A convenient one-pot synthesis of formamide derivatives using thiamine hydrochloride as a novel catalyst

Formamide derivatives have been synthesized in excellent yields from amine and formic acid in the presence of a catalytic amount of thiamine hydrochloride (VB1) at 80 !C. The advantages of this method are the use of a cheap, stable, non-toxic, and readily available catalyst, easy work-up, improved yields, and solvent-free conditions. " 2010 Elsevier Ltd. All rights reserved. Formylation of amines is one of the most important protocols in organic synthesis and medicinal chemistry. Formamides are useful intermediates in various organic syntheses as their skeletons are present in different medicinally important compounds. Moreover, the formyl group is an important amino-protecting group in peptide synthesis. In recent years, formamides are also used as Lewis bases to promote several organic transformations. A number of formylation methods have been reported in recent years. Some of the useful formylation reagents are chloral, formic acid-DCC, formic acid-EDCI, formic acid-ZnCl2, formic acid-PEG 400, formic acid esters, CDMT, and other formylation reagents. However, many of these procedures so far suffer from disadvantages, such as expensive reagents, harsh reaction conditions, prolonged reaction times, high reaction temperature, and low isolation yields. Therefore, there is a need to develop a better catalyst for the synthesis of formamide derivatives in terms of operational simplicity and economic viability. It is well known that thiamine hydrochloride (VB1) is cheap, non-toxic, stable, and can be recovered. VB1 contains a pyrimidine ring and a thiazole ring linked by a methylene bridge (Fig. 1). VB1 analogs have been used as powerful catalysts for many carbon– carbon and carbon–heteroatom bond formation reactions in good yields. As a part of the ongoing interest in VB1-catalyzed reaction for various organic transformations, we had the opportunity to further explore its catalytic activity toward the synthesis of formamides. In this Letter, we wish to report a simple but effective procedure for the synthesis of formamide derivatives from amines and formic acid by employing VB1 as a novel catalyst (Scheme 1). Initially, we studied the catalytic efficiency of VB1 for a model reaction using aniline 1a and formic acid in different reaction conditions (Table 1). It was reported that no reaction was observed when a mixture of aniline 1a and formic acid was heated at 100 !C for 4 h (Table 1, entry 1). However, we obtained the corresponding product 2a in 84% yield by simply mixing aniline 1a and formic acid in the presence of 1 mol % of VB1 at 80 !C for 15 min, thus, highlighting the role of VB1 as a promoter. Further studies revealed that the reaction was sluggish giving poor yields (<20%) in various solvents, such as MeOH, EtOH, THF, DCM, and MeCN (Table 1, entries 6–10). Moreover, we also found that 2 mol % of VB1 was sufficient and an excessive amount of catalyst did not increase the yields (Table 1, entries 2–5). In terms of yields and reaction time, we achieved the best conditions to synthesize formamide 2a by using 2 mol % VB1 under solvent-free conditions. Having established the optimized reaction conditions, we then successfully synthesized a variety of formamide derivatives 2 (Scheme 1), and the results are summarized in Table 2. In all of the studied examples, the aromatic amines, primary amines, and secondary amines could react smoothly to give the 0040-4039/$ see front matter " 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.06.005 * Corresponding author. Tel.: +86 21 6425 3691; fax: +86 21 5027 2221. E-mail address: [email protected] (L. Ma). N N H3C NH3 N S H3C OH Cl Cl Figure 1. The structure of VB1. NH R R1 + HCOOH VB1 2 mol % Solvent-free, 80 oC NCHO R R1