Green and Sustainable Chemistry

Take Green Routes to Amide Formation

by José Barros

July 18, 2016

Figure 1

Forming amide bonds is one of the most important and studied reactions in organic chemistry. Amide bonds are found in many drugs, natural products, and polymers. It is estimated that more than 25% of all drugs contain at least one amide bond. Some examples are shown in Figure 1.

One major family of compounds that contain amide bonds are the peptides—sequences of amino acids. Currently, the synthesis of peptides from individual amino acids consists of this reaction sequence:

  1.  Protecting the carboxyl and amine groups that are not to be involved in the reaction
  2.  Activating the reactive carboxyl group
  3.  Forming the amide bond
  4.  Deprotecting the protected groups
Figure 2

The process is repeated to form the desired peptide from additional amino acids. It can be run in the liquid phase, or in the solid phase when a terminal amino acid is anchored to a solid support such as a Merrifield resin.

An example of the first two cycles of a liquid-phase synthesis is shown in Figure 2. Pn is the amine protecting group; Pc is the carboxyl protecting group. The three starting amino acids are alanine (Ala), valine (Val), and phenylalanine (Phe). The new amide bonds are shown in red.

Preventing byproduct waste

The existing processes for making amides from acids or peptides from amino acids usually generate large amounts of waste that come from the use of protecting and activating groups. Tom D. Sheppard at University College London and colleagues there and at Pfizer (Sandwich, UK) and GlaxoSmithKline (Stevenage, UK) report a method for producing peptides and other amides from amino acids without the need for N-protection.

Figure 3

The key to success in the authors’ process is using the commercially available borate ester B(OCH2CF3)3. They first treated 20 unprotected amino acids with the borate ester and n-propylamine in cyclopentyl methyl ether (CPME), a solvent that is superior for amide synthesis (top line in Figure 3). Filtration through commercially available resins such as Amberlite IRA-743 or Amberlyst A-26(OH) gave high-purity amides from most of the amino acids without the need for chromatographic purification or other workup.

Using their method, the researchers treated 14 proteinogenic and 6 unnatural amino acids with several amines and amino acids. Some degree of racemization occurred; but because the products were solids, their optical purity could be enhanced by recrystallization. The process was used to prepare the epilepsy drug lacosamide (5, bottom line in Figure 3) with an enantiomeric ratio of 94:6 in 62% yield over the two steps shown. DMAP is 4-dimethylaminopyridine.

The authors propose a reaction mechanism in which the borate coordinates with the amino acid’s amine and carboxylic acid groups to form a cyclic intermediate. This intermediate reacts with the amine group of the compound to be coupled to give the product. If the amino acid or the amine is relatively unreactive, the intermediate has time to equilibrate with its achiral cyclic enolate isomer. This complication leads to a less enantiopure product. (Chem. Commun. DOI: 10.1039/C6CC05147B)

Aldehydes to amides

Giorgios Papadopoulos and Christoforos Kokotos* at the National and Kapodestrian University of Athens developed a very different environmentally friendly process for making amides. They used aldehydes as their substrates and converted them to amides with light and a catalyst.

Figure 4

Taking a cue from previous studies of photo-organic catalysis, the authors used phenylglyoxylic acid (7 in the generic reaction shown in the top line of Figure 4) to promote amide formation. They treated heptanal (6; R1 = n-C6H13, R2 = H) with 10 mol% 7 and diisopropylazodicarboxylate (DIAD) in petroleum ether and ordinary household bulbs as the light source. The intermediate was not isolated but reacted with allylamine (8; R3 = –CH2CH=CH2, R4 = H) to produce the corresponding amide in 95% yield with dichloromethane as the preferred solvent.

The researchers tested several primary, secondary, and unsaturated amines and two amino acid derivatives (tert-butyl alaninate and methyl phenylalaninate) and obtained uniformly high yields. All of the aliphatic, aromatic, and olefinic aldehyde substrates that they investigated also produced high yields. The method was applied to the synthesis of the antidepression drug moclobemide (9 in the bottom line of Figure 4) from p-chlorobenzaldehyde in 30% yield after two steps. MsCl is methanesulfonyl chloride.

The authors’ proposed mechanism is based on the role of DIAD, an acylhydrazide that activates the aldehyde carbonyl toward amine attack. Because it is not necessary to isolate the intermediate, the method is a one-pot synthesis. (J. Org. Chem. DOI: 10.1021/acs.joc.6b00488)

Green methods for the future

Both studies describe new methods to produce amides and peptides. The reactions use inexpensive, nontoxic, readily available reagents. They are scalable and should be applicable in medicinal chemistry and organic chemical processing.