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One-Pot Condensation of Carboxylic Acids and Amines Mediated by Ticl4

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One-Pot Condensation of Carboxylic Acids and Amines Mediated by Ticl4 Leggio et al. Chemistry Central Journal (2017) 11:87 DOI 10.1186/s13065-017-0318-9 RESEARCH ARTICLE Open Access Formation of amides: one‑pot condensation of carboxylic acids and amines mediated by ­TiCl4 Antonella Leggio*, Jessica Bagalà, Emilia Lucia Belsito, Alessandra Comandè, Marianna Greco and Angelo Liguori* Abstract A general procedure for the synthesis of amides via the direct condensation of carboxylic acids and amines in the presence of ­TiCl4 is reported. The amidation reaction was performed in pyridine at 85 °C with a wide range of sub- strates providing the corresponding amide products in moderate to excellent yields and high purity. The reaction proceeds with low yields when both the carboxylic acid and the amine are sterically hindered. The process takes place with nearly complete preservation of the stereochemical integrity of chiral substrates. Keywords: Amides, Titanium tetrachloride, Carboxylic acids, Amines, Condensation reaction Introduction Te importance of amides has promoted the devel- Amide is a key functional group in organic chemistry for opment of new protocols and reagents based on these its widespread occurrence in peptide and non-peptide approaches and alternative methods for amide bond for- natural products, therapeutic small molecules, and new mation [13–16]. polymeric materials [1–4]. Te direct formation of amides by condensing non- Te most general way for obtaining amides involves the activated carboxylic acids and amines is extremely attrac- activation of the carboxylic function by means the con- tive because of its low environmental impact. Using version of carboxylic acids into the corresponding acid metal-based catalysis in direct amide preparation, as chlorides [5–8]. Subsequently this reactive derivative is an alternative to coupling reagents, has been reported coupled with the appropriate amine to yield the corre- [17–19]. sponding amide. Te main synthetic catalysts employed for direct ami- Alternatively, carboxylic acids, by the use of activat- dation are boronic acids and esters together with Lewis ing reagents, can be transformed into reactive acylat- acid metal complexes. ing intermediates (acyl chlorides, anhydrides, activated Boron-based compounds are reported as catalysts pro- esters) which directly react in situ with the suitable moting the condensation of carboxylic acids and amines amines without their preliminary isolation and purifca- in refuxing toluene [20, 21]. tion [9–12]. In addition amidation reaction protocols by using Te use of coupling reagents is the only practicable boronic acid and ester catalysts were also developed for way when the reagents useful for obtaining acid chlo- the formation of dipeptide systems [22–24]. rides from carboxylic acids are not compatible with other Under homogeneous conditions, the most used metal chemical functions or protecting groups present on the catalysts for direct coupling of carboxylic acids with substrate. amines are group IV metals. In 1972 Werdehausen et al. [25] developed a catalytic procedure for the direct formation of amides starting *Correspondence: [email protected]; [email protected] Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, from diferent long chain fatty acids and amines by using Università della Calabria Edifcio Polifunzionale, 87036 Arcavacata, CS, Italy © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Leggio et al. Chemistry Central Journal (2017) 11:87 Page 2 of 12 0.6–1 mol% of metal catalysts based on Ti(IV), Zr(IV) Te reaction was previously investigated under cata- and Ta(V), at 120–200 °C. lytic conditions. Benzoic acid (1 mmol) and a catalytic Later carboxyamides from benzoic acids and diferent amount of TiCl4 (30 mol%) were treated with aniline amines were obtained by using stochiometric amounts of (1 mmol) in refuxing dry dichloromethane. During the various Lewis acid catalysts in refuxing toluene [26]. addition of TiCl4 to the carboxylic acid, the production Ti(OBu)4 was used in catalytic amounts for obtain- of hydrochloric acid was observed. After 12 h of reaction ing amides from several carboxylic acids and anilines in small amounts of amide (12%) were obtained. Ten the refuxing o-xylene with yields ranging from 38 to 98%, reaction was repeated for a longer reaction time (24 h). electron donating groups on the aromatic ring of anilines Also in this case the reaction did not proceed and the provided higher conversions than electron withdrawing amide product was recovered with low yield (15%). Te substituents [27, 28]. poor outcome of the reaction prompted us to use a Diferent amides were synthesized using titanium(IV) base to covert the carboxylic acid into the correspond- isopropoxide as catalyst in 10–20 mol% loading in THF ing carboxylate. Pyridine was chosen as base to form [29]. Electronically and sterically demanding substrates the pyridinium carboxylate. It was not possible to use provided their corresponding amides in moderate to non-nucleophilic tertiary nitrogen bases such as trieth- good yields using a reaction temperature of 100 °C. Te ylamine for the known reactivity of the trialkyl amines hydrolytic decomposition of the catalyst caused a dras- with TiCl4 [39, 40]. Te reaction was designed in dichlo- tic lowering of the reaction yields when the reaction was romethane excluding ethereal solvents such as THF performed in air. because, in the presence of TiCl4, O-heterocycle ring Te use of Zirconium(IV) catalysts for the direct ami- opening reaction occurs [41, 42]. Terefore the amida- dation of carboxylic acids and amines was also reported tion reaction was carried out in dichloromethane under [17]. ZrCl4 and ZrCp 2Cl2 were particularly efective refux by treating benzoic acid (1 mmol) with pyridine resulting in high conversions of the substrates after 4 h of (1 mmol) and TiCl4 (1.5 mmol), then aniline was added reaction time at 110 °C using a 5 mol% catalyst. (1 mmol). In the reaction mixture, during the adding Simultaneously, Adolfsson et al. developed a ZrCl4 cat- of pyridine the formation of an insoluble salt, probably alysed amidation protocol at 70 °C in THF with molecu- relating to the pyridinium salt, was observed. After a lar sieves as water scavengers [30, 31]. Both aliphatic and reaction time of 12 h benzanilide was recovered in 38% aromatic carboxylic acids were converted in secondary yield. and tertiary amides in 62–99% yield with 2–10 mol% cat- In the light of these results it was chosen to carry out alyst loading. Aromatic carboxylic acids required reac- the reaction in pyridine, which performs the function tion temperatures of 100 °C and 10% catalyst loading in of solvent and base also by neutralizing the hydrochlo- order to increase the yields after 24 h reaction time. ric acid that develops during the reaction, using a higher Te sandwich complex bis(dicyclopentadienyl)hafnium temperature and an excess of TiCl4 to accelerate the dichloride ([Hf(Cp)2Cl2]) was used as catalyst for direct reaction. amidation of nonactivated carboxylic acids at 26 °C [32]. Benzoic acid (1 mmol) was dissolved in pyridine Te method provided diferent amides in a reaction time (10 mL) in a screw capped vial. Ten, to the resulting of 48 h and using a 10% catalyst loading. Some substrates solution heated at 85 °C, were added TiCl4 (3 mmol) and were converted in the corresponding amides before this aniline (1 mmol). After about 2 h reacting, the reaction time. was completed and the reaction mixture was acidifed In our research activity, in which titanium tetrachloride with 1 N HCl aqueous solution and extracted with meth- was employed, it was observed the oxophilic character ylene chloride. Te organic phase provided the N-phe- of this transition metal towards carbonyl and hydroxyl nylbenzamide in 98% yield and high purity as confrmed groups [33–38]. by GC/MS and NMR analyses. On the base of these observations, we became inter- Previously, TiCl4 was used in stoichiometric amounts ested in investigating the direct coupling of carboxylic to form carboxamides from carboxylic acids [18]. In this acids and amines using TiCl4 as condensing agent. case the reaction was performed in THF or hexane as sol- Here, we report the successful TiCl4-mediated synthe- vent and the nucleophilic amine was used in large excess sis of secondary and tertiary amides starting from various to neutralize the hydrochloric acid produced during the carboxylic acid and amine precursors. reaction. Te reported procedure is poorly applicable as the reaction times are very long (8 h–7 days) also when Results and discussion heating is required. Optimization of amidation reaction conditions was per- Our result was particularly good and interesting, as formed by choosing benzoic acid as model substrate. the product was recovered pure in short times and in Leggio et al. Chemistry Central Journal (2017) 11:87 Page 3 of 12 excellent yield without requiring the use of complex puri- Aliphatic and aromatic carboxylic acids performed fcation procedures. well, delivering the desired amides (1–7) in excellent Encouraged by the success of this preliminary study, yields (entry a–g, Table 1). the adopted procedure was applied for the preparation of Te molecular structure of the obtained amides was a series of N-phenylamides. Diferent alkyl and aryl car- assigned by 1H NMR, 13C NMR and GC/MS analyses. boxylic acids were tested under the developed reaction Additional experiments, that employed 2-fuoroaniline conditions using aniline, the amine component, as a con- and 4-methylaniline as amine components, were car- stant (Scheme 1).
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