Efficient nickel-catalysed N-alkylation of amines with alcohols

(1)

University of Groningen

Efficient nickel-catalysed N-alkylation of amines with alcohols

Afanasenko, Anastasiia; Elangovan, Saravanakumar; Stuart, Marc C. A.; Bonura, Giuseppe;

Frusteri, Francesco; Barta, Katalin

Published in:

Catalysis Science & Technology

DOI:

10.1039/C8CY01200H

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Final author's version (accepted by publisher, after peer review)

Publication date:

2018

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Afanasenko, A., Elangovan, S., Stuart, M. C. A., Bonura, G., Frusteri, F., & Barta, K. (2018). Efficient

nickel-catalysed N-alkylation of amines with alcohols. Catalysis Science & Technology, 8(21), 5498-5505.

https://doi.org/10.1039/C8CY01200H

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

(2)

Catalysis Science & Technology

c8cy01200h

We have presented the Graphical Abstract text and image for your article below. This brief summary of your work will appear in the contents pages of the issue in which your article appears.

Efficient nickel-catalysed

N-alkylation of amines

with alcohols

Anastasiia Afanasenko, Saravanakumar Elangovan, Marc C. A. Stuart, Giuseppe Bonura, Francesco Frusteri and Katalin Barta*

The

Q3 selectiveN-alkylation of amines with alcohols via the

borrowing hydrogen strategy represents a prominent sustainable catalytic method, which produces water as the only by-product and is ideally suited for the catalytic trans-formation of widely available alcohol reaction partners that can be derived from renewable resources.

Please check this proof carefully. Our staff will not read it in detail after you have returned it.

Please send your corrections either as a copy of the proof PDF with electronic notes attached or as a list of corrections. Do not edit the text within the PDF or send a revised manuscript as we will not be able to apply your corrections. Corrections at this stage should be minor and not involve extensive changes.

Proof corrections must be returned as a single set of corrections, approved by all co-authors. No further corrections can be made after you have submitted your proof corrections as we will publish your article online as soon as possible after they are received.

Please ensure that:

• The spelling and format of all author names and affiliations are checked carefully. You can check how we have identified the authors’ first and last names in the researcher information table on the next page. Names will be indexed and cited as shown on the proof, so these must be correct.

• Any funding bodies have been acknowledged appropriately and included both in the paper and in the funder information table on the next page.

• All of the editor’s queries are answered.

• Any necessary attachments, such as updated images or ESI files, are provided.

Translation errors can occur during conversion to typesetting systems so you need to read the whole proof. In particular please check tables, equations, numerical data, figures and graphics, and references carefully.

Please return your final corrections, where possible within 48 hours of receipt, by e-mail to: catalysis@rsc.org. If you re-quire more time, please notify us by email.

(3)

Funding information

Providing accurate funding information will enable us to help you comply with your funders' reporting mandates. Clear acknowledgement of funder support is an important consideration in funding evaluation and can increase your chances of securing funding in the future.

We work closely with Crossref to make your research discoverable through the Funding Data search tool

(http://search.crossref.org/funding). Funding Data provides a reliable way to track the impact of the work that funders support. Accurate funder information will also help us (i) identify articles that are mandated to be deposited in PubMed Central (PMC) and deposit these on your behalf, and (ii) identify articles funded as part of the CHORUS initiative and display the Accepted Manuscript on our web site after an embargo period of 12 months.

Further information can be found on our webpage (http://rsc.li/funding-info). What we do with funding information

We have combined the information you gave us on submission with the information in your acknowledgements. This will help ensure the funding information is as complete as possible and matches funders listed in the Crossref Funder Registry.

If a funding organisation you included in your acknowledgements or on submission of your article is not currently listed in the registry it will not appear in the table on this page. We can only deposit data if funders are already listed in the Crossref Funder Registry, but we will pass all funding information on to Crossref so that additional funders can be included in future.

Please check your funding information

The table below contains the information we will share with Crossref so that your article can be foundvia the Funding Data search tool. Please check that the funder names and grant numbers in the table are correct and indicate if any changes are necessary to the Acknowledgements text.

Funder name Funder's main country

of origin

Funder ID (for RSC use only)

Award/grant number

H2020 European Research Council

European Union 100010663 ERC Starting Grant 2015

(CatASus) 638076 Nederlandse Organisatie

voor Wetenschappelijk Onderzoek

Netherlands 501100003246 Talent Scheme (Vidi) with

project number 723.015.0

Researcher information

Please check that the researcher information in the table below is correct, including the spelling and formatting of all author names, and that the authors’ first, middle and last names have been correctly identified. Names will be indexed and cited as shown on the proof, so these must be correct.

If any authors have ORCID or ResearcherID details that are not listed below, please provide these with your proof corrections. Please ensure that the ORCID and ResearcherID details listed below have been assigned to the correct author. Authors should have their own unique ORCID iD and should not use another researcher's, as errors will delay publication.

Please also update your account on our online manuscript submission system to add your ORCID details, which will then be automatically included in all future submissions. See here for step-by-step instructions and more information on author identifiers.

First (given) and middle name(s) Last (family) name(s) ResearcherID ORCID

Anastasiia Afanasenko

Saravanakumar Elangovan

(4)

Giuseppe Bonura Q-1766-2017 0000-0001-5793-8903

Francesco Frusteri

(5)

Queries for the attention of the authors

Journal: Catalysis Science & Technology

Paper: c8cy01200h

Title: Efficient nickel-catalysed

N-alkylation of amines with alcohols

For your information: You can cite this article before you receive notification of the page numbers by using the

following format: (authors), Catal. Sci. Technol., (year), DOI: 10.1039/c8cy01200h.

Editor

’s queries are marked on your proof like this

Q1

,

Q2

, etc. and for your convenience line numbers are

indicated like this

5 ,

10 ,

15 , ...

Please ensure that all queries are answered when returning your proof corrections so that publication of your

article is not delayed.

Query

Reference Query Remarks

Q1 Please confirm that the spelling and format of all author names is correct. Names will be indexed and cited as shown on the proof, so these must be correct. No late corrections can be made.

Q2 Do you wish to add an e-mail address for the

corresponding author? If so, please provide the relevant information.

Q3 The first line of the Abstract has been inserted as the Graphical Abstract text. Please check that this is suitable. If the text does not fit within the two horizontal lines, please trim the text and/or the title. Q4 Fig. 2 contains labels (a)–(f), but these do not appear

to be mentioned in the caption. Would you like to modify the caption or resupply the artwork (preferably as a TIF file at 600 dots per inch)? Q5 “Fort” is not cited as an author of ref. 38. Please

indicate any changes that are required here.

Q6 Please note that a conflict of interest statement is required for all manuscripts. Please read our policy on Conflicts of interest (http://rsc.li/conflicts) and provide a statement with your proof corrections. If no conflicts exist, please state that “There are no conflicts to declare”.

(6)

Catalysis

Science &

Technology

PAPER

Cite this: DOI: 10.1039/c8cy01200h

Received 8th June 2018, Accepted 11th September 2018 DOI: 10.1039/c8cy01200h rsc.li/catalysis

Efficient nickel-catalysed

N-alkylation of amines

with alcohols

†

Q1

Q2

Anastasiia Afanasenko,

a

Saravanakumar Elangovan,

a

Marc C. A. Stuart,

ab

Giuseppe Bonura,

c

Francesco Frusteri

c

and Katalin Barta

*

a

The selectiveN-alkylation of amines with alcohols via the borrowing hydrogen strategy represents a prom-inent sustainable catalytic method, which produces water as the only by-product and is ideally suited for the catalytic transformation of widely available alcohol reaction partners that can be derived from renew-able resources. Intensive research has been devoted to the development of novel catalysts that are mainly based on expensive noble metals. However, the availability of homogeneous or heterogeneous non-precious metal catalysts for this transformation is very limited. Herein we present a highly active and re-markably easy-to-prepare Ni based catalyst system for the selectiveN-alkylation of amines with alcohols, that isin situ generated from NiĲCOD)2and KOH under ligand-free conditions. This novel method is very

efficient for the functionalization of aniline and derivatives with a wide range of aromatic and aliphatic alco-hols as well as diols and exhibits excellent functional group tolerance including halides, benzodioxane and heteroaromatic groups. Several TEM measurements combined with elemental analysis were conducted in order to gain insight into the nature of the active catalyst and factors influencing reactivity.

Introduction

Amines are centrally important compounds in the bulk and fine chemical industry since they are frequently encountered scaffolds in agrochemicals, dyes, natural products and phar-maceutically active compounds1,2 (Fig. 1a). Conventional methods to access amines include the nucleophilic substitu-tion of halides3 as well as reductive alkylation4 processes. However, these methods suffer from low atom-economy and E factor due to the formation of stoichiometric amounts of waste5and may face limitations in selectivity as well as sub-strate cost or availability. Therefore, special attention has to be devoted to the development of novel catalytic methods6–11 that would allow the selective and environmentally-friendly synthesis of amines.12

The N-alkylation of amines with alcohols via the borrowing hydrogen approach has emerged as a very attractive and waste-free alternative to provide N-alkylated amines.13,14More specifically, the hydrogen borrowing strategy begins with the metal-catalysed dehydrogenation of an alcohol. Further, the

formed carbonyl compound reacts with the amine to form the corresponding imine, which is reduced to the alkylated amine by means of the metal hydride generated during the first dehydrogenation step (Fig. 1b).14 This atom-economic transformation represents a prime example in green chemis-try since it only produces water as by-product and uses widely available alcohol reaction partners that can also be poten-tially derived from renewable resources.15–17

Following the remarkable progress in this field using pre-cious metals,12,13,18 novel methods that utilize inexpensive and widely abundant metals19such as Fe,20,21Co,22Mn (ref. 23) and Ni (ref. 24 and 25) have recently emerged.26 Thus, there is tremendous potential for the development of novel methods using non-precious metals and great demand for improving reaction scope, substrate compatibility and cata-lyst stability as well as decreasing catacata-lyst loading.

In this context and continuing our interest in developing N-alkylation reactions using earth abundant metals,20,21 we sought to develop an efficient catalytic system based on nickel. Searching for a catalytic system that would be conve-nient to prepare, and afford lower catalyst loading without the need of any organic ligand, we have turned our attention to Ni nanoparticle (NiNP) chemistry. Due to the pioneering work of Yus and others, much progress has been made in this area, especially related to transfer hydrogenation chemis-try, typically using 2-pronanol.27 As a specific example, 2-propanol was used as hydrogen source in the reductive amination of aldehydes and ketones catalyzed by NiNP.28

Catal. Sci. Technol., 2018, 00, 1–8 | 1 This journal is © The Royal Society of Chemistry 2018

a_{Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747}

AG Groningen, The Netherlands

b_{Electron Microscopy, Groningen Biomolecular Sciences and Biotechnology}

Institute, University of Groningen, 9747 AG Groningen, The Netherlands

c_CNR-ITAE_{“Nicola Giordano”, Via S. Lucia Sopra Contesse, 5, 98126 Messina,}

Italy

† Electronic supplementary information (ESI) available. See DOI: 10.1039/ c8cy01200h 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55

(7)

2 | Catal. Sci. Technol., 2018, 00, 1–8 This journal is © The Royal Society of Chemistry 2018 Furthermore, NiNP catalyst enabled the activation of primary

alcohols for reductive aza-Wittig reaction.29 Interestingly, NiNP chemistry has recently found application in the chemis-try of renewable resources. Hartwig and coworkers discovered that in situ generated NiNP are highly active for the scission of phenyl ether bonds in simple lignin model compounds,30 while Luque and coworkers have reported on microwave assisted preparation of Ni nanoparticles stabilized by ethyl-ene glycol for the hydrogenolysis of benzyl-phenyl ether.31

Surprisingly, the efficient N-alkylation of amines has not yet been realized with any NiNP system.

Herein, we describe the N-alkylation of amines via the hy-drogen borrowing mechanism, to the best of our knowledge, yet unprecedented by Ni nanoparticles generated in situ. This catalyst is conveniently prepared from NiĲCOD)2in the

pres-ence of sub-stoichiometric amount of base and shows versa-tility in the selective monoalkylation of various aniline deriva-tives with a broad range of alcohols.

Experimental

Representative procedure for catalyticN-alkylation of aniline with benzyl alcohol

An oven-dried 20 mL Schlenk tube, equipped with a stirring bar, was charged with aniline (0.5 mmol, 1 equiv.), benzyl al-cohol (0.75 mmol, 1.5 equiv.), NiĲCOD)2 (0.015 mmol, 3

mol%), KOH (0.15 mmol, 0.3 equiv., 30 mol%) and cyclo-pentyl methyl ether (solvent, 2 mL). The solid materials were weighed into the Schlenk tube under air, NiĲCOD)2 was

weighed in the glovebox; then the Schlenk tube was removed from the glovebox, subsequently connected to an argon line and vacuum–argon exchange was performed three times. Liq-uid starting materials and solvent were charged under an ar-gon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at the appropriate tempera-ture (typically 140 °C) and stirred for a given time (typically

18 hours). The reaction mixture was cooled down to room temperature. After taking a sample (app. 0.5 mL) for GC anal-ysis, the crude mixture was filtered through silica gel, eluted with ethyl-acetate, and concentrated in vacuo. The residue was purified by flash column chromatography to provide the pure amine product.

Representative procedure for generating TEM specimens After reaction, according to the Representative Procedure above indicated, the Schlenk vessel was cooled to room tem-perature and the solvent was evaporated under vacuum for at least 1 h. Then, the concentrated solution was taken by means of a 1 mL glass syringe and resuspended into 1 mL of toluene by discharging two droplets through the septum of the polypropylene screw-thread cap of a 2 mL Amber vial. Af-ter sonication for 15 min, two drops from the solution were sequentially placed onto a TEM grid, which was allowed to dry in the glovebox for 1 h prior to analysis.

Results and discussions

Establishing an active NiNP catalyst system forN-alkylation of amines

In order to establish the desired full hydrogen borrowing cy-cle (Fig. 1b) that involves alcohol dehydrogenation, as well as imine hydrogenation, we selected benzyl alcohol and aniline as model substrates. Initially, the reaction was conducted with various Ni precursors (Table 1, entries 1–4, Table S1†) in the range of 120–140 °C under an argon atmosphere. While relatively low conversion was obtained with precursors NiĲOTf)2 and NiBr2, a high conversion value was detected

with NiĲCOD)2, which can be attributed to the ease of NiNP

generation from this Ni(0) precursor at 140°C even in the ab-sence of hydrogen gas. Selecting NiĲCOD)2 for further study,

the effect of various bases was evaluated (Table 1, entries 1, 5–8, Table S2†) with significant variation in substrate conver-sion and product selectivity. Interestingly, with KOH a perfect Fig. 1 (a) Representative examples of pharmaceuticals comprising anN-alkyl amine moiety; (b) general mechanism of the ‘borrowing hydrogen’ strategy.

Catalysis Science & Technology Paper 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55

(8)

selectivity and conversion was achieved at 140°C, while the use of K2CO3 gave much poorer results. The optimum

reac-tion temperature was found to be 140 °C as shown by the lower conversion values in experiments conducted at lower temperature range (Table 1, entries 9 and 10, Table S4†). Without Ni precursor, only traces of product were observed in the presence of base (Table 1, entry 14). Importantly, the catalyst loading could be lowered to 3 mol% and loading of base to 0.3 equivalents (Table 1, entry 16). Further, in order to exclude the possibility for small amounts of aldehyde or other impurities in the alcohol starting material to exhibit catalytic activity,32 we have conducted an experiment with freshly distilled benzyl alcohol, with unchanged results (entry 17 versus entry 16; see also ESI,† Note 3). Importantly, we also successfully carried out an experiment under non-inert condi-tions during which all starting materials were handled under air (entry 18, see also ESI,† Note 4).

Characterization and nature of the catalyst

To gain additional proof of the heterogeneous nature of the Ni catalyst in situ obtained from NiĲCOD)2, we conducted

sev-eral experiments. When we subjected NiĲCOD)2to thermal

de-composition in CPME, in the absence of the substrates, followed by the addition of all reactants and base, we obtained 99% of conversion and 91% of product (Table 1,

en-try 15), comparable to a regular reaction when typically, sol-vent and all substrates were added at the same time. Further-more, when the reaction was conducted in the presence of mercury (Table 1, entry 19), which is a well-known poison for heterogeneous catalysts, inhibition of the catalysis took place.35,36When the poisoning test was repeated in a differ-ent fashion, namely initially the reaction was conducted for 1 h and analysed, after mercury was added and the reaction was continued for 1 h and analysed again, the two samples taken showed practically identical results, indicating an inhi-bition of catalytic activity upon addition of mercury (see ESI† Table S7). At this point it is worth to mention that although the mercury poisoning test is indicative for a reaction operat-ing with heterogeneous catalyst, it does not exclude processes related to catalyst modification in situ such as leaching of sol-uble monometallic species, or formation of smaller set of clusters of metal particles in solution during catalysis. As de-scribed in the excellent review of Ananikov and co-workers,34 several catalytic systems using metal nanoparticles33 rely on dynamic processes involving a homogeneous or heteroge-neous pre-catalyst.

Recycling experiments were successfully conducted, albeit the results showed gradually declining substrate conversion over four consecutive runs (Fig. S1 and Table S8†).

Next, a series of TEM measurements were conducted in or-der to determine the nature and size distribution of the in Table 1 Optimization of the reaction conditions for amination of benzyl alcohol (1a) with aniline (2a′)

Entry Alcohol (equiv.) Base (equiv.) Precatalyst (mol%) Temp [°C] Conv. [%] Sel. of 3a [%] Sel. of 3a′ [%]

1 2 KOH (0.5) NiĲCOD)2(5) 140 >99 99 1

2 2 KOH (0.5) NiCl2Ĳdme) (5) 140 86 79 7

3 2 KOH (0.5) NiĲOTf)2(5) 140 73 63 10 4 2 KOH (0.5) NiBr2(5) 140 78 70 5 5 2 LiOH (0.5) NiĲCOD)2(5) 140 >99 7 74 6 2 NaOH (0.5) NiĲCOD)2(5) 140 >99 10 90 7 2 KOt_{Bu (0.5)} _Ni_ĲCOD) 2(5) 140 90 87 3 8 2 K2CO3(0.5) NiĲCOD)2(5) 140 10 0 7 9 2 KOH (0.5) NiĲCOD)2(5) 100 23 16 7 10 2 KOH (0.5) NiĲCOD)2(5) 120 31 19 9 11 2 KOH (0.1) NiĲCOD)2(3) 140 67 30 30 12 1.2 KOH (0.3) NiĲCOD)2(3) 140 94 92 2 13 2 — NiĲCOD)2(5) 140 73 48 22 14 2 KOH (0.5) — 140 7 1 6 15a _1.5 _{KOH (0.3)} _Ni_ĲCOD) 2(3) 140 >99 91 5 16 1.5 KOH (0.3) Ni(COD)2(3) 140 >99 >99 <1 17b 1.5 KOH (0.3) NiĲCOD)2(3) 140 >99 95 5 18c 1.5 KOH (0.3) NiĲCOD)2(3) 140 >99 93 7 19 1.5 KOH (0.3) + Hg (30) NiĲCOD)2(3) 140 25 20 5 20d _1.5 _{KOH (0.3)} _Ni_ĲCOD) 2(3) 140 16 0 16

General reaction conditions: general procedure (see ESI, page S5–S9), 0.6–1 mmol of 1a, 0.5 mmol of 2a′, NiĲCOD)2(0.015–0.025 mmol, 3–5

mol%), KOH (0.05–0.25 mmol, 10–50 mol%), 100–140 °C, 2 mL CPME, 18 h. Conversion and selectivity were determined by GC-FID using dec-ane as an internal standard.a_{At the beginning of the reaction NiNP were generated from Ni}_ĲCOD)

2(0.015 mmol, 3 mol%) and 2 mL CPME (as

a solvent) at 140°C during 30 min, later KOH (0.15 mmol, 30 mol%), 1a (0.75 mmol), 2a′ (0.5 mmol) were added and the reaction mixture was stirred and heated at 140°C for 18 h.bReaction performed with freshly distilled benzyl alcohol.cReaction performed under non-inert condi-tions.d_{Used pentylamine (0.5 mmol) instead of aniline (2a}_′).

Catalysis Science & Technology Paper

1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55

(9)

4 | Catal. Sci. Technol., 2018, 00, 1–8 This journal is © The Royal Society of Chemistry 2018 Fig. 2 TEM

Q4 micrographs ofin situ generated Ni-NPs under various reaction conditions and particle size distribution of the investigated samples.

(10)

situ generated NiNP. To gain more insight into the possible structural changes imparted by the various components of this peculiar system, a number of experiments were carried out by systematic variation of the base, alcohol and amine and the corresponding TEM images were recorded (Fig. 2).

The first sample (Fig. 2a), prepared by heating NiĲCOD)2in

CPME showed Ni oxide clusters of ca. 20 nm in large regions with agglomerated particles sized in the range of 2–5 nm, as expected in the absence of the base and any substrates present. The same sample, however in the presence of KOH (30 mol%) (Fig. 2b), displayed larger Ni oxide clusters (50–100 nm) formed by nanoparticles still of 2–5 nm (Fig. 2b) surrounded by potas-sium. Caubère,37 Fort

Q5 38 and Hartwig30 have previously

indi-cated that base can stabilize nickel nanoparticles and this phe-nomenon is observed in our system as well. In contrast to KOH, the specimen obtained using K2CO3 showed particles

with markedly different morphology, with more agglomeration and poor dispersion (≈2%) of Ni nanoparticles (Fig. 2c). This is a likely explanation for the lower catalytic activity of this system (Table 1 entry 1 versus entry 8 and ESI† Table S2 entry 1 versus entry 5). Next, the influence of the benzyl alcohol was investi-gated. Isolated Ni oxide clusters of ca. 25 nm (Fig. 2d) with well dispersed nanoparticles (average size 4 nm) were obtained in presence of 1.5 equivalents of benzyl alcohol that confirmed our assumption of a possible stabilization of metal particles by benzyl alcohol, supporting the alcohol–Ni interaction that is necessary for the dehydrogenation reaction. This effect was even more pronounced in the presence of KOH. The mixture containing benzyl alcohol and KOH after 20 min (Fig. 2e) showed no visible nickel particles at low magnification. How-ever, at higher magnification, very regularly and finely distrib-uted metal Ni nanoparticles of ca. 2 nm were observed, Table 2 Amination of various alcohols with aniline

3a, 90% 3b, 85% 3c, 84% 3d, 98% 3e, 92% 3f, 72% 3g, 62% 3h, 51% 3i, 69% 3j, 38%a,b _{3k, 69%}b _{3l, 90%} 3m, 89% _{3n, 87%} _{3o, 89%} _{3p, 89%} 3q, 88% _{3r, 85%} _{3s, 90%} _{3t, 12%} 3ua, 63% 3ub, 18%a 3va, 67% 3vb, 28%

General reaction conditions: general procedure (see ESI, page S13_{–S15), 1.5 mmol of 1a–v, 1 mmol of aniline, NiĲCOD)}2(0.03 mmol, 3 mol%),

KOH (0.3 mmol, 30 mol%), 140°C, 2 mL CPME, 18 h.aYield was calculated based on GC-FID.b1 mL of methanol or ethanol, 1 mmol of aniline, NiĲCOD)2(0.1 mmol, 10 mol%), KOH (1 mmol), 150°C, 2 mL CPME, 48 h. For details see ESI, Table S9.

1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55

(11)

6 | Catal. Sci. Technol., 2018, 00, 1–8 This journal is © The Royal Society of Chemistry 2018 accounting for a metal dispersion as high as 50% (for EDX

analysis of this sample see ESI† Fig. S4) – signifying the active system prior to the addition of aniline. The actual reaction mix-ture, after 20 minutes reaction time showed similar finely dis-persed particles (see ESI† Fig. S3a), while the reaction mixture imaged after 18 hours (Fig. 2f) still showed well dispersed Ni° nanoparticles, although slightly larger than those observed in the initial phase of the reaction. Interestingly, when the Ni par-ticles were generated in presence of pentylamine (see ESI† Fig. S3c) the TEM images showed that the particles were completely besieged by the amine, whereas in the presence of aniline (see ESI† Fig. S3b) they were well dispersed. A reaction mixture comprising benzyl alcohol and pentylamine showed similar

be-haviour (Fig. S3d†). This can be explained by a stronger coordi-nation of the more basic (aliphatic) amines to the nickel parti-cles and likely the cause of the poor conversion values obtained in the presence of pentylamine (Table 1, entry 20) and similar substrates (ESI† Table S10, entries 28–31).

N-Alkylation of aniline with a wide range of alcohols

To demonstrate the general applicability of the catalytic sys-tem, various (hetero)aromatic and aliphatic alcohols, includ-ing diols, were evaluated in the catalytic N-alkylation of ani-line under optimized conditions (Table 2). Electron-donating and electron-withdrawing substituted benzyl alcohols were Table 3 N-alkylation of various aniline with n-butanol

5a, 78% 5b, 77% 5c, 53% 5d, 32% 5e, 70% 5f, 86% 5g, 65% 5h, 42%b 5i, 72% 5j, 62% 5k, 36% 5l, 64% 5m, 72%b 5n, 32% a 5oa, 25%b 5ob, 39%b 5pa, 32%b 5pb, 43%b 5q, 32%b 5r, 57%c

General reaction conditions: general procedure (see ESI, page S15–S18), 1.5 mmol of n-butanol (4a), 1 mmol of 2a–r, NiĲCOD)2(0.03 mmol, 3

mol%), KOH (0.3 mmol, 30 mol%), 140°C, 2 mL CPME, 18 h.aYield was calculated based on GC-FID.b3 mmol of n-butanol, 1.5 mmol of cor-responding amine, NiĲCOD)2(0.03 mmol, 3 mol%), KOH (0.3 mmol, 30 mol%), 140°C, 2 mL CPME, 48 h.c3 mmol of n-butanol, 1.5 mmol of

corresponding amine, NiĲCOD)2(0.05 mmol, 5 mol%), KOH (0.5 mmol, 50 mol%), 140°C, 2 mL CPME, 72 h. For details see ESI, Table S10. Catalysis Science & Technology Paper 1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55

(12)

successfully used in the selective mono-alkylation of aniline (Table 2). Notably, benzyl alcohols (1a–1e) with electron-donating substituents, including the sterically more hindered 2-methoxy benzyl alcohol (1c) reacted smoothly with aniline, resulting in very good to excellent (84–98%) isolated yields of 3a–e (Table 2). When benzyl alcohols bearing the electron-withdrawing groups –NO2, –CN, –CH3COOCH3, –CF3 were

employed, much lower reactivity was observed (Table S9, en-tries 23–26, in the ESI†). Furthermore, the important building block piperonyl alcohol (1g) was transformed to the desired product 3g with 62% isolated yield. Interestingly, hetero-aromatic alcohols such as the biomass-derived furfuryl alco-hol and 2-(hydroxymethyl)pyridine were alkylated selectively, albeit with moderate yields (Table 2, 3h and i, respectively). Next, aliphatic alcohols as reaction partners in the N-alkylation of aniline were investigated. Gratifyingly, short and long chain aliphatic alcohols (1k–s) readily afforded the corresponding desired amine product (3k–s, 69–90%) under optimized conditions. It was even possible to achieve N-alkylation with methanol, but only 38% GC yield of N-methylated product was seen even at high catalyst/base loading. Notably, when 1,5- and 1,6-diols were examined, the mono-alkylated amino alcohols (3ua) and (3va) were obtained in 63% and 67% isolated yield, respectively, and minor amounts of cyclic products were observed (Table 2).

N-Alkylation of a variety of amines with 1-butanol

Further expanding the scope of the reaction, n-butanol was chosen as coupling partner to a series of diversely substituted aniline derivatives, bearing electron-donating (2a–e) and electron-withdrawing (2i–l) groups as well as sterically hindered amines (2f–g), and diamines (2m, 2o–q), which were selectively alkylated. More specifically, there was no significant difference in the reactivity of p-methoxy-aniline (2a) compared to p-methyl-aniline (2b), however a gradual decrease of product yield was observed (77% for 5b, 53% for 5c, 32% for 5d) when the substrate was changed to the meta- and ortho-substituted analogues. A similar behavior was observed for fluoro-anilines 2i, 2j and 2k. Interestingly, pyrrole substituted aniline furnished 57% isolated yield of 5r. Aromatic amines bearing the electron-withdrawing groups–CN, –CH3COOCH3and–CF3

showed low reactivity with 1-butanol, namely only minor amounts of products were observed (Table S10, entries 19–21, in the ESI†). Next, when aromatic diamines were used as a sub-strate, the corresponding mono and di-N-alkylated amines were isolated (Table 3, 5oa–5ob and 5pa–5pb). When aliphatic amine cyclohexylamine was used, it gave 32% GC yield of desired product 5n and 67% of imine (5n′). Other aliphatic amines (benzylamine, pentylamine and morpholine) did not afford any products under the optimized reaction conditions (Table S10, entries 28–30, in the ESI†), in accordance with previous TEM investigation that shows stronger coordination of aliphatic amines to the Ni particles likely leading to diminished activity.

Examples of heterogeneous catalysts comprising nickel on alumina39,40or silica,41γ-Al2O3supported Ni and Cu

bimetal-lic nanoparticles42 and RANEY®-nickel43 are known for the amination of alcohols. Besides this, a few homogeneous cata-lytic systems using nickel for alkylation of amines24,25 and N-alkylation of hydrazides and arylamines with racemic alco-hols44 were very recently reported, but to the best of our knowledge, the system described above is the first example where in situ generated Ni nanoparticles act as highly effi-cient catalysts for the attractive N-alkylation of amines. Clear advantages are the Ni loading being as low as 3%, and there is no catalyst preparation or any ligand required. Therefore, we believe our system to be a valuable addition to these ex-amples of Ni catalysts that are either homogeneous or supported heterogeneous in nature. This is an excellent starting point for establishing robust, highly active and recy-clable Ni catalyst in the future, for example by using polyeth-ylene glycol (PEG)45or ionic liquids.46

Conclusion

In summary, we have developed a simple and highly active catalytic system for efficient and selective N-alkylation of amines with alcohols that can be conveniently prepared using a catalytic amount (as low as 3 mol%) of NiĲCOD)2and

sub-stoichiometric amount of KOH under ligand-free condi-tions. The described system is tolerant to a variety of func-tional groups such as halides, benzodioxane and hetero-aromatic groups present in either the alcohol or the amine substrate. In order to gain further insight into the nature of the active catalytic system and influence of reaction parame-ters on catalyst morphology, a series of TEM measurements combined with elemental analysis were performed that found finely dispersed in situ generated metal particles in the catalysed reaction. Additional studies revealed that potassium hydroxide is uniquely suited for the stabilization of Ni nano-particles and that the alcohol substrate also has a stabilizing role. Furthermore, clear differences in the morphology of the particles were seen in the presence of aromatic versus ali-phatic amine, the latter leading to poor reactivity due to stronger amine coordination. The substrate scope was well in line with these findings, where the nature of the alcohol reac-tion partner could be broadly varied (benzyl alcohol, short or long chain aliphatic alcohol, diol) while aniline derivatives were better suited substrates than aliphatic amines. To the best of our knowledge this is the first, very simple yet highly active and selective NiNP catalyst system for the N-alkylation of amines with alcohols that operates via the hydrogen bor-rowing strategy.

Conflicts of interest

Q6

Acknowledgements

K. B. is grateful for financial support from the European Re-search Council, ERC Starting Grant 2015 (CatASus) 638076. This work is part of the research program Talent Scheme

1 5 10 15 20 25 30 35 40 45 50 55 1 5 10 15 20 25 30 35 40 45 50 55

(13)

8 | Catal. Sci. Technol., 2018, 00, 1–8 This journal is © The Royal Society of Chemistry 2018 (Vidi) with project number 723.015.005 (K. B.), which is partly

financed by the Netherlands Organization for Scientific Re-search (NWO).

References

1 S. A. Lawerence, Amines: Synthesis Properties, and Applications, Cambridge University, 2004.

2 A. Ricci, Amino Group Chemistry: From Synthesis to the Life Sciences, Wiley-VCH, Weinheim, Germany, 2008.

3 M. B. Smith and J. March, March's Advanced Organic Chemistry, Wiley-Interscience, New York, 2001.

4 G. W. Gribble, Chem. Soc. Rev., 1998, 27, 395–404.

5 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, 1998.

6 J. F. Hartwig, Palladium-Catalyzed Amination of Aryl Halides and Sulfonates, in Modern Arene Chemistry, ed. D. Astruc, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2002, pp. 107–168.

7 C. Sambiagio, S. P. Marsden, A. J. Blacker and P. C. McGowan, Chem. Soc. Rev., 2014, 43, 3525–3550.

8 L. Huang, M. Arndt, K. Gooben, H. Heydt and L. J. Gooben, Chem. Rev., 2015, 115, 2596–2697.

9 T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Chem. Rev., 2008, 108, 3795–3892.

10 D. Chusov and B. List, Angew. Chem., Int. Ed., 2014, 53, 5199–5201.

11 S. Pisiewicz, T. Stemmler, A. E. Surkus, K. Junge and M. Beller, ChemCatChem, 2015, 7, 62–64.

12 S. Bähn, S. Imm, L. Neubert, M. Zhang, H. Neumann and M. Beller, ChemCatChem, 2011, 3, 1853–1864.

13 A. Corma, J. Navas and M. J. Sabater, Chem. Rev., 2018, 118, 1410–1459.

14 A. J. A. Watson and J. M. J. Williams, Science, 2010, 329, 635–636.

15 K. Barta and P. C. Ford, Acc. Chem. Res., 2014, 47, 1503–1512.

16 M. Pelckmans, T. Renders, S. Van de Vyver and B. F. Sels, Green Chem., 2017, 19, 5303–5331.

17 V. Froidevaux, C. Negrell, S. Caillol, J.-P. Pascault and B. Boutevin, Chem. Rev., 2016, 116, 14181–14224.

18 G. Guillena, D. Ramon and M. Yus, Chem. Rev., 2010, 110, 1611–1641.

19 R. M. Bullock, Catalysis Without Precious Metals, Wiley-VCH, 2010.

20 T. Yan, B. L. Feringa and K. Barta, Nat. Commun., 2014, 5, 5602.

21 T. Yan, B. L. Feringa and K. Barta, ACS Catal., 2016, 6, 381–388.

22 S. Rösler, M. Ertl, T. Irrgang and R. Kempe, Angew. Chem., Int. Ed., 2015, 54, 15046–15050.

23 S. Elangovan, J. Neumann, J. B. Sortais, K. Junge, C. Darcel and M. Beller, Nat. Commun., 2016, 7, 12641.

24 M. Vellakkaran, K. Singh and D. Banerjee, ACS Catal., 2017, 7, 8152–8158.

25 S. Das, D. Maiti and S. De Sarkar, J. Org. Chem., 2018, 83, 2309–2316.

26 R. Kempe and F. Kallmeier, Angew. Chem., Int. Ed., 2018, 57, 46–60.

27 F. Alonso, P. Riente and M. Yus, Acc. Chem. Res., 2011, 44, 379–391.

28 F. Alonso, P. Riente and M. Yus, Synlett, 2008, 1289–1292. 29 F. Alonso, P. Riente and M. Yus, Eur. J. Org. Chem.,

2008, 4908–4914.

30 A. G. Sergeev, J. D. Webb and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134, 20226–20229.

31 A. Zuliani, A. M. Balu and R. Luque, ACS Sustainable Chem. Eng., 2017, 5, 11584–11587.

32 Q. Xu, Q. Li, X. Zhu and J. Chen, Adv. Synth. Catal., 2013, 355, 73–80.

33 T. Borkowski, J. Dobosz, W. Tylus and A. M. Trzeciak, J. Catal., 2014, 319, 87–94.

34 D. B. Eremin and V. P. Ananikov, Coord. Chem. Rev., 2017, 346, 2–19.

35 J. A. Widegren and R. G. Finke, J. Mol. Catal. A: Chem., 2003, 198, 317–341.

36 R. H. Crabtree, Chem. Rev., 2012, 112, 1536–1554.

37 P. Gallezot, C. Leclercq, Y. Fort and P. Caubére, J. Mol. Catal., 1994, 93, 79–83.

38 J. J. Brunet, D. Besozzi, A. Courtois and P. Caubere, J. Am. Chem. Soc., 1982, 104, 7130–7135.

39 K. I. Shimizu, N. Imaiida, K. Kon, S. M. A. Hakim Siddiki and A. Satsuma, ACS Catal., 2013, 3, 998–1005.

40 K. I. Shimizu, K. Kon, W. Onodera, H. Yamazaki and J. N. Kondo, ACS Catal., 2013, 3, 112–117.

41 C. M. Barnes and H. F. Rase, Ind. Eng. Chem. Prod. Res. Dev., 1981, 20, 399–407.

42 J. Sun, X. Jin, F. Zhang, W. Hu, J. Liu and R. Li, Catal. Commun., 2012, 24, 30–33.

43 J. L. García Ruano, A. Parra, J. Alemán, F. Yuste and V. M. Mastranzo, Chem. Commun., 2009, 404–406.

44 P. Yang, C. Zhang, Y. Ma, C. Zhang, A. Li, B. Tang and J. S. Zhou, Angew. Chem., Int. Ed., 2017, 56, 14702–14706. 45 J. M. Harris and S. Zalipsky, PolyĲethylene Glycol): Chemistry

and Biological Applications, American Chemical Society, 1997. 46 M. H. G. Prechtl, in Front Matter, in Nanocatalysis in Ionic Liquids, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2016, pp. i–xxii.