Tishchenko reaction

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The Tishchenko reaction refers to the dimerization of an aldehyde in the presence of a metal catalyst to form an ester. Variants of the Tishchenko reaction include the aldol-Tishchenko reaction, in which an aldol reaction precedes a Tishchenko process, and the Evans-Tishchenko reaction, in which samarium diiodide and an aldehyde are used to convert β-hydroxy ketones to anti-1,3-diol monoesters.[1]

Introduction

The dimerization of benzaldehyde to form benzyl benzoate in the presence of a metal alkoxide was first observed by Claisen in 1887.[2] This reaction was subsequently investigated in detail by Tishchenko[3][4] and was eventually given his name in honor of these studies. The classical Tishchenko reaction refers to the metal-catalyzed formation of an ester from two aldehydes or an aldehyde and a ketone. The aldol-Tishchenko reaction involves formation of a β-hydroxy ketone or aldehyde prior to a Tishchenko process. The Evans-Tishchenko reaction employs pre-formed β-hydroxy ketones and a samarium diiodide catalyst to afford 1,3-diol monoesters (Eq. 1).

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The classical Tishchenko reaction and its variants all involve the formation of a metal-coordinated hemiacetal, which transfers hydride to a coordinated carbonyl group either tethered to the hemiacetal or within a separate ketone or aldehyde. In this respect, the Tishchenko reaction is analogous to the Cannizzaro reaction, which involves a similar hydride transfer after addition of hydroxide to an aldehyde.

The Tishchenko reaction is used industrially for the synthesis of esters, and the Evans-Tishchenko reaction has been applied to in several total syntheses. Although the relatively harsh conditions of the classical Tishchenko and aldol-Tishchenko reactions sometimes preclude their use in the late stages of synthetic routes, these reactions are synthetically valuable due to their atom economy and operational simplicity.

Mechanism and Stereochemistry

Prevailing Mechanism

Some uncertainty still exists concerning the mechanism of the Tishchenko reaction. Certain transition-metal complexes, for example, may operate through different mechanisms than more traditional alkali metal and aluminum alkoxides. Nonetheless, a general picture for the mechanism of Tishchenko reactions catalyzed by aluminum alkoxides has emerged and been suggested for other catalysts and promoters.

If the aluminum alkoxide used does not correspond to the aldehyde substrate, the initial steps of the mechanism involve formation of an aluminum alkoxide complex containing at least one such alkoxide ligand. In this case the reaction has an induction period and small amounts of esters containing the original alkoxide are observed in the reaction mixture.

Following coordination of a molecule of aldehyde to aluminum, addition of alkoxide to the coordinated carbonyl group occurs to yield a coordinated hemiacetal. Coordination of a second molecule of aldehyde then occurs. Hydride is subsequently transferred from the hemiacetal to the newly coordinated carbonyl group, the ester product is released, and the aluminum alkoxide is regenerated (Eq. 2).[5]

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TishRxn-Mech-1.png

Tishchenko reactions catalyzed by transition metal complexes may proceed through different mechanisms. For example, it has been proposed that the ruthenium complex RuH2(PPh3)2 catalyzes a formal Tishchenko process via initial reduction to Ru(0), oxidative addition to the aldehyde C–H bond, migratory insertion of a second molecule of aldehyde, and reductive elimination to establish the ester C–O bond.[6]

Aldol-Tishchenko reactions require more basic catalysts than the classical Tishchenko reaction and involve aldol addition followed by Tischchenko-type esterification. Hydride transfer may establish a stereocenter; the diastereoselectivity of most reactions of this type is well rationalized by a six-membered, cyclic transition state.[7] 1,3-Acyl group transfer may occur to yield the more thermodynamically stable 1,3-diol monoester if it is not identical to the kinetically favored product.

The Evans-Tishchenko reaction operates via a mechanism similar to that of the aldol-Tishchenko reaction, but uses pre-formed β-hydroxy ketones.[8] Some complications may arise if the substrate engages in a retro-aldol process under the reaction conditions.

Enantioselective Variants

One notable example of a catalytic, asymmetric classical Tishchenko reaction employs sparteine in conjunction with ethylmagnesium bromide (Eq. 3).[9] Analysis of the product mixture suggests that addition to the (R)-aldehyde is more rapid than addition to the (S)-aldehyde, but that reaction of the (S)-alkoxide is more favorable in the former case and reaction of the (R)-alkoxide more favorable in the latter case. The moderate diastereoselectivity and enantioselectivity observed in this instance point to the challenge of developing stereoselective methods for Tishchenko reaction of simple acyclic substrates.

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A yttrium catalyst bearing a salen ligand effects a croassed aldol-Tishchenko reaction of benzaldehyde and isobutyraldehyde with moderate enantioselectivity (Eq. 4).[10] The development of catalysts for highly enantioselective aldol-Tishchenko reactions remains a challenge as well; however, Evans-Tishchenko reaction of a chiral, nonracemic β-hydroxy ketone represents a viable alternative.

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TishRxn-Stereo-2.png

Scope and Limitations

Alkali metal alkoxides and hydrides (which react to form alkoxides under the reaction conditions) may be used as catalysts for the classical Tishchenko reaction, but their basicity often precludes their use with enolizable aldehydes. For example, the lithium monoalkoxide of 2,2-dimethyl-1,3-propanediol is an efficient catalyst for Tishchenko reaction of dimeric hydroxypivalaldehyde (Eq. 5).[11]

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Aluminum alkoxides are among the oldest catalysts of the classical Tishchenko reaction, and they are still commonly used (Eq. 6).[12] These catalysts are associated with an induction period unless the alkoxide ligand matches the aldehyde. In most cases they may be used in conjunction with enolizable aldehydes without side products of aldol addition or aldol-Tishchenko reactions.

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Just as alkali metal hydrides may be used in place of alkali metal alkoxides, aluminum hydrides can serve as catalysts for the classical Tishchenko reaction. Diisobutyl aluminum hydride (DIBAL-H) is a readily available aluminum hydride that exhibits broad functional group tolerance in Tishchenko dimerizations (Eq. 7).[13]

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Reactions catalyzed by aluminum complexes of bidentate ligands are significantly more rapid than reactions of simple aluminum alkoxides or hydrides, and aliphatic aldehydes react cleanly (Eq. 8).[14] Aromatic aldehydes typically react more slowly, reflecting a common theme among Tishchenko catalysts: few are effective for both aromatic and aliphatic aldehydes.

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Transition metal complexes are also known to catalyze the classical Tishchenko reaction. Ru2(PPh3)4 is a very efficient catalyst that exhibits turnover numbers much greater than catalysts based on alkali metals or aluminum (Eq. 9).[6] Analogous complexes of several other metals (including iron, palladium, and platinum) do not catalyze the reaction.

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The combination of an N-heterocyclic carbene ligand and Ni(cod)2 affords a versatile catalyst for the classical Tishchenko reaction (Eq. 10).[15] Primary, secondary, and tertiary aliphatic aldehydes as well as aromatic aldehydes react efficiently.

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The aldol-Tishchenko reaction involves aldol addition followed by Tishchenko reaction of the resulting β-hydroxy ketone or aldehyde. Because formation of an enolate is necessary, weakly basic catalysts such as aluminum alkoxides cannot be used (these are highly selective for the classical Tishchenko reaction in most cases). Instead, more basic catalysts or promoters must be employed. For example, a superstoichiometric amount of potassium carbonate promotes aldol-Tishchenko trimerization of isobutyraldehyde (Eq. 11).[16]

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Lithium enolates generated through treatment of the carbonyl compound with very strong bases are also amenable to the aldol-Tishchenko reaction. Treatment of the enolate with the aldehyde at –78 ºC followed by warming to room temperature affords the aldol-Tishchenko product after long reaction times (Eq. 12).[17] The aldol adduct can also be isolated and later treated with butyllithium and an excess of benzaldehyde to give the same product.

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Aldol-Tishchenko reactions catalyzed by lanthanoid complexes such as Cp*2Sm(thf)2 and SmI2 can be efficient, rapid, and high yielding. For example, the former complex catalyzes the aldol-Tishchenko trimerization of acetaldehyde in good yield and with moderate selectivity for the internal 1,3-diol monoester.

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Self-adducts may be used in some cases as precursors for aldol_Tishchenko processes. The self-adduct of acetone is commonly employed in this capacity. A rapid retro-aldol process is followed by addition to the aldehyde in excess and Tishchenko reaction (Eq. 14).[18] The products are isolated in good yield, but because both esters are secondary, selectivity is lower in this case.

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The Evans-Tishchenko reaction involves treatment of β-hydroxy ketones (often generated via aldol addition) with catalytic SmI2 and an aldehyde. Esterification occurs with reduction of the ketone on the same side as the ester group, affording anti-1,3-diol monoesters. Additional β-hydroxy groups must be protected (Eq. 15).[19] This reaction has very wide scope and has been applied in a number of syntheses of natural products (see Synthetic Applications below).

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Synthetic Applications

The Tishchenko reaction is widely used in industry for the production of simple esters such as ethyl acetate. Complex esters are often problematic because of the limited scope of the classical Tishchenko and aldol-Tishchenko reactions. However, these reactions can be applied in synthesis with careful choice of a catalyst or promoter compatible with functionality in the starting materials. For example, a Tishchenko reaction mediated by a samarium complex has been applied to the synthesis of the carbohydrates L-idose and L-altrose (Eq. 16).[20] Swern oxidation occurs selectively to yield a 5-ketoaldehyde intermediate. A superstoichiometric amount of a samarium(III) complex is then used to convert the intermediate to a tert-butyl ester, which is subsequently cyclized.

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The mild conditions and diastereoselectivity of the Evans-Tischenko reaction make it an attractive candidate for syntheses of esters containing suitably positioned hydroxyl groups. This reaction has been applied in several distinct syntheses of (+)-discodermolide 1 to establish the configuration of carbon 11 (Eq. 17).[21]

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TishRxn-Synth-2.png

Other complex targets to which the Evans-Tishchenko reaction has been applied include rhizoxin D[22] and bryostatin 2.[23]

Comparison to Other Methods

Tishchenko-based methods exhibit much better atom economy than other methods for synthesizing esters, which may involve leaving groups and other byproducts not incorporated into the ester. However, the Tishchenko reaction is not general for the synthesis of unsymmetrical esters and esters within complex frameworks. Fischer esterifications, Mitsunobu reactions,[24][25] and alcoholysis of activated carboxylic acid derivatives are generally more effective in this context.

Conditions of the Evans-Tishchenko reaction are generally mild, but if a reduced anti-1,3-diol is desired, an additional hydrolysis step is necessary. The Evans variation of the Saksena reduction, which involves the use of Me4NBH(OAc)3, is a useful alternative for reducing β-hydroxy ketones directly to anti-1,3-diols (Eq. 16).[26]

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A method similar in spirit to the Tishchenko reaction uses β-hydroxy ketones containing an intramolecular silyl ether to deliver hydride intramolecularly (Eq. 17).[27] Many different catalysts can be used to achieve the anti reduction step, but lower temperatures (–80 ºC) are required than comparable Evans-Tishchenko reactions. Selectivity for syn- rather than anti-diols is observed for some combinations of catalyst and substrate, which contrasts with the exclusive anti selectivity of the Evans-Tishchenko reaction.

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Experimental Conditions and Procedure

Typical Conditions

The classical Tishchenko reaction and the variants described here are generally carried out under a rigorously dry and inert atmosphere, as the catalyst systems employed are sensitive to hydrolysis. Cooling is usually necessary as the reaction is exothermic and side reactions may occur at higher temperatures. Keeping the reaction temperature below 0 ºC also minimizes thermodynamic ester migration. Evans-Tishchenko reactions employing samarium diiodide are typically carried out in anhydrous THF between 0 and –10 ºC with the exclusion of light.

Example Procedure[28]

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Under an inert argon atmosphere catechol (13.2 mg, 0.12 mmol) was added to an oven-dried Schlenk flask equipped with a stirring bar. To the flask was added 1 mL of dry CH2Cl2 (freshly distilled over CaH2). The reaction flask was then carefully degassed and a 2 M toluene solution of Me3Al (0.12 mL, 0.24 mmol) was added followed by stirring at rt for 30 min. 2-Propanol (0.037 mL, 0.48 mmol; freshly distilled over CaH2) was added, and the mixture was stirred an additional 15 min to give the catalyst. The reaction was initiated by adding freshly distilled n-butyraldehyde (1.1 mL, 12 mmol) dropwise into the reaction flask containing the catalyst (under argon). The resulting mixture was stirred at rt for 2 h, quenched by adding 5 mL of HCl (0.5 M in H2O) and extracted with Et2O (3 × 10 mL). The combined extracts were dried over MgSO4. Purification by flash chromatography (SiO2, hexane/EtOAc = 4:1) gave n-butyl butyrate as a colorless oil (845 mg, 99%): IR (NaCl) 2965, 2875, 1740, 1460, 1255, 1180, 1093 cm–1; 1H NMR (CDCl3) δ 4.08 (t, 2H), 2.28 (t, 2H), 1.68 (m, 4H), 1.38 (sext, 2H), 0.95 (t, 3H), 0.94 (t, 3H); 13C NMR (CDCl3) δ 173.9, 64.1, 36.3, 30.7, 19.2, 18.5, 13.8, 13.7.


References

  1. ↑ Koskinen, A. M. P.; Kataja, A. O. Org. React. 2014, 86, 2. (link)
  2. ↑ Claisen, L. Chem. Ber. 1887, 20, 646.
  3. ↑ Tishchenko, V. E. Chem. Zentralbl. 1906, 77, 1309.
  4. ↑ Tishchenko, V. E. J. Russ. Phys. Chem. Soc. 1906, 38, 355.
  5. ↑ Ogata, Y.; Kawasaki, A. Tetrahedron 1969, 25, 929.
  6. ↑ a b Ito, T.; Horino, H.; Koshiro, Y.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1982, 55, 504.
  7. ↑ Abu-Hasanayn, F.; Streitwieser, A. J. Org. Chem. 1998, 63, 2954.
  8. ↑ Lu, L.; Chang, H.-Y.; Fang, J.-M. J. Org. Chem. 1999, 64, 843.
  9. ↑ Choi, S.-H.; Yashima, E.; Okamoto, Y. Enantiomer 1997, 2, 105.
  10. ↑ Mascarenhas, C. M.; Miller, S. P.; White, P. S.; Morken, J. P. Angew. Chem., Int. Ed. 2001, 40, 601.
  11. ↑ Törmäkangas, O. P.; Koskinen, A. M. P. Tetrahedron Lett. 2001, 42, 2743.
  12. ↑ Lin, I.; Day, A. R. J. Am. Chem. Soc. 1952, 74, 5133.
  13. ↑ Hon, Y.-S.; Wong, Y.-C.; Chang, C.-P.; Hsieh, C.-H. Tetrahedron 2007, 63, 11325.
  14. ↑ Ooi, T.; Ohmatsu, K.; Sasaki, K.; Miura, T.; Maruoka, K. Tetrahedron Lett. 2003, 44, 3191.
  15. ↑ Ogoshi, S.; Hoshimoto, Y.; Ohashi, M. Chem. Commun. 2010, 46, 3354.
  16. ↑ Hesse, G.; Maurer, M. Liebigs Ann. Chem. 1962, 658, 21.
  17. ↑ Baramee, A.; Chaichit, N.; Intawee, P.; Thebtaranonth, C.; Thebtaranonth, Y. J. Chem. Soc., Chem. Commun. 1991, 1016.
  18. ↑ Simpura, I.; Nevalainen, V. Tetrahedron Lett. 2001, 42, 3905.
  19. ↑ Evans, D. S.; Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127.
  20. ↑ Adinolfi, M.; Barone, G.; De Lorenzo, F.; Iadonisi, A. Synlett 1999, 336.
  21. ↑ Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535.
  22. ↑ Lafontaine, J. A.; Provencal, D. P.; Gardelli, C.; Leahy, J. W. Tetrahedron Lett. 1999, 40, 4145.
  23. ↑ Evans, D. A.; Carter, P. J.; Carreira, E. M.; Prunet, J. A.; Charette, A. B.; Lautens, M. Angew. Chem., Int. Ed. 1998, 37, 2354.
  24. ↑ Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
  25. ↑ Hughes, D. L. Org. React. 1992, 42, 335. (link)
  26. ↑ Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988, 110, 3560.
  27. ↑ Anwar, S.; Davis, A. P. Tetrahedron 1988, 44, 3761.
  28. ↑ Morita, K.-I.; Nishiyama, Y.; Ishii, Y. Organometallics 1993, 12, 3748.
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