt. Chem. 1986, 328,
373–379.
26. Balaban, T. S.; Higemann, M. Tetrahedron 1992, 48,
9827–9840.
14. Fischer, G. W.; Zimmermann, T. J. Prakt. Chem. 1984, 326,
657–666.
27. Balaban, A. T.; Nenitzescu, C. D. J. Chem. Soc. 1961,
3566–3572.
15. Fischer, G. W.; Zimmermann, T.; Weissenfels, M. Z. Chem.
1981, 21, 282–283.
28. Bohm, S.; Prantova, R.; Saman, D.; Trska, P.; Kuthan, J.
Collect. Czech. Chem. Commun. 1987, 52, 1305–1314.
29. (a) Uncuta, C.; Tudose, A.; Caproiu, M. T.; Stavarache, C.;
Balaban, A. T. J. Chem. Res. (S) 2001, 170–171. (b) Uncuta,
C.; Tudose, A.; Caproiu, M. T.; Stavarache, C.; Balaban, A. T.
J. Chem. Res. (M) 2001, 0523–0535.
16. Marwell, E. N.; Gosink, T. J. Org. Chem. 1972, 37,
3036–3037.
17. Balaban, T. S.; Balaban, A. T. Tetrahedron Lett. 1987, 28,
1341–1344.
18. Furber, M.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Soc.,
Perkin Trans. 1 1989, 683–690.
30. Balaban, A. T.; Gheorghiu, M. D.; Shcherbakova, I. V.;
Kuznetsov, E. V.; Yudilevich, I. A. Tetrahedron 1987, 43,
409–414.
19. Furber, M.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun.
1985, 782–783.
31. Shcherbakova, I. V.; Kuznetsov, E. V.; Yudilevich, I. A.;
Kompan, O. E.; Balaban, A. T.; Abolin, A. H.; Polyakov,
A. V.; Struchkov, Yu. T. Tetrahedron 1988, 44, 6217–6224.
32. Balaban, A. T.; Nenitzescu, C. D. Organic Synthesis; Wiley:
New York, 1973; Collect. Vol. 5. pp 1106–1111.
33. Balaban, A. T.; Boulton, A. J. Organic Synthesis; 1973;
Collect. Vol. 5. pp 1112–1113.
20. Fischer, G. W.; Zimmermann, T.; Weissenfels, M. Z. Chem.
1981, 21, 446–447.
21. Zimmermann, T.; Fischer, G. W. J. Prakt. Chem. 1986, 328,
359–372.
22. Katritzky, A. R.; Brownlee, R. T. C.; Musumarra, G.
Tetrahedron 1980, 36, 1643–1647.
23. Katritzky, A. R.; Manzo, H. R.; Lloyd, J. M. Angew. Chem.
1980, 92, 315–316.
34. (a) Baeyer, A.; Piccard, J. Liebigs Ann. Chem. 1911, 208–384.
(b) Baeyer, A.; Piccard, J. Liebigs Ann. Chem. 1914, 332–407.
35. Balaban, A. T.; Nenitzescu, C. D. Liebigs Ann. Chem. 1959,
625, 74–88.
24. Fischer, G. W.; Herrmann, M. J. Prakt. Chem. 1984, 326,
287–302.
25. Fischer, G. W.; Mugge, C.; Fink, S. J. Prakt. Chem. 1984, 326,
647–656.