Metal- and solvent-free synthesis of amides using substitute formamides as an amino source under mild conditions

This study described an efficient and practical approach for amide synthesis. The reaction was conducted under metal- and solvent-free conditions at a mild temperature (40 °C) in air, and readily available formamides were used as an amino source. This reaction can be easily upgraded to the gram level with an excellent yield.

The generalizability of this method was explored under the following optimized conditions: peroxoate, 0.5 mmol; substrate amide, 5 equiv; and KO t Bu, 4 equiv at 40 °C in air for 3 h. N,N-disubstituted,  www.nature.com/scientificreports www.nature.com/scientificreports/ N-monosubstituted, and unsubstituted amides 2 were converted into the desired product 3 with good to excellent yields ( Fig. 3a-c). In addition, formyl hydrazine smoothly reacted with tert-butylbenzoperoxoate and obtained the corresponding product with a moderate yield (3d). When the hydrophobicity of the alkyl substituents on the nitrogen of amide 2 was increased, the solubility of KO t Bu decreased, which is unfavorable to this conversion (3e-f). No product was detected when N-cyclohexyl formamide was used as the amino source (3 g). Other tert-butylbenzoperoxoate derivatives were also investigated and found that electron-rich or electron-deficient derivatives render this reaction smooth (3h-q). Naphthylperoxoates also showed high reactivity and obtained good isolated yields (3s-t). Heteroaromatic (including furan, thiophene, and benzothiophene) peroxoates can also be converted into corresponding products with moderate yields (3v-y). However, 3r and 3 u were either undetected or with only a poor yield, which might be caused by the aforementioned poor solubility of KO t Bu on the reaction systems. The reaction of alkyl perester, such as tert-butyl ethaneperoxoate with N-benzylformamide was conducted, but no amide product could be detected.
Several control experiments were conducted to investigate the reaction mechanism. First, we used benzoyl peroxide instead of tert-butylbenzoperoxoate and obtained a poor yield of 32% (Fig. 4, eq. 1). When one of the benzene rings is converted into the product, the remaining ring would probably lose its reactivity. The reaction of other peroxide acids such as 3-chloroperoxybenzoic acid and peroxyacetic acid with formamide derivatives were also tried, but no desired product could be detected (Fig. 4, eqs 2 and 3).
From a general perspective, this transformation was considered as radical process because peroxide was used as a substrate. Hence, the radical block reaction was conducted using TEMPO as a radical inhibitor. The addition of TEMPO showed no evident effect, and the product yield was 79% (Fig. 4, eq. 4). Good and moderate yields were still obtained when BHT and benzoquinone were used as inhibitors, respectively (Fig. 4, eqs 5 and 6). These results excluded the radical process of this transformation. Afterwards, the hydrogen of aldehyde was replaced by methyl, and almost no desired product was detected (Fig. 4, eq. 7). This result indicated the need for decarbonylation, which was blocked by methyl. Then, an isotope labeling experiment was conducted to confirm the source of carbonyl on the target molecules (T.M.) (Fig. 4, eq. 8). Almost all carbon molecules in the carbonyl group of the product were identified as isotope 13 C. Afterward, the decomposition reaction of formamide derivative was tested, and it was found morpholine-4-carbaldehyde could be decomposed to morpholine under the standard condition (Fig. 4, eq. 9). Followed, the reaction of tert-butyl benzoperoxoate and amine were conducted, and the desired product was found with a yield of 38% (Fig. 4, eq. 10). These results indicated that the decomposition of formamide derivative and the corresponding decomposition product amine might be played an important role Isolated yield was showed out brackets, 1 H NMR yield were showed in brackets. b 10 equiv of amide 2 was used, temperature is 70 °C. c 10 equiv of amide 2 was used, temperature 80 °C. d 1.5 mL DMF was used, 4 equiv KO t Bu was used, temperature is 80 °C. e Peroxide (0.1 mmol), KO t Bu (5 equiv), HCONH 2 (25 equiv), temperature is 80 °C.
www.nature.com/scientificreports www.nature.com/scientificreports/ in this amide synthesis procedure. Based on these control experiments and previous studies 13,29 , a possible mechanism was proposed (Fig. 5).
Initially, dimethylamine anion (I) was formed via the decarbonylation of formamide with the release of CO in the presence of KO t Bu 30 . The nucleophilic addition of (I) to tert-butylbenzoperoxoate subsequently occurred while gathering the T.M.

Conclusions
In summary, an efficient and practical approach for the synthesis of amide has been developed. The reaction is conducted in air at a mild temperature (40 °C) under metal-and solvent-free conditions, and the readily available substitute formamides were used as an amino source. This transformation can easily be upgraded to the gram level, thereby providing an avenue for the synthesis of valuable amides.

Materials and Methods
General information. Preparative thin-layer chromatography was performed for product purification using Sorbent Silica Gel 60 F254 TLC plates and visualized with ultraviolet light. IR spectra were recorded on a new Fourier transform infrared spectroscopy. 1 H, 13 C and 19 F NMR spectra were recorded on 400, 100, 377 MHz NMR spectrometer using CDCl 3 as solvent unless otherwise stated. HRMS were made by means of ESI. Melting points were measured on micro melting point apparatus and uncorrected. Unless otherwise noted, all reagents were weighed and handled in air, and all reactions were carried out in a sealed tube under an atmosphere of air. Unless otherwise noted, all reagents were purchased from reagent company, and used without further purifications. Experimental Section. A typical experimental procedure for transamidation was conducted as follows: A solution of peroxoate (0.5 mmol), KO t Bu (2.5 equiv, 140 mg) and amide (5 equiv or 10 equiv) were stirred in a sealed tube under an atmosphere of air at 40 °C for 3 h. The reaction mixture was then extracted with ethyl acetate. Afterward, the solution was evaporated under vacuum. The residue was purified by preparative thin-layer chromatography (TLC) on silica gel with petroleum ether and ethyl acetate (5% triethylamine) to achieve the pure product.