2,4,6-Trimethylpyrylium Tetrafluoroborate1,2

(1; X- = BF4-)

[773-01-3]  · C8H11BF4O  · 2,4,6-Trimethylpyrylium Tetrafluoroborate  · (MW 210.00) (2; X- = ClO4-)

[940-93-2]  · C8H11ClO5  · 2,4,6-Trimethylpyrylium Perchlorate  · (MW 222.64) (3; X- = CF3OSO2-)

[40927-60-4]  · C9H11F3O4S  · 2,4,6-Trimethylpyrylium Triflate  · (MW 272.27) (4; X- = HO2CCH2SO3-)

[80731-12-0]  · C10H14O6S  · 2,4,6-Trimethylpyrylium Sulfoacetate  · (MW 262.31)

(synthon reacting with various nucleophiles)

Physical Data: (1) mp 244 °C (dec). (2) mp 244 °C (dec). (3) mp 119-120 °C. (4) mp 115-116 °C.

Solubility: (1) sol H2O, AcOH, CF3CO2H. (2) sol CF3CO2H. (3) sol H2O, CHCl3, MeOH, EtOH, (ClCH2)2. (4) sol H2O, MeOH, EtOH, AcOH; insol Et2O, Me2CO.

Form Supplied in: white solids.

Preparative Methods: 2,4,6-trimethylpyrylium salts were the first pyrylium salts devoid of hydroxy or alkoxy substituents to be obtained, by Baeyer and Piccard in 1911.3 Until then, protonated or alkylated g-pyrones were the only known pyrylium salts. At that time, pyrones were puzzling nitrogen-free bases; the discussion about which of their two oxygen atoms was attacked lasted a long time and eventually led to the clarification of the concepts of aromaticity and aromatic sextet. Pertinent references may be found in reviews.1

A low-yield synthesis3 was based on the reaction of 2,6-dimethyl-4-pyrone with methylmagnesium iodide, followed by treatment with acid (perchloric acid was then favored).

The preferred syntheses of 2,4,6-trimethylpyrylium perchlorate (2) are based either on the diacetylation of Isobutene (eq 1),4 or on the acetylation of mesityl oxide (eq 2),5 using Acetic Anhydride and 60-70% perchloric acid. In the former synthesis, instead of the gaseous isobutene, one uses t-butanol which is dehydrated in situ.6

In both methods, isomesityl oxide is the actual reaction intermediate. The reaction mechanism is shown in eq 3.

Since organic perchlorates may explode on impact when dry, other anions have lately been preferred, namely tetrafluoroborate or trifluoromethanesulfonate (triflate), obtained from t-butanol with Ac2O and the corresponding acid, analogously to eq 1. When using 48% fluoroboric acid, the yield of fluoroborate (1) is 50%,7 and when using anhydrous triflic acid, the yield of triflate (3) is 42%.8

2,4,6-Trimethylpyrylium sulfoacetate (4) can be prepared inexpensively on a large scale (in kg amounts) according to published procedures9 starting either from isobutene or from t-butanol (eq 4). Excess acetic anhydride is no longer required for reacting with the water from HClO4 or HBF4 solutions. The sulfoacetate (4) crystallizes from the reaction mixture on addition of acetone, in which it is insoluble. It has a high solubility in water.

Purification: recrystallize from: (1), EtOH, MeOH; (2), H2O, AcOH; (3), dioxane-AcOH (7:1) or CHCl3-CCl4 (2:1); (4), MeOH-Me2CO.

Handling, Storage, and Precautions: all salts may be stored indefinitely. Reports on possible mutagenic activity make it desirable to avoid direct contact with skin. The perchlorate (2) is explosive; therefore it should be prepared only in the required amount for further use. The dry perchlorate should be handled with great care, and never be heated, crushed, rubbed, or pushed through a narrow opening. It may be kept in a cork-stoppered flask when moistened with water or dry THF. Use in a fume hood.

Reactions.

Like other pyrylium salts, the title products (1)-(4) react readily with many nucleophiles, yielding adducts initially (usually 2H-pyrans, but exceptionally 4H-pyrans with hydrides or Grignard reagents). The 2H-pyrans are valence isomeric with open-chain 2,4-pentadien-1-ones, which then may recyclize to a variety of products, mainly aromatic or heteroaromatic. The result is the incorporation of the pyrylium five-carbon chain with its substituents into new acyclic, carbocyclic, or heterocyclic systems, triggered by the initial reaction with the nucleophile.2 In the following, (2) or (3) may always replace (1), and the same is true for (4), but in this case one must take into account the CO2H group of the anion which may sometimes interfere with the nucleophile.

In some cases, the recyclization involves one of the a-methyl groups in (1). Thus 3,5-dimethylphenol (5) is formed by boiling (1) with aqueous alkali hydroxides (eq 5), and similar reactions occur with other pyrylium salts having a-methyl or a-methylene groups.5a,10 With secondary amines, (1) affords N,N-dialkyl-3,5-dimethylaniline derivatives similarly (6).11

Reactions With Oxygen Nucleophiles.

Hydrogen Peroxide converts (1) into 2-acetyl-3,5-dimethylfuran.12 The yield is increased appreciably if the reaction is carried out in a phosphate buffer; enol esters have been identified as byproducts.13

Reactions With Nitrogen Nucleophiles.

Ammonia and primary amines (RNH2) react with (1), yielding sym-collidine and N-substituted collidinium salts, respectively. In the latter reaction, depending on the R group, an aniline derivative (secondary amine) analogous to the tertiary amine (6) may be obtained as a byproduct, but in some cases this may become the main product.14 Amino acids and terminal amino groups in polypeptides give rise to pyridinium salts on reacting with (1); this reaction may have biochemical significance.15

The N-substituted pyridinium salts prepared from isopropylamine (7a) or from amino alcohols or their esters (7b-7d) present 1H and 13C NMR chemical shift nonequivalence of their a-methyl peaks; the intramolecular rotation barriers DG+ are 13-15 kcal mol-1 for (7a) and (7b), 17 kcal mol-1 for (7c), and 19 kcal mol-1 for (7d). Such values are among the highest for sp2-sp3 single bonds.16

X-ray crystallography showed that the dihedral angle of N-phenyl-2,4,6-trimethylpyridinium perchlorate is 85°.17 The N-aryl ring current therefore strongly shields the six a-methyl protons and deshields slightly the three g-methyl protons relative to N-alkyl-2,4,6-trimethylpyridinium. The chemical shift difference between the two a/g methyl peaks in (8), when the sizes of N-aryl or -hetaryl groups are similar, measures the relative ring current in these groups.18

Hydroxylamine affords 2,4,6-trimethylpyridine N-oxide with (1).6a,19 An indolizine (10) synthesis is based on the reaction between (1) and aminoacetaldehyde acetals (9) (R = Me or Et) (eq 6).20

Reactions With Carbon Nucleophiles.

With sodium cyclopentadienide, (1) yields 4,6,8-trimethylazulene.21 Alkali cyanides react with (1), yielding (Z)-5-cyano-2,4-dien-1-ones; these are converted to (E)-isomers by cold mineral acids.22 Benzylmagnesium chloride attacks (1) in the g-position, yielding a 4H-pyran which, on treatment with strong acids, undergoes ring opening and recyclizes to 1,3-dimethylnaphthalene, splitting off acetone (eq 7).23 Since the 2,4,6-trimethylpyrylium cation may be synthesized from acetone and acetylacetone in the presence of strong acids,24 it was logical to devise a synthesis of naphthalene derivatives from 1,3-diketones and benzylmagnesium chloride.25

Nitronate anions (e.g. Nitromethane with 2 equiv of Potassium t-Butoxide) convert (1) into aromatic nitro derivatives (i.e. 2,4,6-trimethylnitrobenzene).26 With acetylacetone or Ethyl Acetoacetate, (1) affords 2,4,6-trimethylacetophenone, whereas with Ethyl Cyanoacetate it forms mesitonitrile;27 such reactions exemplify the versatility of pyrylium synthons.2

Isotopic Exchange of Methyl Hydrogens.

Brief heating of (1) in D2O, namely for 10 min at 80 °C (the less-soluble perchlorate (2) works even better because it crystallizes at the end of the isotopic exchange), leads mainly to g-methyl deuteration. On further refluxing in D2O for 1 h, all nine methyl hydrogens are deuterated. If this fully deuterated salt is heated in H2O for 20 min, only the g-methyl is de-deuterated (eq 8). Thus, specifically methyl-deuterated 2,4,6-trimethylpyrylium salts (i.e. only in g, only in a, or in both a and g) may be obtained and converted afterwards, without loss of isotopic labels, into pyridines, azulenes, benzene derivatives, etc.28 Secondary isotope effects of deuterium in specifically labeled 2,4,6-trimethylpyridine were thus investigated, proving that lanthanide shift reagents feel only the smaller size of CD3 vs. CH3, pKa differences are due only to the higher donor ability of CD3 groups, and quaternization by CH3I or CD3I is affected comparably by both steric and electronic differences between CH3 and CD3 groups.29


1. (a) 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. Suppl., Vol. 2); Academic: New York, 1982. (b) Balaban, A. T.; Schroth, W.; Fischer, G. W. Adv. Heterocycl. Chem. 1969, 10, 241. (c) Schroth, W.; Balaban, A. T. MOC 1992, E7b, 1.
2. (a) Balaban, A. T. In New Trends in Heterocyclic Chemistry; Mitra, R. B., et al., Eds.; Elsevier: Amsterdam, 1979; p 79. (b) Balaban, A. T. In Organic Synthesis: Modern Trends; Chizov, O., Ed.; Blackwell: Oxford, 1987; p 2633. (c) Dimroth, K.; Wolf, K. H. In Newer Methods of Preparative Organic Chemistry; Foerst, W. Ed.; Academic: New York, 1964; Vol. 3, p 357.
3. Baeyer, A.; Piccard, J. LA 1911, 384, 208.
4. Balaban, A. T.; Nenitzescu, C. D. OSC 1973, 5, 1106.
5. Hafner, K.; Kaiser, H. OSC 1973, 5, 1108.
6. (a) Balaban, A. T.; Nenitzescu, C. D. LA 1959, 625, 74. (b) Balaban, A. T.; Nenitzescu, C. D. JCS 1961, 3553. (c) Praill, P. F. G.; Whitear, L. A. JCS 1961, 3573.
7. Balaban, A. T.; Boulton, A. J. OSC 1973, 5, 1112.
8. Balaban, A. T.; Boulton, A. J. OSC 1973, 5, 1114.
9. Dinculescu, A.; Balaban, A. T. OPP 1982, 14, 39.
10. Rajoharison, H. G.; Soltani, H.; Arnaud, M.; Roussel, C.; Metzger, J. SC 1980, 10, 195.
11. Diels, O.; Alder, K. CB 1927, 60, 716.
12. (a) Balaban, A. T.; Nenitzescu, C. D. CB 1960, 93, 599. (b) Balaban, A. T. OPP 1969, 1, 63.
13. Balaban, T. S.; Hiegemann, M. T 1992, 48, 9827.
14. Uncuta, C.; Balaban, T. S.; Petride, A.; Chiraleu, F.; Balaban, A. T. RRC 1989, 34, 1425.
15. (a) Toma, C.; Balaban, A. T. T 1966, Suppl. 7, 9. (b) Katritzky, A. R.; Grzeskowiak, N. E.; Eweiss, N. F.; Elsherbini, E. A. JCS(P1) 1983, 497.
16. (a) Balaban, A. T.; Uncuta, C.; Dinculescu, A.; Elian, M.; Chiraleu, F. TL 1980, 21, 1553. (b) Roussel, C.; Balaban, A. T.; Berg, U.; Chanon, M.; Gallo, R.; Klatte, G.; Memiaghe, J. A.; Metzger, J.; Oniciu, D.; Pierrot-Sanders, J. T 1983, 39, 4209.
17. Camerman, A.; Jensen, L. H.; Balaban, A. T. Acta Crystallogr. 1969, 25B, 2623.
18. (a) Balaban, A. T. PAC 1980, 52, 1409. (b) Balaban, A. T.; Dinculescu, A.; Koutrakis, H. N.; Chiraleu, F. TL 1979, 20, 437. (c) Balaban, A. T.; Dinculescu, A.; Iordache, F.; Chiraleu, F.; Patrascoiu, D. CS 1981, 18, 230.
19. Schmitz, E. CB 1958, 91, 1488.
20. (a) Dinculescu, A.; Balaban, T. S.; Balaban, A. T. TL 1987, 28, 3145. (b) Dinculescu, A.; Balaban, T. S.; Balaban, A. T. OPP 1988, 20, 237.
21. (a) Hafner, K.; Kaiser, H. LA 1958, 618, 140. (b) Hafner, K.; Kaiser, H. OSC 1973, 5, 1088.
22. (a) Balaban, A. T.; Nenitzescu, C. D. JCS 1961, 3566. (b) Balaban, A. T.; Crawford, T. H.; Wiley, R. H. JOC 1965, 30, 879.
23. Dimroth, K.; Neugebauer, G.; Mollenkamp, H.; Oosterloo, G. CB 1957, 90, 1668.
24. (a) Schroth, W.; Fischer, G. ZC 1963, 3, 147. (b) Fischer, G., Schroth, W. ZC 1963, 3, 266.
25. (a) Barabas, A.; Balaban, A. T. T 1971, 27, 5495. (b) see also Canonne, P.; Leitch, L. C. CJC 1967, 45, 1761.
26. Dimroth, K.; Bräuniger, G.; Neugebauer, G. CB 1957, 90, 1634.
27. Dimroth, K.; Neugebauer, G. CB 1959, 92, 2042.
28. (a) Balaban, A. T. J. Labelled Comp. Radiopharm. 1981, 18, 1621. (b) Balaban, A. T.; Uncuta, C.; Chiraleu, F. J. Labelled Comp. Radiopharm. 1982, 20, 399.
29. Balaban, A. T. In Water and Ions in Biological Systems; Pullman, A.; Vasilescu, V.; Packer, L. Eds.; Plenum: New York, 1985; p 655.

Alexandru T. Balaban

Polytechnic University Bucharest, Romania

&

Texas A & M University, Galveston, TX, USA



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