Selective Mixed Tishchenko Reaction via Substituted 1,3-Dioxan-4-ols

Monoesters of 1,3-diols can be prepared with the mixed Tishchenko reaction from â-hydroxy aldehydes and another aldehyde. These two aldehydes form a diastereomeric mixture of 1,3-dioxan-4-ol hemiacetal derivatives which can be further converted to monoesters with suitable catalysts. Limitations in the formation and esterification of this hemiacetal intermediate have been investigated in this work and the formation and stability of 1,3-dioxan-4-ols was found to be aldehyde-, temperature-, and solvent-dependent. A new method was developed for selective preparation of monoesters of 1,3-diols with this mixed Tishchenko reaction via 1,3-dioxan-4-ols without any significant side products. During the development of this method a possibility to scale up the reactions to reach a selective and economical process was one of the main targets in this work. The conventional Tishchenko reaction of aldehydes gives simple esters with moderate-to-excellent yield (Scheme 1; 1f2)1 typically in the presence of Lewis acidic catalysts such as aluminium alcoholates.2 Several Lewis acidic transition metal complexes have also been found effective.3 For enolizable aldehydes, sequential aldol-Tishchenko reaction can become competing if the catalyst is sufficiently basic (Scheme 1; 1f3f5).4 The basic catalyst first accomplishes the aldol reaction which is followed by Tishchenko esterification by the Lewis acidic nature of the same catalyst. In the mixed Tishchenko reaction between different aldehydes the product distribution is difficult to control.5 1,3-Dioxan4-ols 4 have been reported as reaction intermediates in the homoaldol-Tishchenko reaction (Scheme 1) with only one enolizable aldehyde.6 Dioxanol 4 type intermediates react further to the monoester 5. In other reports the formation of 4 has not been disclosed, but a direct Tishchenko step (3f5) via a [6,6]-membered bicyclic transition state has been suggested.7 Our interest in this topic was originally triggered by the potential versatility of the mixed aldol-Tishchenko reaction and the possible applications of mixed esters in more complex natural product syntheses where the target molecules bear monoester moieties of diols (e.g., polyketides). However, the most important application of 1,3-diol monoesters is their use as the most common coalescing agents in the paint and coating industry, and this was also the main focus of our work.8 Herein we report our results on the formation and stability of the mixed 1,3-dioxan-4-ols of type 8 and their further esterification to a variety of 1,3-diol monoesters. * To whom correspondence may be sent. Telephone: +358 9 451 2526. Fax: +358 9 451 2538. E-mail: [email protected]. † Helsinki University of Technology. ‡ University of Jyväskylä. § X-ray crystal structure analysis. (1) (a) Tischtschenko, W. J. Russ. Phys. Chem. 1906, 38, 355, 482. (b) Tischtschenko, W. E. Chem. Zentr. 1906, 77, I, 1309, 1554, 1556. For mechanism, see: (c) Ogata, Y.; Kawasaki, A.; Kishi, I. Tetrahedron 1967, 23, 825-830. (2) (a) Ogata, Y.; Kawasaki, A. Tetrahedron 1969, 25, 2845-2851. (b) Saegusa, T.; Hirota, K.; Hirasawa, E.; Fujii, H. Bull. Chem. Soc. Jpn. 1967, 40, 967972. (c) Child, W. C.; Adkins, H. J. Am. Chem. Soc. 1923, 45, 30133023. Fast Tishchenko reaction has been reported recently with bidentate aluminum alcoholate catalysts: (a) Ooi, T.; Miura, T.; Takaya, K.; Maruoka, K. Tetrahedron Lett. 1999, 40, 7695-7698. (3) (a) Menashe, N.; Shvo, Y. Organometallics 1991, 10, 3885-3891. (b) Ito, T.; Horino, H.; Koshiro, Y.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1982, 55, 504-512. (4) (a) Villani, F. J.; Nord, F. F. J. Am. Chem. Soc. 1947, 69, 2605-2607. (b) Kuplinski, M. S.; Nord, F. F. J. Org. Chem. 1943, 8, 256-270. (5) (a) Ogata, Y.; Kawasaki, A. Tetrahedron 1969, 25, 929-935. (b) Lin, I.; Day, A. R. J. Am. Chem. Soc. 1952, 74, 5133-5135. (c) For transition metal-catalyzed crossed Tishchenko reaction, see: Morita, K.-I.; Nishiyama, Y.; Ishii, Y. Organometallics 1993, 12, 3748-3752. (6) (a) Törmäkangas, O. P.; Koskinen, A. M. P. Org. Process Res. DeV. 2001, 5 (4), 421-425. (b) Villani, F. J.; Nord, F. F. J. Am. Chem. Soc. 1946, 68, 1674-1675. (7) (a) Mascarenhas, C. M.; Duffey, M. O.; Liu, S.-Y.; Morken, J. P. Org. Lett. 1999, 1, 1427-1429. (b) Bodnar, P. M.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62, 5674-5675. (c) Umekawa, Y.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1997, 62, 3409-3412. (8) Kirk, R. E.; Othmer, D. F. Encyclopedia of Chemical Technology, 3rd ed.; Wiley-Interscience: New York, 1984; Vol. 11, p 966-967. Scheme 1. Tishchenko and homoaldol-Tishchenko reactions with enolizable aldehydes Organic Process Research & Development 2002, 6, 125−131 10.1021/op0100652 CCC: $22.00 © 2002 American Chemical Society Vol. 6, No. 2, 2002 / Organic Process Research & Development • 125 Published on Web 02/05/2002 Results and Discussion The purpose of our studies was to gain insight into the formation and properties of mixed dioxanols 8 as well as to develop a selective process where their Tishchenko reaction to 1,3-diol monoesters takes place while competing reactions are avoided.9 One goal was to create an economically and environmentally advantageous process which would be possible to scale up to industrial scale without any hazardous or expensive steps. However, the work reported in this paper describes the main features of the method including the possibilities and the limitations. For synthetic versatility, differing from typical aldol-Tishchenko reactions, a mixed aldol-Tishchenko reaction was investigated (Scheme 2). The Tishchenko reaction of 1,3-dioxan-4-ols has been reported typically for dimeric aldol products.10 Mixed dimers from a â-hydroxyaldehyde and a second aldehyde have been suspected for instability, but detailed investigations on their esterification have not been reported.11 Very little is known about the effects of different substituents on the formation, stability, stereochemistry, and reactivity of dioxanols similar to 8. 2,2-Dimethyl-3-hydroxypropanal 6 (3-hydroxypivalaldehyde [HPA])12 was chosen as the starting material because of its stability and easy detection. Aldehyde 6 was isolated as the dimer 10, which by 1H NMR (CDCl3) was a mixture of diastereomers in 60:40 ratio (Scheme 3). By 1H NMR in D2O, at room temperature the equilibrium consisted of 56% 6 and 44% 10, and at 35 °C, the equilibrium rapidly shifted completely to monomer 6. In contrast, in CDCl3 at 35 °C only 9% was in monomeric form, and heating at 50 °C for 90 min was required to shift equilibrium to monomer 6. Slow dimerisation of 6 was observed in CDCl3 when the solution was cooled back to room temperature. We next optimized the reaction conditions and requirements for preparation of mixed dimers. The first “mixed” dioxanol 8 we tried to prepare was the dimer of 6 and 2-methylpropanal 7b. In our normal procedure to produce new “mixed” 1,3-dioxan-4-ols dimeric, 10 was first monomerized in the presence of a large excess (10 mol equiv) of 7b by heating at 65 °C without solvent (Scheme 3). At higher temperatures 6 started to decompose via retro-aldol reaction. Heating (monomerisation) should be continued for at least 3 h at 65 °C to monomerize all the dimeric 10. When the solution was cooled to room temperature, slow formation of 8b was observed, and a stable equilibrium was reached only in 2.5-3 days, and monomer 6 was still present (1H NMR in CDCl3). When the cooling was repeated at 0 °C, the formation of dioxanol 8 was already complete in less than 3 h, and only a trace of monomeric 6 was observed with 1H NMR. The product mixture contained the desired dimer 8b, dimer 10, free aldehyde 7, and sometimes a trace of monomeric 6.13 The role of the free aldehyde 7 was also studied to uncover its effect on the stereochemistry and the rate of formation of dioxanols 8 (Table 1). Both steric and electronic effects of the aldehydes 7 were studied by varying the substituents R to obtain a mixture of diastereomers of compounds 8a-f. All dimers were prepared with the method described above. The product distribution was measured directly after step 6f8 by 1H NMR. Due to the vulnerability of the products to decomposition, the product mixture was acetylated or esterified directly to the corresponding monoesters 9 for further analysis. The two dioxanol diastereomers formed in practically identical ratios regardless of the substituent R. The identity of the cis/trans isomers was secured through an X-ray crystallographic analysis of the crystalline major diastereomer of 8c, separable by careful chromatography and crystallisation from MeOH:H2O. Dimer 10 is rather stable even at room temperature, and there are no problems in isolation and storing, but most of the dioxanols 8 prepared here were found to be relatively unstable. The reason for the better stability of dimer 10 compared to that of 8 was studied by means of molecular modelling. The calculations (MacroModel 6.0; Monte Carlo, solvent CDCl3) gave some evidence for the possibility of intramolecular hydrogen bonding in the dimeric (9) Aldol reaction: (a) Casiraghi, C.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000, 100, 1929-1972. (b) Machajewski, T. D.; Wong, C.-H.; Lerner, R. A. Angew. Chem., Int. Ed. 2000, 39, 1352-1374. (c) Mahrwald, R. Chem. ReV. 1999, 99, 1095-1120. (d) Cowden, C.; Paterson, I. Org. React. 1997, 51, 1-200. (e) Sawamura, M.; Ito, Y. Catal. Asymmetric Synth. 1993, 367-388. (f) Bednarski, M. D. Appl. Biocatal. 1991, 1, 87-116. Cannizzaro reaction: (g) Kharasch, M. S.; Snyder, R. H. J. Org. Chem. 1949, 14, 819-835. (h) Pfeil, E. Ber. 1951, 84, 229-45. MeerweinPonndorf-Verley reduction/Oppenauer oxidation: (i) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007-1017. (j) Pickart, D. E.; Hancock, C. K. J. Am. Chem. Soc. 1955, 77, 46424643. Tollens reaction: (k) March, J. AdVanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th ed.; John Wiley & Sons: 1993; p 955. (10) Fouquet, G.; Merger, F.; Platz, R. Liebigs Ann. Chem. 1979, 46, 15911601. (11) Späth, E.; Szilâgui, I. v. Ber. Dtsch. Chem. Ges. 1943, 76, 949-956. (12) Merger, F.; Platz, R.; Fuchs, W. (Badische Anilinund Soda-Fabrik A.G.). Ger. Offen. Pat. 1957301, 1971; Chem. Abstr. 1971, 75, 76165b. (13) Similar results have been obtained under rather vigorous reaction conditions (8 h, 160 °C, under 3.5 MPa pressure): Duke, R. B.; Perry, M. A. (Eastman Kodak Company). FR Pat. 1414216, 1964; Chem. Abstr. 1966, 64, 11090c. Scheme 2. Aldol-Tishchenko type-mixed Tishchenko reaction Scheme 3. Preparation of monoesters of 1,3-diols with mixed Tishchenko reaction via 1,3-dioxan-4-ol intermediates 126 • Vol. 6, No. 2, 2002 / Organic Process Research & Development â-hydroxyl aldehydes between oxygen at ring position 1 and the hydroxyl group in the side chain at ring position 2. Also, the differences in calculated minimum energies between the diastereomers were compared to the ratio of diastereomers obtained with NMR. In the case of dioxanol 8b the calculations gave the axial anomers 8b the energy minimum of ∆G ) -177.6 kJ, and for the equatorial anomers 8b′ ∆G ) -166.7 kJ, corresponding to a ratio of 80:20, in good agreement with the observed ratio 73:27. After the formation of the new dioxanal-type mixed dimer, the 2-methylpropanal (7b) excess was removed under reduced pressure (0.1 mmHg) at 0 °C. The product distribution was followed with 1H NMR during the evaporation, and the new dimer 8b was observed to slowly decompose. The reaction was found to be limited to low-boiling aldehydes 7. With higher-boiling aldehydes such as 2-ethylhexanal (7d) the reaction had to be heated to room temperature (under reduced pressure of 0.1 mmHg) to evacuate an excess of free aldehyde. This caused significant decomposition of dioxanol 8d. The effect of the solvent on the stability of mixed dimer 8b was studied by 1H NMR. Dioxanol 8b was prepared at 0 °C, dissolved in different deuterated solvents. The decomposition was followed as a function of time at room temperature. After 3 days 8b was partly decomposed in d6-benzene (33%) and CDCl3 (61%). On the other hand, in d6-DMSO the decomposition was not observed (<1%). The reason for this is believed to be the hydrogen bonding between the hydroxyl group of the dioxanol and DMSO which stabilizes the acetaltype dioxanol structure. In our earlier studies we have shown that the catalyst in the Tishchenko esterification of such dimers should bear sufficient basicity to deprotonate the hydroxyl proton and Lewis acidity for the intramolecular hydride shift from ring position 2 to position 4.6a,14 Esterification of dioxanol 8b to the corresponding monoester 9 (R ) i-Pr) was first carried out with 30-40 mol % of traditional metal hydroxide catalysts such as LiOH (4.55 M) or Ba(OH)2‚H2O with low isolated yield (0-35%). Monoester 12 was formed with Tishchenko esterification of 10 (formed due to equilibration, Scheme 3). Products 13, 14, and 15 were formed by irreversible hydrolysis of monoesters 9b and 12. Use of 1,3diol-based alkali metal monoalcoholates as catalysts was then investigated.14a Gratifyingly, the esterification of dioxanol 8b occurred almost quantitatively in the presence of 30 mol % of 0.1 M solution (in THF) of monolithium alcoholate of diol 13. Monoester 9b was obtained in 86% isolated yield after 50 min. Monoesters 9a and 9c were obtained with the similar manner in 41 and 60% isolated yield, respectively. However, these two latter experiments were carried in several-times-smaller scales. The reaction was quenched with the addition of a catalytic amount of 2 M HCl to avoid side reactions during the workup. In larger scale the products can be isolated by fractional distillation under reduced pressure (14) (a) Törmäkangas, O. P.; Koskinen, A. M. P. Tetrahedron Lett. 2001, 42, 2743-2746. (b) See also: Abu-Hasanayn, F.; Streitwieser, A. J. Org. Chem. 1998, 63, 2954-2960. Table 1. Product distribution for the preparation of new dimers entry aldehyde 7 R 6 (mol %)a 8 (mol %)a,b trans 8 (mol %)a,b cis 10 (mol %)a (diastereomers) 1 a propanal Et 0 22 48 30 (40:60) 2 b 2-methylpropanal i-Pr 0 25 50 25 (41:59) 3 c pivalaldehyde t-Bu 0 32 60 8 (40:60) 4 d 2-ethylhexanal 1′-Et-pentyl 0 38 49 13 (31:69) 5 e crotonaldehyde CHdCHCH3 62 0 0 38 (41:59) 6 f benzaldehyde Ph 51 42 58 34 (40:60) 7 g cyclohexylcarboxaldehyde C6H11 0 34 66 18 (40:60) a The product distribution was determined by 1H NMR. b Relative stereochemistry has been detemined by X-ray crystallography of acetylated 8c. Figure 1. X-ray structure of the cis-enantiomers of 4-acetoxy5,5-dimethyl-2-tert-butyl-1,3-dioxane 8c, crystallized in a centrosymmetric space group P-1. Unit cell contained both enantiomers of 8c which are shown in the figure.