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Volumn , Issue 25, 2007, Pages 4205-4216

Rapid organocatalytic aldehyde-aldehyde condensation reactions

Author keywords

Aldehydes; Amines; Kinetics; Linear free energy relationships; Synthetic methods

Indexed keywords


EID: 34548367558     PISSN: 1434193X     EISSN: 10990690     Source Type: Journal    
DOI: 10.1002/ejoc.200700292     Document Type: Article
Times cited : (76)

References (52)
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    • The boric acid mediated self-condensation of aldehydes requires fairly drastic conditions (refluxing xylenes). The reactions take up to 18 h to reach full conversion with heptanal: R. D. Offenhauer, S. F. Nelsen. J. Org. Chem. 1968, 33, 775-777.
    • The boric acid mediated self-condensation of aldehydes requires fairly drastic conditions (refluxing xylenes). The reactions take up to 18 h to reach full conversion with heptanal: R. D. Offenhauer, S. F. Nelsen. J. Org. Chem. 1968, 33, 775-777.
  • 4
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    • These condensation reactions likely proceed according to Mannich- or Knoevenagel-type mechanisms. For examples of previous base- and acid-catalyzed Knoevenagel-Mannich-type reactions, see:a M. Shirai, Y. Yoshida, T. Furuya, S. Sadaike, JP2006045160, 2006;
    • These condensation reactions likely proceed according to Mannich- or Knoevenagel-type mechanisms. For examples of previous base- and acid-catalyzed Knoevenagel-Mannich-type reactions, see:a) M. Shirai, Y. Yoshida, T. Furuya, S. Sadaike, JP2006045160, 2006;
  • 5
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    • b) R. M. Deshpande, M. M. Diwakar, R. V. Chaudhari, WO2005063668A1, 2005;
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    • e) K. Matsuoka, JP04173757, 1992;
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    • Nagareda, K.: Yoshimura, N. JP 06263683, 1994. JP3324820, 2002;
    • f) Nagareda, K.: Yoshimura, N. JP 06263683, 1994. JP3324820, 2002;
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    • G. Duembgen, G. Fouquet, R. Krabetz, E. Lucas, F. Merger, F. Nees, EP0092097A1, 1983;
    • g) G. Duembgen, G. Fouquet, R. Krabetz, E. Lucas, F. Merger, F. Nees, EP0092097A1, 1983;
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    • G. Duembge, G. Fouquet, R. Krabetz, E. Lucas, F. Merger, F. Nees, DE3213681, 1983;
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    • For examples of stoichiometric Mannich α-methylenations, see: k C. S. Marvel, R. L. Myers, J. H. Saunders, J. Am. Chem. Soc. 1948, 70, 1694-1699;
    • For examples of stoichiometric Mannich α-methylenations, see: k) C. S. Marvel, R. L. Myers, J. H. Saunders, J. Am. Chem. Soc. 1948, 70, 1694-1699;
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    • this paper also includes an excellent introduction to the state-of-the-art methods for the synthesis of α-substituted acroleins
    • m) K. Basu, J. Richards, L. A. Paquette, Synthesis 2004, 2841-2844, this paper also includes an excellent introduction to the state-of-the-art methods for the synthesis of α-substituted acroleins.
    • (2004) Synthesis , pp. 2841-2844
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    • For experimental examples with more complex aldehydes. see:a
    • For experimental examples with more complex aldehydes. see:a) K. Yoshida, P. Grieco, J. Org. Chem. 1984, 49, 5257-5260;
    • (1984) J. Org. Chem , vol.49 , pp. 5257-5260
    • Yoshida, K.1    Grieco, P.2
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    • A particularly mild method based on dibromomethane has also been described: a Y.-S. Hon, F.-J. Chang, L. Lu, J. Chem. Soc., Chem. Commun. 1994, 2041-2042;
    • A particularly mild method based on dibromomethane has also been described: a) Y.-S. Hon, F.-J. Chang, L. Lu, J. Chem. Soc., Chem. Commun. 1994, 2041-2042;
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    • Total synthesis of brevetoxin B (second to last step): K. C. Nicolaou, F. P. J. T. Rutjes, E. A. Theodorakis, J. Tiebes, M. Sato, E. Untersteller, J. Am. Chem. Soc. 1995, 117, 1173-1174;
    • a) Total synthesis of brevetoxin B (second to last step): K. C. Nicolaou, F. P. J. T. Rutjes, E. A. Theodorakis, J. Tiebes, M. Sato, E. Untersteller, J. Am. Chem. Soc. 1995, 117, 1173-1174;
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    • Total synthesis of laulimalide: M. T. Crimmins, M. G. Stanton, S. P. Allwein, J. Am. Chem. Soc. 2002, 124, 5958-5959;
    • b) Total synthesis of laulimalide: M. T. Crimmins, M. G. Stanton, S. P. Allwein, J. Am. Chem. Soc. 2002, 124, 5958-5959;
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    • Further solvent screening with our first-generation catalyst system in the reaction between hydrocinnamaldehyde and formaldehyde had indicated that dichloromethane provides better reaction rates that our original solvent system
    • Further solvent screening with our first-generation catalyst system in the reaction between hydrocinnamaldehyde and formaldehyde had indicated that dichloromethane provides better reaction rates that our original solvent system.
  • 33
    • 34548300478 scopus 로고    scopus 로고
    • a becomes larger, the rate increases, presumably because the conjugate base of the benzoic acid is acting as a general base in the reaction. In the reaction mixture, the benzoic acids are expected to exist predominantly as their conjugate bases, and as such the use of the β term may be justified.
    • a becomes larger, the rate increases, presumably because the conjugate base of the benzoic acid is acting as a general base in the reaction. In the reaction mixture, the benzoic acids are expected to exist predominantly as their conjugate bases, and as such the use of the β term may be justified.
  • 34
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    • See the Supporting Information for full details of the reaction optimization
    • See the Supporting Information for full details of the reaction optimization.
  • 37
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    • No product was formed after 6 h with 10 mol-% of the catalyst with aldehyde 1g. However, the use of 20 mol-% of the catalyst promoted 86% conversion to 11g in the same time.
    • No product was formed after 6 h with 10 mol-% of the catalyst with aldehyde 1g. However, the use of 20 mol-% of the catalyst promoted 86% conversion to 11g in the same time.
  • 38
    • 34548357722 scopus 로고    scopus 로고
    • We used formaldehyde as 36.5 wt, solution in water. Under these conditions, the amount of formaldehyde was 16.5 μL. This would correlate to 10.5 μL of H2O under the reaction conditions
    • 2O under the reaction conditions.
  • 39
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    • [15]
    • [15]
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    • See p. 137 in ref.[1
    • [1]
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    • for a discussion on the mechanistic explanation of the observed condensation side-product, see
    • c) for a discussion on the mechanistic explanation of the observed condensation side-product, see: B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000, 122, 2395-2396.
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    • List, B.1    Lerner, R.A.2    Barbas III, C.F.3
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    • For the observation of a similar inverse relationship, see
    • For the observation of a similar inverse relationship, see: D. J. Parks, J. M. Blackwell, W. E. Piers, J. Org. Chem. 2000, 65, 3090-3098.
    • (2000) J. Org. Chem , vol.65 , pp. 3090-3098
    • Parks, D.J.1    Blackwell, J.M.2    Piers, W.E.3
  • 45
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    • The formation of an enamine species from the iminium cation is favored at least by a rate factor of 103 over the amine-catalyzed enolization reaction, see:a R. D. Roberts, H. E. Ferran Jr, M. J. Gula, T. A. Spencer, J. Am. Chem. Soc. 1980, 102, 7054-7058
    • 3 over the amine-catalyzed enolization reaction, see:a) R. D. Roberts, H. E. Ferran Jr, M. J. Gula, T. A. Spencer, J. Am. Chem. Soc. 1980, 102, 7054-7058:
  • 47
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    • The previously determined β values for iminium → enamine conversions are in the ranae of 0.5-0.6. See ref.[22
    • [22]
  • 48
    • 34548337735 scopus 로고    scopus 로고
    • In preliminary experiments, these catalyst systems are also active in the α-methylenation reactions with ketones. However, these products are much more sensitive to dimerization and oligomerization reactions than the corresponding aldehydes
    • In preliminary experiments, these catalyst systems are also active in the α-methylenation reactions with ketones. However, these products are much more sensitive to dimerization and oligomerization reactions than the corresponding aldehydes.


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