Ferrocenium Promoted Oxidation of Benzyl Amines to Imines Using

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Ferrocenium promoted oxidation of benzyl amines to imines using water as the solvent and air as the oxidant Mayukh Deb, Susanta Hazra, Pritam Dolui, and Anil J. Elias ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b03966 • Publication Date (Web): 13 Nov 2018 Downloaded from http://pubs.acs.org on November 13, 2018

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ACS Sustainable Chemistry & Engineering

Ferrocenium promoted oxidation of benzyl amines to imines using water as the solvent and air as the oxidant Mayukh Deb, Susanta Hazra, Pritam Dolui and Anil J. Elias* Department of Chemistry, Indian Institute of Technology Delhi, IIT Delhi Main Road, Hauz Khas, New Delhi-110016, India. Email: [email protected] KEYWORDS: Amine oxidation, Water as solvent, air as oxidant, ferrocenium.

ABSTRACT: A ferrocenium promoted method for the chemoselective oxidation of benzylic amines to imines has been developed with yields varying from 53-93%. Use of 5 mol% ferrocenium hexafluorophosphate as a promoter was sufficient for this radical based oxidation reaction. Air was bubbled into the reaction mixture, which worked as the oxidant for this transformation. Most importantly, the reaction was carried out in pure aqueous medium at 65 oC. A ten-gram scale reaction with benzylamine was successfully carried out to show the practical applicability of this methodology.

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INTRODUCTION The oxidation of benzyl amines to the corresponding imines have received considerable attention in recent times due to the C=N motif, which has been utilized in the preparation of biologically active, pharmaceutically important aromatic and heterocyclic products as well as in the synthesis of many natural products.1-4 Direct oxidation of benzyl amines is advantageous over the traditional Lewis acid catalyzed amine-carbonyl condensation approach due to the inherent kinetic lability of the aldehydes and involvement of strictly anhydrous conditions.5-7 Noticeable development has been achieved in the strategy involving in situ alcohol oxidation and coupling of alcohols with amines to obtain imines.8-17 However, direct methods to oxidize amines to imines have been relatively less explored due to lack of chemoselectivity leading to the possibility of mixtures of products, such as nitriles, amides and azo compounds.18 In the past decade, transition metal catalysed oxidation of amines to imines has been explored producing appreciable yields and good selectivity for imine synthesis (Scheme 1a).18-30, 53 While many of the methods involved the use of pure O2 as oxidant, use of atmospheric air as the only oxidant remained less explored. Numerous challenges still remain to be addressed and satisfactorily surmounted, such as, the requirement of the use of organic solvents, use of expensive metal catalysts with ligands-prepared by cumbersome synthetic methods, use of stoichiometric amounts of oxidants and formation of environmentally unfriendly side products.31 Some of these hurdles have been overcome recently, using metal-free, photo-catalytic and biomimetic catalytic systems using transition metals or non-metals.18,

32-39

However, addressing

many of the above concerns using a single catalytic system have not been achieved so far.


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Since, iron is the second most abundant metal on the earth’s crust, which is inexpensive and is also present in several bio-molecules; it naturally becomes the first choice for catalyst design. Iron catalysed oxidation of primary amines to the corresponding imines has recently been achieved by Xu and co-workers (Scheme 1b).40 Although this methodology was applicable for aromatic, hetero-aromatic as well as alcohol-amine cross-coupling reactions, toluene was used as the solvent in this reaction. A greener reaction medium is highly desirable for the production of imines by direct oxidation of primary amines. In another report, a heterogeneous BTC ligand based iron complex was used under solvent free conditions for this transformation at 100 oC with N-hydroxyphthalimide (NHPI) as the external oxidant (Scheme 1c).41 Sundararaju and coworkers reported a [Fe]-catalyzed dehydrogenation of allylic alcohols and amines giving in-situ generation of imine, which led to the formation of valuable pyrrole derivatives.42 We envisioned that atmospheric oxygen being a safe and green oxidant, the aerobic oxidation strategy by bubbling of air would be a greener, pollution free and more practically useful method for imine synthesis.



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Scheme 1. Direct oxidation of primary amines into imines via iron and other metal catalysts. Ferrocene, since its discovery, has been a molecule of choice for the organometallic chemists due to its unique structural features and range of applications in medicinal chemistry, in the synthesis of dendrimers, biosensors, in electrochemical processes, in material chemistry and most importantly in chiral and achiral catalysis.43-44 Ferrocene/ferrocenium cation couple have been used as a redox based catalytic system in various organic transformations.45, 50 However, to the best of our knowledge, oxidation reactions involving amines have not been attempted using any ferrocene based catalysts. Herein, we report for the first time a ferrocenium ion promoted chemoselective oxidation of benzyl amines to the corresponding imines using atmospheric air as the only oxidant and the reaction was carried out in pure aqueous medium.


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EXPERIMENTAL SECTION General procedure for ferrocenium hexafluorophosphate promoted oxidation of benzyl amines to imines: A 15mL reaction vial was charged with a magnetic stir-bar. Ferrocenium hexafluorophosphate (60 mg, 0.182 mmol, 5 mol%) was dissolved in 2 mL of deionized water. An aquarium air pump [SOBO aquarium SB-9905 air pump] was set up and a controlled air flow was adjusted such that it gives 200-210 bubbles of air per minute. Different benzyl amines (3.64 mmol, 1 equiv.) were added to this mixture. When the mixture was allowed to stir at 65 oC for 10 minutes, a gradual change in colour from bluish green to red-orange with constant bubbling of air was observed. The solution was allowed to stir at 65 oC for 8-12 h. Ethyl acetate was added (5 mL x 3 times) and the organic layer was taken out using a syringe. The solution was dried over sodium sulfate for 3-4 hours and evaporated. The mixture was then separated by column chromatography on silica gel neutralized with a solution of triethylamine : hexane (1:9 v/v) by using a mixture of hexane, ethyl acetate and TEA (95:4:1 v/v ratio) as eluent. The catalyst was recovered in the form of ferrocene by elution with hexane: ethylacetate (99:1 v/v), prior to the collection of the imine product (76% recovery).

RESULTS AND DISCUSSION A reaction of 4-methoxybenzylamine carried out with 5 mol% ferrocenium hexafluorophosphate in water and tert-butyl hydroperoxide as oxidant yielded 14% of the desired imine 3a, along with traces (1-3%) of nitrile and aldehyde as side products. This observation inspired us to carry out the optimization for the iron catalyzed amine oxidation reaction in aqueous medium. We tried Fe(III) salts, such as, FeCl3 and K3[Fe(CN)6] for the oxidation reaction in water which yielded



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the imine in 45% and 16%, respectively. Use of Fe(II) compounds, such as ferrocene and FeCl2 with air as oxidant were not successful leading to only 17% and 15% yields of the desired imine (Table 1, entry 1). Afterwards, we tried two different ferrocenium salts namely, ferrocenium tetrafluoroborate [FeCp2][BF4] and acetylferrocenium tetrafluoroborate. Both salts showed yields of the imine in the moderate range (54-57%) under bubbling of air (Table 1, entries 2, 3). Ferrocenium hexafluorophosphate gave the best yield for the product. We realized that ferrocenium salts have a significant role in the above reaction. We attempted to optimize the amount of promoter required by carrying out reactions with 20, 15, 10, 5 and 2 mol% of [FeCp2][PF6] for the reaction. A higher loading of 20 mol% showed a yield of 78% (TON 3.9) while using 15 mol% of [FeCp2][PF6] yielded 72% of the desired imine product 3a (TON 4.8). With 10 mol% promoter loading the yield was 74% (TON 7.4). Further lowering of the loading to 5 mol% gave 76% of the desired product (TON 15.2). Still lower promoter loading to 2 mol% increased the TON to 31.0 but the overall yield of the imine decreased to 62% and hence was not found to be useful for practical purposes. In the absence of the ferrocenium salt, the bubbling of air alone for 6-8 hrs at 65 oC was able to oxidize the amine to the corresponding imine 3a, but giving only a yield of 11% (See SI, Table S2). NOESY NMR studies carried out on selected imines in this study indicated the formation of the E-isomer exclusively (See supporting info, pages S14-S16). To standardize the oxidant needed for this transformation, use of different oxidants were attempted. A reaction carried out with H2O2 as an oxidant yielded 10% of the desired imine 3a (Table 1, entry 5). Use of other peroxides e. g. tert-butyl peroxybenzoate (TBPB) and di-tertbutyl peroxide (DTBP) as oxidants gave relatively poor yields of 11-16% (Table 1, entries 7, 8). Use of other organic oxidants such as N-methyl morpholine N-oxide (NMO), benzoquinone


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(BQ) or N-hydroxyphthalimide (NHPI) remained unsuccessful (

Ferrocenium Promoted Oxidation of Benzyl Amines to Imines Using

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