Synthetic toolbox: Amidation

CHEM21 Case Study: Catalytic Bio-Chemo Amide bond formation

There has been an increased interest in the development of catalytic oxidative amidation reactions to form amide bonds through the coupling of aldehydes to amines.  The reactions are thought to proceed via oxidation of the resultant imine or hemi-aminal intermediates and are catalysed by transition metals such the platinum group metals, base metals such as iron and copper,[1][2][3][4][5][6][7] lanthanides as well as organo-catalysts.[8][9] These are normally associated with stoichiometric terminal oxidants such as tert-butyl hydroperoxide (TBHP), hydrogen peroxide or oxone.

It is possible to achieve the product amide from the alcohol derivative (usually used in large excess), which would undergo oxidation to the aldehyde in situ as shown in Scheme 1.[10] Coupling methods from the aldehyde starting material give good to excellent yields however, aliphatic and heteroaryl aldehydes are known to give a lower yield and as such require higher reaction temperatures. Therefore, the development of a catalytic methodology for the formation of amides from such starting materials without the need for stoichiometric chlorinating agents or a large excess in aldehyde could offer an attractive alternative.  

Scheme 1: Iron catalysed tandem reaction for the formation of amides from benzylic alcohols (De Luca et al., 2013 [10])

CHEM21 researchers have developed a one-pot tandem reaction for the Bio-Chemo catalytic conversion of benzylic alcohols to aldehydes in the first step, with subsequent reaction with an amine in the presence of TBHP to give the product tertiary amide. The reaction proceeds at mild temperatures (25-37 ˚C), and proceeds as a one-pot, two-step process (Scheme 2).[11]

Scheme 2: Catalytic Bio-Chemo Cascade for the formation of amides (Turner et al. 2014[11])

The system tolerates a wide range of benzylic alcohols containing electron deficient aromatic rings, with 4‑nitrobenzene exhibiting the highest yield in product amide at 91%.  This bio-chemo cascade offers mild reaction conditions, material efficiency and circumvents the need for air and moisture exclusion. Although method the shown in Scheme 1 is an excellent example of where the synthetic community is beginning to move away from the use of catalysts based on precious metals and making use of the more earth abundant metals such as iron, one could argue on closer scrutiny of the both approaches, that there is little difference between them. However, we chose such an example to highlight the energy and material savings that can be made when biocatalysts are considered over chemocatalysts.

  1. W. - K. Chan, C. - M. Ho, M. - K. Wong and C. - M. Che, Oxidative Amide Synthesis and N-Terminal α-Amino Group Ligation of Peptides in Aqueous Medium, J. Am. Chem. Soc., 2006, 128, 14796-14797.
  2. Y. Suto, N. Yamagiwa and Y. Torisawa, Pd-catalyzed oxidative amidation of aldehydes with hydrogen peroxide, Tetrahedron Lett., 2008, 49, 5732-5735.
  3. J. Wei Wei Chang and P. Wai Hong Chan, Highly Efficient Ruthenium(II) Porphyrin Catalyzed Amidation of Aldehydes, Angew. Chem. Int. Ed., 2008, 47, 1138-1140.
  4. S. Muthaiah, S. Chandra Ghosh, J. - E. Jee, C. Chen, J. Zhang and S. Hyeok Hong, Direct Amide Synthesis from Either Alcohols or Aldehydes with Amines: Activity of Ru(II) Hydride and Ru(0) Complexes, J. Org. Chem., 2010, 75, 3002-3006.
  5. S. Chandra Ghosh, J. S. Y. Ngiam, A. M. Seayad, D. Thanh Tuan, C. L. L. Chai and A. Chen, Copper-Catalyzed Oxidative Amidation of Aldehydes with Amine Salts: Synthesis of Primary, Secondary, and Tertiary Amides, J. Org. Chem., 2012, 77, 8007-8015.
  6. J. Li, F. Xu, Y. Zhang and Q. Shen, Heterobimetallic Lanthanide/Sodium Phenoxides: Efficient Catalysts for Amidation of Aldehydes with Amines, J. Org. Chem., 2009, 74, 2575-2577.
  7. C. Qian, X. Zhang, J. Li, F. Xu, Y. Zhang and Q. Shen, Trisguanidinate Lanthanide Complexes: Syntheses, Structures, and Catalytic Activity for Mild Amidation of Aldehydes with Amines, Organometallics, 2009, 28, 3856-3862.
  8. H. U. Vora and T. Rovis, Nucleophilic Carbene and HOAt Relay Catalysis in an Amide Bond Coupling:  An Orthogonal Peptide Bond Forming Reaction, J. Am. Chem. Soc., 2007, 129, 13796-13797.
  9. J. W. Bode and S. S. Sohn, N-Heterocyclic Carbene-Catalyzed Redox Amidations of α-Functionalized Aldehydes with Amines, J. Am. Chem. Soc., 2007, 129, 13798-13799.
  10. S. Gaspa, A. Porcheddu and L. De Luca, Iron-catalysed oxidative amidation of alcohols with amines, Org. Biomol. Chem., 2013, 11, 3803-3807.
  11. B. Bechi, S. Herter, C. McKenna Shane and Riley, S. Leimkühler, N. J. Turner and A. J. Carnell, Catalytic bio–chemo and bio–bio tandem oxidation reactions for amide and carboxylic acid synthesis, Green Chem., 2014, 16, 4524–4529.