Borrowing Hydrogen Mediated N-Alkylation Reactions by a Well

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Borrowing Hydrogen Mediated N-Alkylation Reactions by a Well-Defined Homogeneous Nickel Catalyst Amreen K Bains, Abhishek Kundu, Sudha Yadav, and Debashis Adhikari ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02977 • Publication Date (Web): 19 Aug 2019 Downloaded from pubs.acs.org on August 19, 2019

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ACS Catalysis

Borrowing Hydrogen Mediated N-Alkylation Reactions by a WellDefined Homogeneous Nickel Catalyst Amreen K. Bains, Abhishek Kundu, Sudha Yadav, Debashis Adhikari*† †Department

of Chemical Sciences, Indian Institute of Science Education and Research Mohali, SAS Nagar-140306, India.

ABSTRACT: We report herein a well-defined and bench- stable azo-phenolate ligand coordinated nickel catalyst which can efficiently execute N-alkylation of a variety of anilines by alcohol. We demonstrate that the redox-active azo ligand can store hydrogen generated during alcohol oxidation and redelivers the same to an in situ generated imine bond to result N-alkylation of amines. The reaction has wide scope and a large array of alcohols can directly couple to a variety of anilines. Mechanistic studies including deuterium-labelling to the substrate establishes borrowing hydrogen method from alcohols and pinpoints the crucial role of the redox active azo moiety present on the ligand backbone. Isolation of the ketyl intermediate in its trapped form with a radical quencher, higher kH/kD for the alcohol oxidation step suggest altogether a hydrogen atom transfer (HAT) to the reduced azo backbone to pave alcohol oxidation as opposed to conventional metal-ligand bifunctional mechanism. This example clearly demonstrates that an inexpensive base metal catalyst can accomplish an important coupling reaction with the help of a redox-active ligand backbone. KEYWORDS: hydrogen-borrowing catalysis, N-alkylation, Ni(Azo-phenolate)2 complex, Base metal, Redox active ligand

The C–N bond formation maintaining atom economy represents an extremely important goal in contemporary catalysis research, owing to the ubiquitous presence of nitrogenated products in chemistry, biology and pharmaceuticals.1 Powerful older methods toward this target are hydroamination,2, 3 Buchwald-Hartwig coupling,4 and Ullmann reactions5 which despite their efficiency are either based on precious metals or generate considerable amount of side-products. In this context, a significant impetus has been propelled for N-alkylation reactions to furnish new C–N bond using alcohols as the cheap and abundant source of alkyl groups following hydrogen borrowing (HB) or hydrogen autotransfer.6-11 This atom-economic transformation appeals further since water is the sole by-product, that is environmentally benign. As an alkyl source, alcohol draws great attention due to its abundant supply from indigestible lignocellulose biomass degradation that is very important to make the chemistry sustainable.12-14 Hence, alcohol refunctionalization can immensely contribute towards protecting earth’s fossil fuel reserve and abating CO2

emission. The N-alkylation of amines using alcohols could be envisaged as the successful merger of three different steps: an alcohol oxidation by borrowing hydrogen method, in situ imine formation from the resulting carbonyl species in presence of an amine, and finally hydrogenation of the imine by the borrowed hydrogen from alcohol.15, 16 Several reports disclose single-site catalytic system comprising 4d, 5d transition metals towards effective Nalkylations,17-23 but cost-effective and environment-friendly base metal representatives24-29 for this class of catalysts are relatively rare and sought-after synthetic goals. A thorough literature survey further reveals that nickel for N-alkylation reactions are extremely sparse. Some examples report heterogeneous Raney nickel systems for N-alkylation using HB, but often the system works in combination of a second metal whose role is not clearly defined.30-32 In the heterogeneous front, Yus has extensively worked on hydrogen transfer reactions using nickel nanoparticles.33, 34 Barta and coworkers recently reported the use of Ni(COD)2 to develop a N-alkylation protocol via heterogeneous nickel oxide cluster.35 In contrast, to our knowledge, there are only two examples of nickel based homogeneous catalyst for Nalkylation reactions.36, 37Recently, a nickel bromide and 1,10phenanthrolene combination has been reported that can effectively N-alkylate a large group of amine substrates.36 Interestingly, asymmetric version of N-alkylation has also been investigated to furnish chiral N-benzylamine, utilizing Ni(OTf)2 and chiral phosphine, following HB technique.37

Scheme 1. N-Alkylation Reaction of Anilines via Hydrogen Borrowing using Earth-abundant Ni Catalyst

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Though effective, the synthetic protocols have problems of using expensive phosphine and operational difficulty associated with the putative ligand. Henceforth, single-site nickel catalyst is still scarce and highly coveted in base metal catalyzed HB-based N-alkylation reactions. To this end, we are intrigued by the development of a well-defined, phosphine free homogeneous nickel catalyst which can be effective in N-alkylation reactions utilizing a wide variety of alcohols (Scheme 1). Moreover, starting with a well-defined, bench-stable molecule will greatly assist unraveling the reaction mechanism which will potentially be useful for further catalyst discovery. Having this target in mind, we searched for an appropriate ligand backbone which can help dehydrogenation of alcohol and simultaneously store the borrowed hydrogen for further delivery. The known redox activity of the azo38, 39 group suggests that this could be suitable for both redox-driven alcohol dehydrogenation and hydrogen storage.40-42 To test this conjecture, we designed a bidentate ligand, 3,5-di(tertbutyl)-2-hydroxy azobenzene (L), and two of the ligands can coordinate nickel in a square planar environment. This complex, 1 being diamagnetic, offers further advantage of tracking the key catalytic steps by 1H, 13C NMR spectroscopies, which can shed significant insight on the mechanistic aspect of alcohol dehydrogenation as well as imine hydrogenation reactions. We also posit that using the redox activity of the azo group for the alcohol oxidation circumventing the nickel-hydride formation can make the protocol more rewarding with respect to functional group tolerance. The complex was prepared by adding a methanolic solution of L to anhydrous Ni(OAc)2 and refluxing the mixture for 30 minutes. The isolated dark brown colored complex 1 is diamagnetic, and its C2 symmetry affirms the Ni(II) is confined in a square-planar environment via trans N,Ocoordination of the azo-phenolic ligands. It is noteworthy that this class of complex was synthesized earlier to establish basic coordination chemistry of the azo-phenolate ligand but the utility of these molecules to catalytic reactions were never tested.43 Our preliminary investigation of tandem acceptorless dehydrogenation and imine hydrogenation started with oxidizing benzyl alcohol and coupling with aniline, followed by hydrogenation of imine to obtain N-benzyl aniline. In a typical reaction, 1 mmol of benzyl alcohol was mixed with 0.25 mmol of aniline in presence of 7 mol% of catalyst 1 (wrt aniline) and 0.25 mmol of KOtBu, and the reaction was heated to 130 oC for 24 h. Monitoring the reaction by 1H NMR spectroscopy and thin layer chromatography typically reveals the full consumption of benzyl alcohol, remnant aldehyde (from excess substrate alcohol) and the desired aminated product. Although, the oxidation of alcohols by the same catalyst can be finished in shorter time span, the imination and subsequent hydrogenation takes longer period of time (vide infra). Standard work up of the reaction mixture under optimized reaction conditions provides the desired aminated product (86%) exclusively (see SI, Table S1). The yield could be

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slightly lower (75%) with 5% catalyst loading. The catalytic system is attractive owing to moderate loading (7 mol%) of an inexpensive, air-stable, well-defined nickel molecule. It is noteworthy that few reported systems utilizing phosphine ligands are very efficient for Nalkylation reactions. Notable examples are Kempe’s PN5P ligand with triazine backbone44 or Shafir’s phosphino amine ligands.45 However, our azo phenolato ligand is considerably cheaper compared to any phosphine based ligands without sacrificing any efficiency. The broad substrate scope and functional group tolerance of the reaction is highlighted with respect to both amine and alcohol components. As displayed in the Table 1, a wide variety of benzyl alcohol was used for the purpose of Nalkylation to aniline. An array of diverse functionalities such as methyl (2d, 2f), naphthyl (2g), different halides on the benzyl alcohols were well tolerated and gave products in high yield. Furthermore, sterically encumbering o-bromo (2i), o-methoxy (2h) effectively converted the benzyl alcohols to expected secondary amines in great yield (8689%). Similarly, highly electron donating p-OMe (2c), – NMe2 (2e) group present in benzyl alcohol afforded good yield of the corresponding aminated products. Notably, electron withdrawing groups such as Cl, Br, F, NO2 (2b, 2i, 2l, 2m, 2n) present in the benzyl alcohol furnished the similar N-alkylated product in very good yield. Furthermore, the scope of the reaction methodology was expanded to variety of substituted anilines. In this case also highly electron withdrawing groups present on aniline such as nitro (3d), trifluoro methyl (3h, 3i), cyano (3k) resulted excellent yield of aminated products. Table 1. Substrate Scope for Alcohols NH2 Ar

+

OH

2a-2n

1 (7mol%), KOtBu Toluene, 130 oC, 24 h

Ar

3a

N H

N H

4a (92%)

Cl

N H

4b (82%)

MeO

N

4d (76%)

N H

4e (73%)

4f (89%) Br

OMe N H

N H

N H

4g (86%)

a

4h (86%)

4ja (79%)

4k (74%)

N H

4mb (92%)

4i (89%)

N H

N H

F

4c (86%)

N H

N H

N

N H

4a-4n

N H

Br

4l (80%)

N H

O2N

4nb (80%)

Reaction conditions: 1 (7 mol%, w.r.t. aniline), 2 (1 mmol), 3a (0.25 mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield); a30 h; b36 h


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Simultaneously, presence of electron donating groups on the aniline (Table 2) component also efficiently transformed it to the respective amine in very high yield (3b and 3g in 80 and 90% respectively). Gratifyingly, the protocol is very chemoselective, since presence of hydroxy (3j), cyano, trifluoromethyl groups in the aniline did not cause any detrimental reaction or reduction of yield. Table 2. Substrate Scope for Amines NH2 OH

+


2a

R

3b-3m H N

MeO

O2N

Pr

3a

Aliphatic

6a-6h

N H

N H

N H

N H

6b (68%)

6c (79%)

6d (85%)

Pr

5f (86%) H N

F3C

H N

CN

NH

5g (90%) H N

tBu

5ia (82%)

H N

5k (92%)

2'

6a (75%)

H N

H N


+

OH

Aliphatic

i

Br

5ha (87%)

5da (78%) i

H N

5e (82%)

F3C

5b-5m H N

5c (75%)

H N

H N

NH2

H N

5b (80%)

Cl

Table 3. Substrate Scope for Aliphatic Alcohols

H N

R

pyridyl amine gave respective amines in good yield (6681%), as well as pyridine dimethanol was easily dialkylated with two equivalents of aniline to furnish 7d in excellent yield (87%). Next, we attempted to N-alkylate the diamines. Under the optimized protocol, 1,8-napthelene diamine smoothly transformed to N-alkylated product (8a) in 78% yield.

OH

5j (80%) H N

5l (90%)

N H

N H

N H

6e (55%)

N H

6g (58%)

6f (78%)

6h (89%)

Reaction conditions: 1 (7 mol%, w.r.t. aniline), 2' (1 mmol), 3a (0.25 mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield)

Table 4. Substrate Scope for Heteroaromatic Amines or Alcohols 5m (75%)

Reaction conditions: 1 (7 mol%, w.r.t. amine), 2a (1 mmol), 3 (0.25 mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield); a30 h


NH2

OH

+ Ar(het)

Ar(het)

2''

Ar

3'

N H

Ar

7a-7d

N

Succeeding with the diverse range of benzylic alcohols and substituted anilines, we turned our attention to aliphatic alcohols (Table 3). To examine whether our homogeneous catalyst can also span the scope of aliphatic alcohols, we screened a diverse range of this substrate. Encouragingly, aminated products from isopropyl alcohol, cyclohexanol, cyclopentanol, octanol and heptanol (6b-6d, 6f-6g) all were successfully isolated in good to excellent yield. Additionally, citronellol that is a renewable terpenoid and contains unsaturation, smoothly alkylated aniline to give the aminated product (6h) in 89% yield. This result is very inspiring since it further supports the chemoselective nature of the transformation. This methodology affords the presence of reducible groups in the substrate and hints that nickel hydride formation during β-hydride elimination from a nickel bound alkoxide might not be happening (vide infra). Moreover, this synthetic protocol is highly attractive since multiple noble metal catalysts cannot be tolerant to unsaturated alcohols,24, 46that may be attributed to metal hydride generation during the reaction.47, 48

N H

N H

7a (81%)

N

7b (66%) H N

N

N H

N

7c (72%) H N

7da (87%) Reaction conditions: 1 (7 mol%, w.r.t. mono-amine), 2'' (1 mmol), 3' (0.25 mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield); a2'' (0.5 mmol), 36 h

Similarly, o- and p-phenylene diamine (Table 5) both were converted to the respective product (8b-8c) in slightly lower yield (52-53%). Intriguingly, when diols (8d, 8f) and even triols (8e) were used as an alkylating agent the multiple motifs were alkylating the respective amine in commendable yields (74-92%). In essence, the screening of the substrate scope can easily span the multifunctional amines and alcohols resulting secondary amine products in good yield.

To diversify the scope of this N-alkylation protocol, we further screened heteroaromatic amine and heteroaromatic alcohol as substrates (Table 4). Interestingly, o-, m- and pTable 5. N-Alkylation of Diamines and Diol, Triol as Alkyl Sources ACS Paragon Plus Environment

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OH

HO

+

2"'

NH2


Aminated Product 8a-8f

3"

H N

NH HN NH HN N H

8b (53%)

8a (78%)

H N

N H

8c (52%)

H N

NH

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signal at g = 2.004. Simulation of the experimental EPR spectrum suggests the triplet signal for a nitrogen centered radical results from hyperfine coupling (15 Hz) with the nitrogen nucleus. Coupling with the second nitrogen is very small (~1-2 Hz), and we expect that the localized character of the radical helps in hydrogen atom transfer (HAT) step during alcohol oxidation. In essence, the g value and hyperfine features of the EPR signal affirm that the reduction is fully azo-based and a nitrogen centric radical is generated without affecting the preferable oxidation state of Ni (+2).

H N

8f a (92%)

8da (74%)

H N

H N

8eb (86%)

Reaction conditions: 1 (7 mol%, w.r.t. mono-amine), 2''' (1 mmol), 3'' (0.125 mmol), KOtBu (0.25 mmol), toluene (10 mL), 130 oC, 24 h (isolated yield); a 2''' (0.5 mmol) 3'' (0.25 mmol), 30 h; b 2''' (0.33 mmol) 3'' (0.25 mmol), 36 h

Mechanistic Consideration We assume that the development of a well-defined homogenous system will inarguably help to delineate the mechanism for this N-alkylation reaction by HB. At first, to prove homogeneous nature of the catalyst we performed mercury drop test, and observed no inhibition of the reaction or reduction of product yield. The redox non-innocence of the azo motif is known for a long time which can undergo twoelectron redox in a reversible fashion.49 Our choice of the ligand was motivated by the proximity of the azo functionality to nickel, which can supposedly help in alcohol dehydrogenation without the intermediacy of the relatively unstable nickel hydride. In our HB protocol, KOtBu is indispensable, and the same can reduce the azo-motif in the backbone. Notably, role of KOtBu as a reductant has been documented in earlier literature reports.50-52 An array of control reactions proved that the reduced azo backbone is extremely crucial for the success of the catalyst (see SI). In agreement with the above proposition, use of reductant (Zn) and base (KOH) in combination, can convert primary alcohol to corresponding aldehyde and N-alkylated product catalyzed by 1. To investigate the most reduction-prone motif in the catalyst molecule, we resorted on preliminary DFT calculations to validate that the LUMO of 1 is π* orbital of N=N functionality (Figure 1). Interestingly, one electron reduction of 1 generated a burgundy colored paramagnetic material which under X-band EPR analysis exhibited an isotropic

Figure 1. a) The LUMO of pre-catalyst 1 depicting predominantly the π* of N=N, isosurface value is set to 0.02 (e.bohr-3)1/2 b) X-band EPR signal obtained from the singly reduced product of 1 Intuitively, the borrowed hydrogen from an alcohol will remain stored in 1, and convert the azo to a hydrazo functionality. To substantiate our claim that the azo motif, when reduced, can be converted to hydrazo, we did a stoichiometric control experiment. Reducing 1 in presence of 1 equivalent KOtBu and exposing the mixture to substrate alcohol for 4 hours clearly evinced new proton resonance at 4.14 ppm. The integration of the peak is consistent with both the nitrogen being hydrogenated resulting a hydrazo species. As it will be proved later, this is an important intermediate along the catalytic cycle and its isolation (IV’ in Figure 4, vide infra) and characterization by 1H, 13C NMR and IR spectroscopies add valuable support to the postulated mechanistic course. To further understand the nature of intermediate formation and to quantify the progress of reaction over time, the reaction was stopped after 6 h and clear imine formation was observed which conclusively prove that the species is a true intermediate en route to subsequent hydrogenation. This NMR experiment is additionally supported by GC/MS probation during the reaction (Table S5, SI). After 6 h, imine formation remains 36% while the amine is only slightly formed (20%). Growth of the aminated product is lot higher after 12 h, 52% which reaches a completion providing 86% yield after 24 h. Thus, the reaction can be clearly dissected in the sequence of alcohol dehydrogenation- condensationimine hydrogenation steps.


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Figure 2. Kinetic time profile of the alcohol oxidation (substrate equivalence variation). a) growth of oxidized product by UVVis spectroscopy. b) rate constant calculation for a first order kinetics. (Reaction conditions: 1 (7 mol%), 2a (variable concentration w.r.t. catalyst), KOtBu (0.25 mmol), toluene (10 mL), 130 oC. To examine the dependence of reaction rate on the catalyst and substrate during benzyl alcohol oxidation, we studied the rate of benzaldehyde formation as a function of both catalyst loading and substrate equivalence variation. Increasing the concentration of 1 over the range from (2.5 to 10 mol% with respect to benzyl alcohol) displayed a linear increase in the rate, kobs for the oxidation of alcohol (Figure S18). Moreover, similar study to figure out the dependence of rate on the substrate loading over a range of 80-140 times (with respect to catalyst) further exhibits same linear dependence (Figure 2). From these set of experiments the rate law for the alcohol dehydrogenation can be derived as rate = k[1][benzyl alcohol] which further suggests the substrate remains bound to the catalyst at the rate determining step. To shed light on the imine hydrogenation step, we further performed the kinetic run on a previously synthesized imine in the presence of catalyst 1 and alcohol, and monitored the growth of secondary amine by UV-Visible spectroscopy. Likewise, amount of catalyst variation disclosed similar first order dependence of the hydrogenated amine formation on catalyst loading (Figure S20). As examined by the kinetic studies for the entire reaction, imine hydrogenation step is much slower compared to the alcohol oxidation part of the reaction. Rate calculation of these steps with 7.5 mol % of 1 loading revealed the kobs = 2.5 x 10-3 s-1 for alcohol oxidation, whereas the rate for imine hydrogenation was 5.5 x 10-5 s-1. The rate comparison clearly corroborates with faster alcohol oxidation and lot slower subsequent imine hydrogenation step. The imine hydrogenation rate was also measured earlier by Bäckvall to be slow for Ru-based Shvo catalyst53, 54. To further unambiguously establish N-alkylation process as HB, we conducted deuterium labeling experiments. Starting from isotopically enriched PhCD2OH, deuterium incorporation at N- benzylaniline product was evident. The product distribution analysis by 1H NMR spectroscopy uncovered the selective transformation to 4a-d1 along with 4a and 4a-d2 and displayed 51% deuterium incorporation at the benzylic position of 4a-d1. Additional experiment with imine hydrogenation with deuterated benzyl alcohol also displays deuterium incorporation in the aminated product.

Focusing only the hydrogenation step with a pre-synthesized imine, shows the ratio of products 4a: 4a-d1: 4a-d2 as 25:44:31 (Scheme 2). The formation of some amount of 4ad2 strongly indicates the reversibility in the imine formation, which can be partly responsible for the slower kinetics of imination and imine hydrogenation reactions. In essence, the obtained ratio of deuterated products starting from a deuterium labelled alcohol is in consonance with the HB method for N-alkylation step.23 D D + H2N Ph Ph OH

Optimized condition

H/D H/D Ph Ph N

4a 4a-d1 4a-d2

H/H = 16 % H/D = 51 % D/D = 33 %

D D + Ph OH

Optimized condition

H/D H/D Ph Ph N

4a 4a-d1 4a-d2

H/H = 25 % H/D = 44 % D/D = 31 %

H Ph

N

Ph

H/D

H/D

Scheme 2. Deuterium Labeling Experiments To generate deeper insight regarding the mechanistic course, we analyzed some of the key steps by preliminary DFT computation (M06/Ni(Lanl2dz) and 6-31G* for C, H, N, O).55 Interestingly, the alkoxide binding to the fourcoordinate nickel failed to reach convergence due to the strong propensity of nickel for square planar geometry. We realized during optimization of the intermediate, that one of the phenolate arm of the ligand can be protonated, and consequently be detached to reduce coordination, facilitating substrate binding. Notably, a zinc-bound water has been shown to protonate a phenolate arm augmenting detachment of the ligand earlier.56 The incoming alkoxide now can bind the nickel maintaining a slightly distorted square planar geometry, where one of the azo ligand is mono-reduced. As expected, in this intermediate (I, Figure 3) significant spin density is observed on the nitrogen which is connected to the phenolic ring (Figure S23). Computational isolation of the intermediate I and subsequent HAT is fully consistent with the 1st order dependence of the substrate from kinetic experiments. Encouragingly, in I the β-hydrogen of the bound alkoxide is properly oriented towards the nitrogencentric azo radical maintaining a distance of 2.58 Å. Notably, the distance between two termini during HAT has a profound influence on the rate of hydrogen transfer, as has


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been revealed by Klinman during her study on enzymatic models.57 Upon further search, we were able to locate the transition state (TSI-II) for HAT that crosses an energy barrier (ΔGǂ) of 10.79 kcal mol-1 with respect to the reference state, where all the reactants are infinitely apart. In the TSI-II, the C---H and N---H distances (1.346 and 1.339 Å respectively) are almost similar (Figure 3b). When the barrier is compared to the alkoxide-bound intermediate I, the value is only 5.73 kcal mol-1. The low-energy barrier associated with HAT suggests the process to be very favorable once the reduced azo backbone finds the βhydrogen of nickel-bound alkoxide in the right alignment. Inspired by this computational clue, we attempted further to find experimental evidence for the HAT process. The measured kH/kD for this step at 130 0C was found to be 6.8. Such a large value implicates a tunneling of the hydrogen atom might be operative and provides strong support for HAT step during alcohol oxidation.58, 59 The resulting ketyl radical upon this HAT is not stable on the potential energy

Figure 3. a) DFT optimized structure (tBu groups are truncated to Me) of I, where the reduced azo group poses a N---N bond length of 1.32 Å. b) Optimized TSI-II for HAT, upon which a ketyl radical is transiently generated. All hydrogens except chemically important ones are removed for clarity. surface and an aldehyde formation was eminent, giving one electron back to the unreduced azo-motif in the ligand, III. In strong support to our conjecture that the ketyl radical forms during catalytic cycle, we were able to trap the intermediate in the form of a TEMPO adduct (Figure 4). In our computation, the product aldehyde formation with concomitant reduction of the second azo motif is thermodynamically downhill by 12.73 kcal mol-1 with respect to the reference state. So the presence of two redoxactive azo moieties ensure that nickel’s preferable oxidation state (+2) is consistently preserved during the catalytic cycle. Subsequently, the anionic azo motif is protonated by the phenol, giving hydrazo intermediate IV, and nickel regains the four-coordinate geometry from bisazophenolato ligand in a square planar environment. As discussed earlier IV’ has been isolated and well characterized with a battery of spectroscopic techniques. In IR spectroscopic analysis, stretching frequency for the N─H group was clearly observed at 3357 cm-1. This value corroborates extremely well with the theoretically

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computed N─H stretching values at 3301 and 3354 cm-1.60 Since radicals are involved in the reaction pathway, it is expected that a radical quencher will inhibit the reaction. Indeed, complete stoppage of the reaction was realized when TEMPO was used in two equivalents. This fact also strongly contradicts with any traditional metal-ligand bifunctional mechanism in our system for alcohol oxidation reaction, as radical intermediates are not to be invoked in that case. Intimate participation of the azo function in alcohol oxidation reactions was first proposed by Markó using azodicarboxylate as a cocatalyst61 and has been recently scrutinized further by Sthal.62 Importantly, HAT from a bound substrate to the reduced ligand backbone is a hallmark of galactose oxidase (GO) chemistry and similar events have been elegantly established in the synthetic mimic of GO by Wieghardt et al.59 Our proposed mechanism is significantly different from the traditional metal-ligand bifunctionality observed in a large body of systems. In such systems established by Shvo, Noyori, Milstein, and Morris, a metal and nearby heteroatom work in a cooperative fashion to primarily result a metal hydride intermediate.63-66 In the present report, the strong requirement of one-electron reduction of pre-catalyst, isolation of the ketyl radical and IV’ along the catalytic cycle, computational probation of the low-energy HAT step, all oppose the conventional metal-ligand bifunctional cooperative activation of a bond. This is a rare example where a reduced ligand backbone plays a preponderant role with some assistance from metal to accomplish this important transformation and the azo-radical based HAT contrasts the abundant examples of efficient catalysts for Nalkylation reactions which largely involve metal hydride generation. Once the imine is formed by carbonyl and amine condensation, the borrowed hydrogen from the alcohol can hydrogenate it to result N-alkylated product. Likely, the imine hydrogenation can follow a very similar pathway to the alcohol oxidation process. A SET from IV to the in situ generated imine is likely to form a benzylic radical, which may undergo HAT from the hydrazo fragment of the ligand. In close resemblance to the alcohol oxidation component, detachment of the ligand phenoxide arm to converting it to phenol is necessary to pave imine binding to the nickel center. Imine binding to the nickel center is crucial and also supported by the first order dependence of this substrate from kinetic experiments (Figure S20). Finally, protonation of the bound amide by the phenolic arm engender the N-alkylated product, and the resting state of the catalyst is back (Figure S21). Of note, similar sequence of one-electron reduction followed by HAT to reduce imine has been recently established by Guo and Wenger.67 Although, we prefer the singleelectron reduction of the imine following HAT as a plausible mechanistic scenario for imine hydrogenation, under the current stage, hydrogen walk68 from the hydrazo fragment to nickel cannot be fully discarded.


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Figure 4. Plausible mechanistic scheme for the direct coupling of alcohol and amine to yield N-alkylated product Conclusion

ASSOCIATED CONTENT:

In summary, we present a well-defined, homogeneous, single-site catalyst comprising of a redox-active azo ligand and base metal nickel which efficiently N-alkylate a variety of amines with alcohols. As a distinct advantage, this catalyst is highly stable and can be handled in aerobic atmosphere. As an alkyl source, a diverse range of alcohol has been used including aliphatic alcohols which are challenging substrates even for noble metal catalysts. Our catalytic protocol is tolerant to extensive functional groups including cyano, nitro, hydroxy, methoxy, olefin and efficiently perform N-alkylation in a chemoselective manner. The ligand chosen for such base metal catalyst is instrumental given its direct participation in the alcohol oxidation step via HAT. Furthermore, azo to hydrazo transformation is feasible which helps to store the borrowed hydrogen and promotes its delivery to imines. Deuterium labelling to the starting benzyl alcohol conclusively proves the process to be classified as borrowing hydrogen method. Isolation of some key intermediates along the catalytic cycle unambiguously proves a radical is involved and the pathway differs considerably from conventional metal-ligand bifunctional mechanism in N-alkylation reactions. We assume that the mechanistic understanding from such a welldefined catalyst will further help in designing base-metal catalysts for transfer hydrogenation reactions. Current efforts in our laboratory focus on expanding the scope of Nalkylation for other class of substrates and synthesizing value-added heterocycles using this methodology.

Supporting Information: The Supporting Information is available free of charge on the ACS Publications website. Experimental procedure, spectroscopic data, kinetic data, coordinates of computed structures and NMR spectra for products.

AUTHOR INFORMATION Corresponding Authors *E-mail for D.A.: [email protected] NOTES The authors declare no competing financial interests. ACKOWLEDGEMENT We thank SERB (DST), India (Grant No. ECR/2017/001764) for financial support and IISER Mohali for seed grant. AKB thanks IISER Mohali for a research fellowship, AK thanks CSIR for junior research fellowship, and SY thanks DST for an Inspire fellowship. The authors sincerely thank Prof. Sanjay Singh for giving access to his glove box.


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Borrowing Hydrogen Mediated N-Alkylation Reactions by a Well

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