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Direct Synthesis of Amides by Dehydrogenative Coupling of Amines with Alcohols or Esters Catalysed by a Manganese Pincer Complex
| Content Provider | Semantic Scholar |
|---|---|
| Author | Kumar, Amit Espinosa-Jalapa, Noel Angel Leitus, Gregory Diskin-Posner, Yael Avram, Liat Milstein, David |
| Copyright Year | 2017 |
| Abstract | The first example of base-metal-catalyzed synthesis of amides from the coupling of primary amines with alcohols or esters is reported. The reactions are catalyzed by a new manganese pincer complex and generate hydrogen gas as the sole by-product, making the overall process atom economical and sustainable. Amide bond formation is one of the most fundamental reactions in chemistry and biology. Compounds containing amide groups are prevalent in both synthetic and natural products and are of much importance in the chemical and pharmaceutical industries, being present in approximately 25% of the available drugs. Conventional methods for the synthesis of amides involve the reaction of carboxylic acids or their activated derivatives with amines in presence of promoters, generating stoichiometric amounts of waste. There is considerable interest in the development of atomeconomic routes for the synthesis of amides. A few years ago ACS Green Chemistry Institute Pharmaceutical Roundtable reported ‘amide bond formation avoiding poor atom economy’ as the most preferred reaction to be developed. In 2007 we reported the synthesis of amides by dehydrogenative coupling of alcohols and amines, generating hydrogen gas as the only byproduct. This opened up a new area for the atom economic and environmental benign synthesis of amides and several precious metal-based catalysts were subsequently reported. The development of synthetic methods that avoid the use of noble metals is in high current demand. Regarding coupling of alcohols and amines, we reported the formation of imines and the formation of formamide derivatives using manganese-pincer catalysts. Beller has reported the synthesis of various lactams from amino-alcohols using an iron pincer catalyst. Bernskoetter and Hazari have recently reported an iron-based catalyst for the dehydrogenative coupling of methanol and secondary amines to generate formamides. However, while efficient with methanol, the catalyst showed poor catalytic activity with alcohols higher than methanol, such as ethanol or hexanol. Also, amidation of primary, rather than secondary amines, is significantly more challenging, since in case of secondary amines, the possibility of competing imine formation is avoided, whereas a primary amine faces this selectivity challenge as it can liberate both water and hydrogen from a hemiaminal intermediate. Very recently, we reported that the MnPNNH complex 1 in the presence of two equivalents of KH catalyses the dehydrogenative coupling of diols and amines to form cyclic imides. We now report the Mn-pincer complex 3 and its catalytic activity in the synthesis of amides. Figure 1. Manganese pincer complexes used in this report. Inspired by the efficient catalytic activity of complex 1 for the synthesis of cyclic imides, we first tested its reactivity for the synthesis of amides. Reaction of hexanol and benzylamine with 1 (5 mol%) and KH (10 mol%) for 40 h at 120C resulted in a mixture of amide (34%), imine (26%) and ester (18%) as detected by H NMR spectroscopy and GC-MS. Although, amide formation was encouraging, we were unable to avoid the formation of imine (Table S3 in SI). The dearomatized Mn-PNN complex (2), analogous to the Ru-PNN complex, which is a well-known catalyst of the amidation reaction, was found to be inactive for amide formation by reaction of hexanol and 4-methylbenzylamine. Modifying the structure of complex 1 we have now synthesized the PPh2 analogue, complex 3 by the reaction of the new ligand L with Mn(CO)5Br (Scheme 1, see SI for synthesis and characterization details). Scheme 1. Synthesis of complex 3 and its single crystal X-ray structure at 50% probability. Hydrogen atoms except the NH proton are omitted for clarity. See SI for full description of the structure. We then tested the catalytic activity of 3 towards the amidation reaction (equation 1). Interestingly, when a toluene solution of hexanol (0.5 mmol) and 4-methylbenzylamine (0.5 mmol) in presence of 5 mol% 3 and 5 mol% KOBu was refluxed at 110C for 24 h, 70% alcohol conversion was observed with concomitant formation of 45% amide, the rest being hexyl hexanoate, as detected by H NMR spectroscopy. When the amount of base was increased to 10 mol% keeping the remaining conditions the same, better conversion (75%) of alcohol to amide (55% yield) was observed. Increasing the reaction time to 48 h under the same conditions resulted in 99% conversion of the alcohol to amide (89%) and ester (5%) (see SI, Table S4 for optimization details). Gratifyingly, no [*] Dr. A. Kumar, Dr. N. A. Espinosa-Jalapa, Prof. D. Milstein Department of Organic Chemistry, Weizmann Institute of Institution Rehovot, Israel, 76100 E-mail: david.milstein@weizmann.ac.il Dr. G. Leitus, Dr. Y. Diskin-Posner, Dr. L. Avram Chemical Research Support, Weizmann Institute of Science Rehovot, Israel, 76100 Supporting information for this article is given via a link at the end of the document. 10.1002/anie.201709180 Angewandte Chemie International Edition This article is protected by copyright. All rights reserved. |
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| Alternate Webpage(s) | http://www.weizmann.ac.il/Organic_Chemistry/milstein/sites/Organic_Chemistry.milstein/files/uploads/angew_amides_accpted_article_2017.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
