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Eur. J. Org. Chem. 12 (2015) 2727-2732; Doi: 10.1002/Ejoc.201500051 Eur. J. Org. Chem. 12 (2015) 2727-2732; doi: 10.1002/ejoc.201500051. Mechanochemical Ritter reaction: a rapid approach to functionalized amides at room temperature Irena Dokli and Matija Gredičak*[a] mostly prepared by standard acid chloride-amine couplings or by recently developed ortho-directed functionalizations,[13] metal- catalysed amidations[14] and metal-free carboxyamidations.[15] Abstract: A fast and efficient mechanochemical Ritter reaction In this paper, we report a general procedure for Brønsted acid between alcohols and nitriles under mild conditions is demonstrated. catalysed mechanochemical Ritter reaction under mild The reaction proceeds rapidly at room temperature in a solvent-free conditions: room temperature, short reaction time, and a solvent- or low-solvent environment, utilizing a Brønsted acid catalyst. Its free or low-solvent environment. The versatility of the protocol is general application has been verified through a substrate screening veryfied through a wide substrate scope investigation, including investigation comprising a wide range of functionalized nitriles, as functionalized nitriles, as well as secondary and tertiary alcohols. well as secondary and tertiary alcohols. Mechanochemistry has been recognized as one of the most successful modes of solvent-free synthesis.[16] Introduction Mechanochemical reactions, usually performed in ball mills, are now present in all fields of chemistry, and their application in [17] The Ritter reaction is an organic reaction that allows formation of organic synthesis is increasing. Recently, it has been shown amides from a carbocation precursor (tertiary alcohol or that conditions produced by a ball mill could be compared to substituted olefin) and a nitrile using a strong acid catalyst.[1] those produced when performing the same reaction at elevated Although the Ritter reaction found its application in drug,[2] and temperature in a solution, though the temperature in the vial [18] natural product and natural product-like syntheses,[3] the remains virtually ambient. Hence, we reasoned that the traditional use of stoichiometric amounts of strong corrosive activation energy of the Ritter reaction could be overcome during acids at elevated temperatures limits its wider application in ball milling. terms of functional group stability. Various procedures comprising sub-stoichiometric amounts of Results and Discussion mineral acids (usually sulfuric acid) have been reported.[4] However, over the past decade, non-nucleophilic organic In order to test our hypothesis, we prepared a model reaction [19] Brønsted acids have emerged as viable catalysts, mostly between benzonitrile and tert-butanol with Brønsted acid sulfonic acids[5]. The Ritter and Ritter-type reactions have also catalyst (Table 1). been successfully catalysed with organic[6] and metal[7] Lewis acids. Table 1. Optimization of the Ritter reaction performed in a ball mill. On the other hand, research attempts to perform the reaction under mild conditions, and thus making it more environmentally friendly, were met with limited success. Shorter reaction times [7c] [7e] were achieved utilizing FeCl3 and Ca(OTf)2 catalysts, though high temperatures were still required. A fast protocol at room temperature with an excess of sulfuric acid was established,[8] however, the reaction was substrate specific for Entry Acid (eq.) Time Conversion (%)a tert-butyl acetate as a carbocation precursor. In further pursue of convenient and efficient Ritter reaction, 1 TfOH (1) 60 min 53 solvent-free procedures employing solid-supported catalysts[9] 2 H3PO4 (1) 60 min 96 and ionic liquids[10] have been reported, but the main issue remains high reaction temperature. Recently, an environmentally 3 H3PO4 (0.5) 60 min 74 benign solvent-free protocol at room temperature was published, 4 H SO (0.5) 30 min 98 however, the reaction time was substantially prolonged.[11] 2 4 Neutral and mild Ritter reaction was achieved with gold(I) 5 CF3COOH (2) 9 min 42 catalyst, yet the protocol was not suitable for solid nitriles, as nitrile was used as the solvent.[12] 6 HCOOH (5) 180 min 40 In addition, abovementioned protocols mostly describe 7 BF3 x OEt2 (1) 60 min 12 employment of non-functionalized nitriles as substrates, and provide a narrow substrate scope; functionalized amides are still 8 FeCl3 x 6 H2O (1) 60 min - 9 H2SO4 (0.25) 60 min 23 [a] Dr. I. Dokli, Dr. M. Gredičak 10 H SO (0.1) 90 min - Division of Organic Chemistry and Biochemistry 2 4 Ruđer Bošković Institute 11 H SO (0.5)b 8 days 43 Bijenička cesta 54, 10 000 Zagreb 2 4 E-mail: [email protected] [a] Determined by 1H NMR. [b] Reaction performed in a flask with stirring at Supporting information for this article is given via a link at the end of room temperature. the document. Eur. J. Org. Chem. 12 (2015) 2727-2732; doi: 10.1002/ejoc.201500051. ® ® Due to the corrosive nature of strong acids, a Teflon vial and When larger, but lighter Teflon ball (d = 10 mm, m = 1.76 g) a tungsten carbide ball (WC; d = 7 mm, m = 4 g) were used. In was used, the reaction yielded 73 % conversion after 60 min, the first reaction, trifluoromethanesulfonic acid (1 eq.) was used. while in the reaction with a corundum ball (d = 6 mm, m = 1 g), After 1 hour, the conversion to tert-butylbenzamide 1 was 88 % conversion was observed within the same period of time observed in 53 % yield (Table 1, entry 1). Encouraged by this (Table 2, entries 3 and 4). Excellent conversion after 30 min was result, we approached catalyst screening and the study of obtained with two corundum balls (Table 2, entry 5), however, reaction conditions. Employing phosphoric acid (1 eq.) as a due to an excessive deterioration of the balls during milling, this catalyst resulted in 96 % conversion after 60 min (Table 1, entry protocol was not found suitable for the indicated reaction. Thus, 2), while lowering its loading diminished conversion to 74 % best parameter combination for investigated process includes (Table 1, entry 3). On the other hand, 98 % conversion was ball milling at 30 Hz with a single tungsten carbide ball.[21] observed after 30 min of ball milling when 0.5 eq. of sulfuric acid With optimized reaction conditions at hand, we turned our was used as a catalyst (Table 1, entry 4). attention to investigate substrate scope and reaction limitations. Nucleophilic organic acids usually hinder the Ritter reaction, The first substrate scope comprised the Ritter reaction of various since they react with carbocations to yield esters.[19] We decided nitriles with tert-butanol as a model alcohol (Table 3). here to test nucleophilic organic acids, and were pleased to see that reactions with trifluoroacetic and formic acid proceed a without traces of ester (Table 1, entries 5 and 6). However, the Table 3. Substrate scope I: Nitriles. transformation results in moderate conversions and requires longer reaction times with an excess of acid (2 eq. of formic acid and 5 eq. of trifluoroacetic acid, respectively). Lewis acids were also tested, but poor conversions were observed (Table 1, entries 7 and 8). Lowering the sulfuric acid loading increased reaction times and significantly decreased conversion (Table 1, entries 9 and 10). Hence, the optimized procedure employed solvent-free ball milling of a nitrile (1 eq.) and an alcohol (1.1 eq.) with sulfuric acid as a catalyst (0.5 eq.) at 30 Hz for 30 min. In order to prove the efficiency of the mechanochemical Ritter reaction, optimized reaction conditions were used for a reaction in a flask with stirring at room temperature; after 8 days, the conversion was 43 % (Table 1, entry 11). Besides chemical parameters, technical and process parameters also require attention, such as the frequency of milling, size and number of balls, and the material from which balls are made of.[17c] Firstly, model reaction was performed at 25 Hz in order to test the influence of milling frequency. After 60 min, 86 % conversion was observed (Table 2, entry 2). Table 2. Optimization of the ball mill conditions. Ball Number Conversion Entry Frequency Time material of balls (%)a 1 WC 1 30 Hz 30 min 98 2 WC 1 25 Hz 60 min 86 [a] Yields are for isolated material. [b] LAG: MeNO (1 eq.). [c] 60 min. 3 Teflon® 1 30 Hz 60 min 73 2 4 corundum 1 30 Hz 60 min 88 When 2-iodobenzonitrile was used in the reaction, only traces 5 corundum 2 30 Hz 30 min 94 of amide 2 were observed. Since the reaction mixture was a solid, we presumed that the carbocation could not be stabilized [a] Determined by 1H NMR. long enough for the reaction to occur. Therefore, liquid-assisted grinding (LAG)[22] was performed with a polar, non-nucleophilic Eur. J. Org. Chem. 12 (2015) 2727-2732; doi: 10.1002/ejoc.201500051. additive possessing the ability to stabilize the carbocation. elimination product styrene, rather than amide 20. The increase Indeed, upon the addition of nitromethane (1 eq., η = 0.26 µL/ of the nitrile amount did not change the reaction outcome. In mg),[23] the reaction rapidly improved to 79 % isolated yield addition to 5 eq. of acetonitrile, 2 eq. of sulfuric acid and longer (Table 3, 2). The transformation maintained its effectiveness reaction time were required to afford desired amide in 84 % upon introducing various halogen atoms on different positions isolated yield. The Ritter reaction between diphenylmethanol throughout the aromatic ring (Table 3, 3–6). The reaction was and acetonitrile to afford amide 21 required longer reaction time, tolerant of other aromatic ring deactivating groups (nitro group 7, most likely due to sterical hindrances of two phenyl groups. ester group 8, CF3 group 9), as well as of aromatic ring It is worth noting that many of prepared amides have been activating groups (methyl group in ortho 10 and para 11 obtained for the first time, while a number of others by positions, methoxy group 12).
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