Direct Catalytic Amidation 2015

Abstract and Introduction;

The use of B(OCH2CF3)3 for mediating direct amidation reactions of a wide range of pharmaceutically relevant carboxylic acids and amines is described, including numerous heterocycle-containing examples. An initial screen of solvents for the direct amidation reaction suggested that cyclopentyl methyl ether, a solvent with a very good safety profile suitable for use over a wide temperature range, was an excellent replacement for the previously used solvent acetonitrile. Under these conditions amides could be prepared from 18 of the 21 carboxylic acids and 18 of the 21 amines examined. Further optimisation of one of the low yielding amidation reactions (36% yield) via a design of experiments approach enabled an 84% yield of the amide to be obtained.

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Introduction

Amides are highly important in pharmaceuticals and it is well documented that amidation is one of the most commonly used processes in the synthesis of medicinally relevant compounds.¹ Amides are typically synthesised either via preparation of a highly reactive acyl derivative (acyl chloride, mixed anhydride, etc.) or via use of a coupling reagent.² These processes are not without significant drawbacks, however, as they often involve the use of toxic reagents or solvents and lead to the generation of large quantities of waste products. As a consequence of this, there has been considerable interest in the development of alternative methods for achieving direct amidation between carboxylic acids and amines, a process which formally only requires the removal of a molecule of water.³ Notable developments have included the identification of numerous catalysts for mediating amidation reactions under dehydrating conditions (e.g. Dean–Stark water removal or molecular sieves) including systems based around boron,⁴ group IV metals,⁵ or other inorganic compounds.⁶ Progress has also been made on the improvement of direct thermal amidation reactions without a catalyst.⁷ However, these methods are largely limited to more reactive carboxylic acids and amines (e.g. simple relatively lipophilic alkyl or aryl systems), with very few successful reactions of functionalised compounds being reported. The synthesis of pharmaceutically relevant compounds inherently requires the amidation of such polar functionalised molecules,⁸ however, with heterocyclic compounds in particular being an essential component of many drug molecules. These highly polar heterocycle-containing acids and amines often show low reactivity in direct amidation reactions (e.g. electron-deficient aminoheterocycles are typically very poor nucleophiles), and the presence of co-ordinating heteroatoms is incompatible with many of the catalytic amidation systems reported to date. In our previous work, we have shown that borate esters⁹ such as B(OMe)₃ and B(OCH₂CF₃)₃ are effective amidation reagents,^10,11 and that purification of the amide products can be achieved using a simple filtration work-up in many cases, without any need for chromatography or aqueous work-up.¹¹ In this paper we report new conditions for direct amidation using a simple borate ester that are effective with a wide range of pharmaceutically relevant carboxylic acids and amines.

Results and discussion

Solvent screen

In our original report of borate-mediated amidation reactions we screened a selection of different solvents for the B(OMe)₃-mediated reaction between phenylacetic acid 1a and benzylamine 2 to give amide 3a.¹⁰ From this initial screen, acetonitrile was selected as a solvent for further study and this was employed for subsequent amidation reactions with other borate esters from which B(OCH₂CF₃)₃ emerged as the most promising reagent, especially for less reactive substrates. However, no subsequent screen of solvents using B(OCH₂CF₃)₃ was carried out. In general, amidation reactions with less reactive substrates were observed to proceed more effectively at higher temperatures, but using acetonitrile as solvent, this led to the need to carry out reactions of particularly difficult substrates at 100 °C in a sealed tube. Even under these conditions, very unreactive substrates such as the poorly nucleophilic 2-aminopyridine gave <20% yield of the corresponding amide.¹¹ Before challenging our amidation method with a set of highly functionalised acids and amines, we therefore elected to carry out a further solvent screen to determine whether other solvents might be more suitable for carrying out B(OCH₂CF₃)₃-mediated amidation reactions (Scheme 1 and Table 1).¹² As in our previous work, we used the reaction of phenylacetic acid and benzylamine as a benchmark to screen the different solvents. The amidation product in this case can easily be isolated rapidly via a filtration work-up, without the need for aqueous work-up or chromatography.

	Scheme 1 Direct amidation between phenylacetic acid and benzylamine.

Table 1 Direct amidation between 1a and 2 in a variety of solvents

Entry	Solvent	Temperature	Yielda
a Isolated yields.
1	MeCN	80	87%
2	DMSO	80	35%
3	tert-Amyl methyl ether (TAME)	80	88%
4	Cyclopentyl methyl ether (CPME)	80	87%
5	4-Methyltetrahydropyran	80	43%
6	Tetrahydrofuran (THF)	80	58%
7	2-Methyltetrahydrofuran (2-MeTHF)	80	56%
8	tert-Butyl methyl ether (TBME)	80	53%
9	Ethyl acetate (EtOAc)	80	50%

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Dimethylsulfoxide (entry 2), selected as it readily dissolves most polar acids/amines, was a poor solvent for the reaction. Ethereal solvents (entries 3–8) proved particularly promising, however, although it should be noted that there was considerable variation in yield within this class of solvent. tert-Amyl methyl ether (TAME, entry 3) and cyclopentyl methyl ether (CPME, entry 4)¹³ were both excellent solvents for the amidation reaction, whereas the use of 4-methyltetrahydropyran (entry 5) resulted in only a moderate yield of the product. Notably, in this latter solvent immediate precipitation was observed on mixing the acid/amine suggesting that salt formation is particularly favourable. This was not the case in the other solvents examined. Other ether solvents including THF, 2-MeTHF and TBME gave the amide in moderate yield, as did ethyl acetate. The latter example elegantly demonstrates the compatibility of esters with the reaction conditions. We selected CPME for further use as it has a relatively high boiling point (bp 106 °C), providing scope for increasing the reaction temperature when studying the amidation of less-reactive substrates. Preliminary studies suggested that whilst many heterocyclic acids/amines may not readily dissolve in CPME at room temperature, they typically dissolve and react at higher temperatures.