Mimicking Transition Metals in Borrowing Hydrogen from Alcohols†‡ Cite This: Chem

Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Mimicking transition metals in borrowing hydrogen from alcohols†‡ Cite this: Chem. Sci.,2021,12,8353 All publication charges for this article Ananya Banik, Jasimuddin Ahmed, Swagata Sil and Swadhin K. Mandal * have been paid for by the Royal Society of Chemistry Borrowing hydrogen from alcohols, storing it on a catalyst and subsequent transfer of the hydrogen from the catalyst to an in situ generated imine is the hallmark of a transition metal mediated catalytic N-alkylation of amines. However, such a borrowing hydrogen mechanism with a transition metal free catalytic system which stores hydrogen molecules in the catalyst backbone is yet to be established. Herein, we demonstrate that a phenalenyl ligand can imitate the role of transition metals in storing and transferring hydrogen molecules leading to borrowing hydrogen mediated alkylation of anilines by alcohols including a wide range of substrate scope. A close inspection of the mechanistic pathway by characterizing several Received 24th March 2021 intermediates through various spectroscopic techniques, deuterium labelling experiments, and DFT study Accepted 7th May 2021 concluded that the phenalenyl radical based backbone sequentially adds H+,Hc and an electron through DOI: 10.1039/d1sc01681d a dearomatization process which are subsequently used as reducing equivalents to the C–N double Creative Commons Attribution-NonCommercial 3.0 Unported Licence. rsc.li/chemical-science bond in a catalytic fashion. Introduction sustainable and environmentally safe process. In this regard, Winans and Adkins14 have discovered this reaction and later Borrowing hydrogen from alcohols, and utilization of the har- Grigg15 and Watanabe16 have reported the rst homogeneous vested hydrogen for further reduction of in situ generated catalysis towards the alkylation of amines using an alcohol, imines is the hallmark of a transition metal mediated catalytic which has been termed ‘Borrowing Hydrogen or Hydrogen process which leads to the synthesis of N-alkylated amines. It Autotransfer (BH/HA)’. In this methodology, an alcohol is This article is licensed under a may be noted that N-alkylated amines have widespread appli- dehydrogenated to a more reactive carbonyl compound, where cations in chemistry and biology. These amines are extensively a proton and a hydride are transferred to the transition metal- utilized as universal building blocks for organic synthesis, based catalyst and typically stored as the metal dihydride Open Access Article. Published on 07 May 2021. Downloaded 10/1/2021 6:15:38 PM. pharmaceuticals, agrochemicals, drugs, materials science, the (Scheme 1). Next, the carbonyl compound undergoes polymer industry, and various natural products.1–5 Traditional a condensation reaction with an amine generating an imine methods for the preparation of substituted amines followed the which subsequently undergoes reduction to an N-alkylated reductions of imines6 and amides,7,8 hydroamination,9,10 reductive amination11 and also, there are straight forward methods such as the N-alkylation of amines.12,13 The conventional methods for the alkylation of amines involve the use of highly genotoxic alkylating agents such as alkyl halides or sulfonate esters. However, these methods suffer from the generation of stoichiometric amounts of halide waste, and the chemoselectivity issue for the formation of over alkylated by- products. In this regard, the use of an alcohol as a benign alkylating agent has drawn considerable attention due to its remarkable abundance in biomass as well as for the generation of green waste (water as the sole by-product). Thus, the use of an alcohol for N-alkylation of amines is considered as a green, Department of Chemical Sciences, Indian Institute of Science Education and Research-Kolkata, Mohanpur, 741246, India. E-mail: [email protected] † Dedicated to Professor Christian Bruneau. ‡ Electronic supplementary information (ESI) available: Detailed experimental Scheme 1 Alkylation of amines by alcohols via hydrogen borrowing: procedures, NMR and HRMS spectra, and coordinates of the computed conventional approach and our strategy. structures. See DOI: 10.1039/d1sc01681d © 2021 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.,2021,12, 8353–8361 | 8353 View Article Online Chemical Science Edge Article amine through the transfer of the stored hydride and proton In the current study, we have established that the PLY based when the catalyst is regenerated. This method involves the use catalyst can store the borrowed hydrogen molecule by addition of precious metals such as ruthenium,17,18 rhodium19 and of H+,Hc and an electron sequentially from the alcohol partner iridium20-based catalysts and was extensively used in early and stores in the form of two C–H bonds through a dearomati- studies. In more recent years, the alkylation of amines through zation process which are subsequently transferred to the in situ the borrowing hydrogen strategy was dominated by inexpensive, generated imines to realize the corresponding alkylated earth-abundant metal-based catalysts21–35 replacing the expen- aromatic amines (Scheme 1). This study presents an alternative sive noble metal catalysts. In this regard, substantial progress strategy for replacing the transition metal based catalysts in the has been demonstrated by the group of Feringa and Barta,21,22 alkylation of aromatic amines through the borrowing hydrogen Beller,23 Milstein,24 Kempe,25–27 and others28–31 using early tran- methodology. sition metals such as iron, manganese, cobalt, nickel and chromium-based catalysts to make the processes more envi- Results and discussion ronmentally benign. Towards the sustainable synthesis of alkylated amines, the need for a transition metal-free catalyst is At rst, several redox non-innocent PLY based molecules [(O,O)- inevitable. In this regard, a bioinspired catalytic combination PLY, various (N,O)-PLY and (O,N,N,O)-PLY] were synthesized such as NADH-ADH36,37 or transition metal free combination according to literature methods.59–62 The preliminary investi- using pyridine/KOtBu38 evolved recently for the alkylation of gation of transition metal-free alkylation of amines started with amines, but they differ conceptually from the borrowing probing the reaction of aniline and benzyl alcohol in the pres- hydrogen mechanism followed typically by a transition metal ence of a catalytic amount of these PLY molecules with 1.2 based catalyst. The transition metal based catalyst stores both equivalents of base, KOtBu, to realize the corresponding N- proton and hydride in its backbone (Scheme 1), which in turn benzylaniline (Table 1, also see ESI, Table S1‡). The reaction of can deliver a hydrogen molecule for further reductions. On the aniline, 1a (0.3 mmol), and benzyl alcohol, 2a (0.33 mmol), in the presence of a catalytic amount of (N,O)-PLY (5.0 mol%) with Creative Commons Attribution-NonCommercial 3.0 Unported Licence. other hand, the existing metal-free catalysts are not capable of mimicking such a role as they can store only hydride while KOtBu (1.2 equivalents) in toluene at 130 Cafforded 43% yield proton is stored in a different molecule. Although a few other of the N-alkylated amine, 3a (N-benzylaniline) within 18 hours studies have been reported where a purely base mediated39–43 N- (entry 1, Table S1, ESI‡). Further increasing the loading of (N,O)- alkylation by an alcohol is achieved using KOH, CsOH and PLY (10.0 mol%) and scrutinizing different PLY molecules NaOH respectively, they do not follow the borrowing hydrogen (Table 1), the maximum NMR yield (99%) of N-alkylated amine, pathway as observed in transition metal based catalysis. Such 3a, was realized (entries 3–8, Table S1, ESI‡). Moreover, a dras- an observation in the existing literature prompted us to strate- tically reduced yield was observed when the temperature or gize a transition metal-free catalyst, which can conceptually amount of KOtBu was lowered (entries 9–11, Table S1, ESI‡). This article is licensed under a mimic the role of a transition metal in borrowing hydrogen Notably, with the help of further trials using different bases, mediated N-alkylation of amines involving the storage and solvents, and durations of the reaction, optimized conditions transfer of hydrogen molecules from the catalyst backbone. were accomplished in the presence of 10.0 mol% (N,O)-PLY and t Open Access Article. Published on 07 May 2021. Downloaded 10/1/2021 6:15:38 PM. Herein, we present the alkylation of anilines by various 1.2 equivalents of KO Bu in toluene at 130 C within 18 hours, alcohols using a redox non-innocent phenalenyl (PLY) based providing 91% isolated yield of N-benzylaniline (entry 3, Table ligand as a transition metal-free catalyst. It is well established S1, ESI‡). Control experiments unarguably validated that the that PLY based molecules can access three redox active states, alkylation of amines could not materialize in the absence of namely a closed shell cation, an open shell radical, and a closed base, and only a trace (5%) amount of N-benzylaniline, 3a, was shell anion using the non-bonding molecular orbital (NBMO).44 realized in the absence of (N,O)-PLY. Over the past few decades, a remarkable advance has been envisaged in the eld of quantum spin simulators,45–48 organic molecular conductors,49–52 molecular batteries,53 and spin elec- Table 1 Optimization of ligands for the N-alkylation of aminesa tronic devices54 by the

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