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Zincke aldehydes, or 5-amino-2,4-pentadienals, are the product of the reaction of a pyridinium salt with two equivalents of any secondary amine, followed by basic hydrolysis. Using secondary amines (as opposed to primary amines) the Zincke reaction takes on a different shape forming Zincke aldehydes in which the pyridine ring is ring-opened with the terminal iminium group hydrolyzed to an aldehyde. The use of the dinitrophenyl group for pyridine activation was first reported by Theodor Zincke. [1][2][3] The use of cyanogen bromide for pyridine activation was independently reported by W. König [4]:

Zincke aldehydes

The synthesis and utility of Zincke aldehydes has been reviewed.[5][6][7]

A variation of the Zincke reaction has been applied in the synthesis of novel indoles [8] :

Zincke aldehydes Kearney 2006

with cyanogen bromide mediated pyridine activation (König method).[4]

More recently, an interesting rearrangement of Zincke aldehydes to Z-unsaturated amides was discovered serendipitously while trying to do an intramolecular Diels-Alder reaction.[9] The rearrangement gives the Z-product stereospecifically. In a follow-up paper, allylic amines were used and gave products of a rearrangement/intramolecular Diels-Alder cascade.[10] Mechanistic details were also discussed.

Rearrangement of Zincke aldehydes to Z-unsaturated amides

The Vanderwal group has also reported the synthesis of 4-stannyldienals from Zincke aldehydes by addition of tributylstannyl anion and quenching with acetyl chloride.[11] The products are useful substrates for Stille cross-coupling reactions to give interesting polyene structures.

Formation of stannyldienals from Zincke aldehydes

In 2009, the Vanderwal group reported another interesting rearrangement of Zincke aldehydes. Tryptamine-derived Zincke aldehydes are heated with strong base to give the rearranged enal as shown below. This reaction was the key step in their total synthesis of norfluorocurarine, a Strychnos alkaloid.[12]

Formal cycloaddition of Zincke aldehydes

Also in 2009, the first reports of Zincke aldehydes undergoing a Pictet-Spengler reaction appeared from the group of Delpech and the late Christian Marazano. [13] This reaction provided the tetrahydro-β-carboline or tetrahydroisoquinoline core present in many alkaloid natural products, and was applied to the construction of a known intermediate in a previous total synthesis.

N-Acyl Pictet−Spengler Reaction by Treatment of Tryptamine and Homoveratrylamine Derived Aminopentadienals with TFAA

References

  1. ^ Zincke, Th.; Heuser, G.; Moller, W. (1904). "Ueber Dinitrophenylpyridiniumchlorid und dessen Umwandlungsproducte". Justus Liebigs Annalen der Chemie 333 (2-3): 296–345. doi:10.1002/jlac.19043330212.  
  2. ^ Zincke, Th.; Heuser, G.; Moller, W. (1904). "Ueber Dinitrophenylpyridiniumchlorid und dessen Umwandlungsproducte". Justus Liebigs Annalen der Chemie 330 (2): 361–374. doi:10.1002/jlac.19043300217.  
  3. ^ Zincke, T. H.; Weisspfenning, G. (1913). "Über Dinitrophenylisochinoliniumchlorid und dessen Umwandlungsprodukte". Justus Liebigs Annalen der Chemie 396 (1): 103–131. doi:10.1002/jlac.19133960107.  
  4. ^ a b König, W. (1904). J. Prakt. Chem. 69: 105–137.  
  5. ^ Becher, J. (1980). Synthesis: 589–612.  
  6. ^ Becher, J.; Finsen, L.; Winckelmann, I. (1981). Tetrahedron 37: 2375–2378.  
  7. ^ Cheng, W.-C.; Kurth, M. J. (2002). Org. Prep. Proced. Int. 34: 587–608.  
  8. ^ Synthesis of Nitrogen Heterocycles by the Ring Opening of Pyridinium Salts Aaron M. Kearney, Christopher D. Vanderwal Angew. Chem. Int. Ed. 2006, 45, 7803 –7806 doi:10.1002/anie.200602996
  9. ^ Steinhardt, S.E.; Silverston, J.S.; Vanderwal, C.D. (2008). "Stereocontrolled Synthesis of Z-Dienes via an Unexpected Pericyclic Cascade Rearrangement of 5-Amino-2,4-pentadienals". J. Am. Chem. Soc. 130: 7560–7561. doi:10.1021/ja8028125.  
  10. ^ Steinhardt, S.E.; Vanderwal, C.D. (2009). "Complex Polycyclic Lactams from Pericyclic Cascade Reactions of Zincke Aldehydes". J. Am. Chem. Soc. 131: 7546–7547. doi:10.1021/ja902439f.  
  11. ^ Michels, T.; Rhee, J.U.; Vanderwal, C.D. (2008). "Synthesis of delta-Tributylstannyl Unsaturated Aldehydes from Pyridines". Org. Lett. 10: 4787–4790. doi:10.1021/ol8020435.  
  12. ^ Martin, D.B.C.; Vanderwal, C.D. (2009). "Efficient Access to the Core of the Strychnos, Aspidosperma and Iboga Alkaloids. A Short Synthesis of Norfluorocurarine". J. Am. Chem. Soc. 131: 3472–3473. doi:10.1021/ja900640v.  
  13. ^ Nuhant, P.; Raikar, S.B.; Wypych, J.-C.; Delpech, B.; Marazano, C. (2009). "Enhancement of 5-Aminopenta-2,4-dienals Electrophilicity via Activation by O,N-Bistrifluoroacetylation. Application to an N-Acyl Pictet−Spengler Reaction". J. Org. Chem. 74. doi:10.1021/jo9019545.  

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