Study of 1,3,5-Triazine-Based Catalytic Amide-Forming Reactions: Effect of Solvents and Basicity of Reactants

Abstract

Effect of the basic property of reactants (tertiary amine catalysts, a substrate amine, and acid neutralizers) on catalytic dehydrocondensation between a carboxylic acid and an amine by using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) was studied. The reaction yield was affected by the acid-base equilibrium among reactants. In dichloromethane, a representative aprotic solvent, a strongly basic catalyst gave amides in higher yields than weakly basic catalysts, regardless of the basicity of the acid neutralizer, which is called the proton capture agent (PCA). In contrast, in protic solvents, such as methanol or aqueous methanol, weakly basic catalysts gave amides in somewhat better yields than the strongly basic catalysts. In general, PCAs with weakly basic properties are favorable, because those with strongly basic properties tend to give byproducts arising from the reaction between CDMT and the substrate amine.Key words amide; dehydrocondensation; 1,3,5-triazine; catalytic reaction; solvent effect Dehydrocondensation to form amides and esters is an essential tool for organic and medicinal chemists, and various dehydrocondensing reagents have been developed for the past several decades.1,2) Among them, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM, Fig. 1), has proven to be useful because of its stability, reactivities, and low synthetic cost. [3][4][5] In particular, it selectively produces amides from carboxylic acids and amines even in alcoholic or aqueous media.6-8) Related triazine-based compounds, N- (4,6-dimethoxy-1,3,5-triazin-2-yl)-N,N,N-trialkylammonium chloride (DMT-Ams), which consist of tertiary amines (tertamine) instead of N-methylmorpholine (NMM), have a similar reactivity for dehydrocondensation. [9][10][11][12] We found catalytic dehydrocondensation involving the in situ generation of DMT-Am from a stoichiometric amount of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a catalytic amount of a tert-amine, as summarized in Chart 1. 13) In this system, the addition of a base, proton capture agent (PCA), 14) which is inert toward CDMT, is essential for the regeneration of the tert-amine from its hydrochloride.From this understanding, we have developed catalytic dehydrocondensing reactions using a tert-amine with a specific functional property, such as molecular recognition.13,15-19) As functionalized catalysts, we employed an N,N-dimethylglycine ester as a catalytic tert-amine part because of its facile introduction into functional molecules via the ester group and also because of its potent catalytic activity in a protic solvent. However, the details of the choice of catalytic tert-amine parts depending on the reaction conditions have not been described.Very recently, we have studied the structure-reactivity relationship of tert-amines reacting with CDMT for the generation of DMT-Am, and proposed the gauche β-alkyl group effect.12) This effect indicates that a steric environment around the nitrogen atom rather than the basicity of the tert-amines is predominantly c...

Investigating triazine-based modification of hyaluronan using statistical designs

“…The DMT-MM intermediate reacts with a carboxylate (reaction (2)) to give a DMT-activated ester, followed by its reaction with a cystamine (reaction (3)) yielding the desired product (Scheme 2). The major side reactions in this study would be the hydrolysis (S1 and S2) of CDMT and DMT-activated ester (due to the large amount of water in the aqueous solution), and the aminolysis (S3) of CDMT (due to the high reactivity of amine) (Kunishima et al, 2013). Other possible side reactions include the reactions of CDMT and the CDMT intermediates with the hydroxyl groups and carboxylates in HA.…”

“…Although the carbodiimide method is well established, there is room for significant improvement to overcome the low efficiency of carbodiimide and inevitable N -acylurea side product on the HA backbone. A triazine-based coupling method, which postulates the concept of a “superactive ester” intermediate, has gained much attention (Kaminski et al, 2005; Kunishima et al, 2012, 2013). Because of its excellent efficiency and low cost, the triazine-based coupling method has been used for synthesizing or modifying peptides (Higashibayashi et al, 2004; Tachibana, Monde, & Nishimura, 2004), nucleic acids (Chhabra, Sharma, Liu, & Yan, 2006; Gartner, Kanan, & Liu, 2002; Li, Gartner, Tse, & Liu, 2004; Liu et al, 2008) and polysaccharides (Aoki, Arai, & Hattori, 2004; Aoki, Kinoshita, Mikuni, Nakanishi, & Hattori, 2007; Farkas & Bystricky, 2007; Worthen & Lapitsky, 2011).…”

Specific Labeling of Streptavidin for Better Understanding of Ligand Modification in Modular Method for Affinity Labeling (MoAL)

“…In addition, protein labeling can be achieved just by mixing the target protein with these modules. Because MoAL was designed on the basis of the catalytic dehydrocondensation that proceeds in aqueous solution through the combination of CDMT and a tertiary amine catalyst, 5,6) the target functional group is the carboxy group of an Asp or Glu residue located near the ligand-binding site. This is in contrast to the fact that nucleophilic amino acid residues, such as Cys, His, Lys, Arg, Ser, and Tyr, have been the most common target amino acids in the bioconjugation techniques used for protein modification.…”

Catalytic role of PPh3 and its polymer bound analog in the amidation of carboxylic acids mediated by 2,4,6-trichloro-1,3,5-triazine

“…Derivatization of Nprotected amino acids using PS-PPh 3 as a catalyst also gave the corresponding diamide and dipeptides in high yields (entries [17][18][19][20]. The method was found to be compatible with a range of protecting groups (Fmoc, Cbz, Boc) and each dipeptide was obtained as a single diastereomer based on 1 H-NMR.…”

“…Systems such as TCT/Et 3 N 7,12 or N-methylmorpholine (NMM), 5,6,9 oligomeric dichlorotriazine/NMM, 13 CDMT/NMM, [14][15][16]10,17,18 CDMT/N,N-dimethylglycine esters, 19,20 and CDMT/chiral tertiary amines 21 have all been successfully applied to the amidation of various carboxylic acids. While the mechanism for the TCT-mediated reactions remains unclear, 1 the added tertiary amine is believed to play an important role (apart from acting as a base) in functioning as a catalyst for preactivation of the triazine ring toward nucleophilic substitution.…”