One-pot reductive amination of carbonyl compounds with ammonia via ‘hydrogen borrowing’ using hydrido- and bis-ammine P,O(Me)-ruthenacycles

Article abstract of DOI:10.1016/j.jorganchem.2016.10.038

The novel cationic [RuH{PPh₂(2-OMeC₆H₄)}₂]BPh₄and neutral trans-[Ru(NH₃)₂{PPh₂(2-OC₆H₄)}₂] complexes were isolated from phosphine substitution reactions with [RuH(1,5-cod)(NH₂NMe₂)₃]BPh₄and [RuCl(1,5-cod)(NH₃)₂(NH₂NMe₂)]BPh₄respectively. Ligand induced bisdemethylation of the pendent ether moieties of the phosphines occurred to give rise to the bis-phosphanylphenoxy moieties. Both complexes catalyzed the one-pot reductive amination of carbonyl compounds where excellent selectivity of aryl aldehydes over aryl ketones as precursors to the alcoholic species existed. Through substrate screening and¹H NMR studies, both steric and electronic effects of the substrates were found to influence the hydrogenation/amination mechanistic pathway, as well as direct the alcohol:amine selectivity.

Full text of DOI:10.1016/j.jorganchem.2016.10.038

Accepted Manuscript
One-pot reductive amination of carbonyl compounds with ammonia via ‘hydrogen
borrowing’ using hydrido- and bis-ammine P,O(Me)-ruthenacycles
Frederick P. Malan, Ji-Hyang Noh, Gadada Naganagowda, Eric Singleton, Reinout
Meijboom
PII:
S0022-328X(16)30494-6
10.1016/j.jorganchem.2016.10.038
JOM 19682
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 15 August 2016
Revised Date: 13 October 2016
Accepted Date: 25 October 2016
Please cite this article as: F.P. Malan, J.-H. Noh, G. Naganagowda, E. Singleton, R. Meijboom, One-
pot reductive amination of carbonyl compounds with ammonia via ‘hydrogen borrowing’ using hydrido-
and bis-ammine P,O(Me)-ruthenacycles, Journal of Organometallic Chemistry (2016), doi: 10.1016/
j.jorganchem.2016.10.038.
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One-pot reductive amination of carbonyl compounds with ammonia via ‘hydrogen
borrowing’ using hydrido- and bis-ammine P,O(Me)-ruthenacycles
Frederick P. Malan, Ji-Hyang Noh, Gadada Naganagowda, Eric Singleton, Reinout
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Meijboom*
Research Centre for Synthesis and Catalysis, Department of Chemistry, University of Johannesburg,
PO Box 524, Auckland Park, 2006, Johannesburg, South Africa. *E-mail: rmeijboom@uj.ac.za
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Abstract
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The novel cationic [RuH{PPh (2-OMeC H )} ]BPh and neutral trans-[Ru(NH ) {PPh (2-
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3 2
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OC H )} ] complexes were isolated from phosphine substitution reactions with [RuH(1,5-
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cod)(NH NMe ) ]BPh and [RuCl(1,5-cod)(NH ) (NH NMe )]BPh respectively. Ligand
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induced bisdemethylation of the pendent ether moieties of the phosphines occurred to give
rise to the bis-phosphanylphenoxy moieties. Both complexes catalyzed the one-pot reductive
amination of carbonyl compounds where excellent selectivity of aryl aldehydes over aryl
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ketones as precursors to the alcoholic species existed. Through substrate screening and H-
NMR studies, both steric and electronic effects of the substrates were found to influence the
hydrogenation/amination mechanistic pathway, as well as direct the alcohol:amine
selectivity.
Keywords: ruthenium(II); hemilability; reductive amination; transfer hydrogenation
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1. Introduction
The availability of a vacant coordination site(s) on a metal complex through ligand mobility
is an important property usually exhibited by atom efficient, highly catalytically active
transition metal complexes [1-12]. Transition-metal complexes containing ether and thio-
ether phosphine ligands, and their dealkylated oxo- and thio-donor ligands, especially
phosphanylphenoxides, have received much attention due to their wide-range of utility in
homogeneous asymmetric and transfer hydrogenation catalysis [7, 11, 13-16], small molecule
activation [17], biological applications [18], and chemosensors [17, 19, 20].
Ruthenium(II) complexes bearing phosphines with pendant ether and thio-ether moieties in
particular have been investigated as highly active regio-, stereo-, and chemo-selective
catalysts by various groups [6, 9, 13] over the last 15 years because of the advantageous self-
modifying properties of the ligands. This is because phosphorous(III) and their ether O- or S-
atoms may coordinate to and stabilize a low valent metal centre, where after the ancillary
ligand-assisted demethylation of the ether moiety may readily occur to form a hemilabile
thio- or oxo-functionality when it is required in a catalytic or biological process [4, 6, 21].
The reductive amination of carbonyls is a popular class of C-N asymmetric catalysis that
continues to be investigated because of the sought after primary, secondary, and tertiary
amines that are obtainable [22-28]. Numerous Ru(II) systems bearing rigid and hemilabile
ligand systems have been reported to exhibit catalytic activity in asymmetric transfer
hydrogenation reactions, although much less in reductive amination as a class of
carbonyl/alcohol transformation reactions [14, 19, 26, 27, 29-31]. The ability to atom-
economically convert alcohols into primary amines using ammonia remains a challenge,
where in some respects considerable progress has been made [28, 32-36]. Apart from the
i
known [Cp*IrCl(Tsdpen-H)] [16], [Rh(Cp*)Cl ] [14], and Ti(O Pr) [15] catalysts known to
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be able to help produce primary amines from ketones and aldehydes, the catalysts [((R)-tol-
binap)RuCl (DMF) ] [14], [Ru(OAc) ((R)-dm-segphos)] [29], [RuHCl(CO)(PNP)] [28, 33,
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x
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36], [RuHCl(CO)(triphos)] [34, 35], and the combination of [Ru (CO) ] with phosphine
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ligands are to date the only known Ru(II) catalysts with the ability to use NH as feedstock
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for transformation into primary amines (Figure 1). To the best of our knowledge, there are no
existing isolated mono- and bis-ammine Ru(II) catalysts that may actively provide an
additional source of NH as part of the catalytic intermediates involved in these reactions
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[37].
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Figure 1: Reductive amination: (1) (NH )(OOCH), NH /MeOH, 85 °C, 17-48h. (2)
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(NH )(OOCCH ), (NH )(OOCC H OH), 30 bar H (g), 80 °C, 15h. (3) 6 bar NH , 140-170
4 3 4 6 4 2 3
ºC, 20h, molecular sieves; excess NH (aq), 140 ºC, 21h (4) 76 bar NH , 135 ºC, 18-36h; 35-
3
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40 bar NH , 135 ºC, 12h (5) 35-40 bar NH , NH Cl, 155-165 ºC, 12-15h. For
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[Ru(CO)ClH(PPh ) ]: 4-9 bar NH , dppe (1.1 mol%), 10 mol% Al(OTf) , 120 ºC, 16h. (6)
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(NH )(OOCCH ), NH OH, NaBH /EtOH, 90 °C, 24h.
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We recently published the syntheses of cationic ruthenium(II) mono- and bis-ammine
complexes of [RuH(1,5-cod)(NH NMe ) ]A, [RuH(1,5-cod)(NH )(NH NMe ) ]A, and
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2 3
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[RuCl(1,5-cod)(NH ) (NH NMe )]A (A = PF , BPh ) [38]. Of particular interest to us, was
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the novel hydrido- and chlorido-ammine phosphine-bearing complexes obtained from the
reactions of these precursors with chelating phosphines. This study focuses on (i) the
syntheses of two new Ru(II) complexes bearing PPh (2-OMeC H ) and PPh (2-OC H )
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4
2
6
4
moieties; (ii) full characterisation of both complexes including the X-ray structure
determination of 4; (iii) and the results of the one-pot reductive amination catalytic study
performed using both complexes.
2. Experimental
2.1 General
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All experiments were carried out under an argon atmosphere using standard Schlenk
techniques [39], using solvents that were dried using standard techniques [40]. The
complexes [RuH(1,5-cod)(NH NMe ) ]BPh (1) and [RuCl(1,5-cod)(NH ) (NH NMe )]BPh
4
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2 3
4
2 2
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(2) were prepared according to the reported procedure [38]. All other chemicals were
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purchased from Sigma-Aldrich and used without further purification. H (400 MHz), C{H}
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(101 MHz), and P{H} (162 MHz) and N- H HMBC NMR spectra were recorded on a
Bruker Avance III Ultrashield 400 MHz spectrometer fitted with a B-ACS 60 auto-sampler
using CDCl solutions. Chemical shifts were referenced to the internal residual protio
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impurities in the solvent (δ 7.24 ppm) or carbon signals (δ 77.0 ppm in CDCl ). Solid state
H
H
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FT-IR experiments were carried out on a Bruker Tensor 27 FT-IR as pressed KBr pellets in
air. Melting points were performed in air on a Stuart SMP10 and are uncorrected.
Microanalytical analyses (%CHNS) were performed at Rhodes University (RSA) using an
Elementar Vario Micro cube instrument with a TCD detector. Gas chromatography (FID)
analyses were performed on a Shimadzu GC-2010 Plus equipped with a 30 m Restek Rtx-5
capillary column, and GC/MS analyses using a Shimadzu GCMS-QP2010.
2.2 Synthesis of [RuH{PPh (2-MeOC H )} ]BPh (3)
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A brown solution of [RuH(1,5-cod)(NH NMe ) ]BPh (1, 0.496 g, 0.7 mmol) in MeOH (12
2
2 3
4
mL) containing PPh (2-MeOC H ) (0.497 g, 1.7 mmol) was heated under reflux for 2 hours.
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EtOH (10 mL) was added to the dark brown solution and concentrated to 5 mL. The reaction
mixture was vacuum-filtered, washed with EtOH/Et O (8 mL), which gave a dark blue
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powder (0.231 g, 33%). Full characterization details are included in the Supplementary
Information.
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2.3 Synthesis of trans-[Ru(NH ) {PPh (2-OC H )} ] (4)
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A brown solution of [RuCl(1,5-cod)(NH ) (NH NMe )]BPh (2, 0.518 g, 1.1 mmol) in N -
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purged acetone (12 mL) containing PPh (2-MeOC H ) (0.794 g, 2.7 mmol) was stirred at
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room temperature overnight. EtOH (10 mL) was added to the yellow-orange solution,
concentrated (~5 mL), vacuum filtered, and washed with EtOH/Et O (10 mL) from which
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yellow-orange cuboid crystals were isolated. These were recrystallized using CHCl /EtOH
3
(0.431 g, 58%). Full characterization details are included in the Supplementary Information.
2.4
Reductive amination
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In a typical experiment the carbonyl substrate (0.6 mmol), catalyst (1 mol%, 6 mg for 3, 5 mg
for 4), (NH )(OOCCH ) (6 mmol, 460 mg), NH OH (0.3 mmol, 42 ꢀL of a 28% w/w
4
3
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aqueous solution, or NH Cl, 0.3 mmol, 16 mg; either of the two added as an additive), n-
4
decane (0.6 mmol, 117 ꢀL, internal standard), and EtOH (5 mL) were added together in a
Schlenk flask fitted with a dropping funnel and a bubbler. A solution of NaBH (0.6 mmol,
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23 mg; or 1.2 mmol in the case of glyoxal, 46 mg) in EtOH (5 mL) was added dropwise over
30 minutes after which the reaction mixture was heated at the desired temperature (60 °C, 90
°C) for several hours (12 h, 24 h, 48 h) under Ar(g), depending on the specific experiment.
After cooling, the mixture was quenched with water, extracted with EtOAc, and purified
using flash column chromatography (silica, EtOAc). The collected fractions were
concentrated to near-dryness and made up as a solution with either CH Cl or EtOH
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(depending on the product solubility), and analysed using GC(FID) and GC/MS.
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2.5
H-NMR reductive amination experiments
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In a typical experiment a H-NMR spectrum of a heated (90 ºC) EtOD solution (4 mL) of the
carbonyl substrate (0.1 mmol), catalyst (1 mol%, 0.9 mg for 4), (NH )(OOCCH ) (1 mmol,
4
3
77 mg), and NH OH (50 ꢀmol, 7 ꢀL of a 28% w/w aqueous solution) was taken as a
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reference time = 0 min spectrum. Thereafter a EtOD solution (1 mL) of NaBH (0.1 mmol, 4
4
mg) was added and heated in a Schlenk flask fitted with a dropping funnel and a bubbler
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under Ar(g) at 90ºC for 24 hours. H-NMR spectra of a sample of the resulting reaction
mixture was taken at intervals of 25, 60, 80, 120, 200, 400, 600, 900, 1100, and 1400 min
respectively, after which the NMR sample was returned to the reaction mixture after
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measurement. All H-NMR yields and conversions are based on the integration ratios
obtained between the aldehyde, alcohol, amine, and imine products observed.
3. Results and Discussion
3.1
Synthesis and Characterisation of 3 and 4
Reaction of a methanolic solution of [RuH(1,5-cod)(NH NMe ) ]BPh (1) with 2.4
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2 3
4
equivalents of PPh (2-MeOC H ) gave the novel five-coordinate complex trans-
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[RuH{PPh (2-MeOC H )} ]BPh (3) (Scheme 1). This complex was found to be air-
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2
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sensitive, with an associated molecule of H O stabilising the vacant coordination site which is
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suggested through FTIR, H-NMR, and CHN analyses of 3. The source of the H O is
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reasoned to originate from the hygroscopic complex 1, which is usually crystallised from a
wet DCM/EtOH solvent mixture.
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Scheme 1: Synthesis of cationic complex 3, and neutral complex 4.
In contrast, reaction of [RuCl(1,5-cod)(NH ) (NH NMe )]BPh (2) with 2.4 molar
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4
equivalents of the phosphine in boiling acetone gives the novel ruthenacycle trans-
[Ru(NH ) {PPh (2-OC H )} ] (4). Bisdemethylation of the phosphine ligands to form σ-
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donating oxo-functionalities, along with the subsequent cis-coordination of both oxo-moieties
with respect to the ruthenium atom is rare, since mono-demethylation usually occurs in
neutral Ru and Pd systems [7, 11, 13, 41]. Only one account reports the loss of both methyl
groups of the 2-MeOC H moieties through ligand-assisted C-O bond cleavage in the
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chelating phosphine to form the Ru(II) complex [Ru(CH CN) {PPh (2-OC H )} ] [41]. Two
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mechanisms for the transformation of the latter product were proposed by Hsu et al. [41], one
involving successive reductive elimination reactions of OMe moieties and coordinated
chloride ligands to expel CH Cl in the reaction mixture with subsequent coordination of oxo-
3
moieties to the ruthenium atom. This mechanism was adapted for the formation of 4, and is
included in the Supplementary Information.
The UV/vis spectra of both the (formal) coordinatively unsaturated dark blue complex 3, and
orange colored octahedral complex 4 revealed peak absorptions at λ 453 nm (3) and 616 nm
(4) (Supplementary Information). The presence of the hydride ligand in [RuH{PPh (2-
2
-1
1
MeOC H )} ]BPh (3) was confirmed by FTIR (ν(Ru-H) = 2038 cm ), and H-NMR with δ
H
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4
2
4
3
1
-8.57 (t, J = 36 Hz), with none observed for 4. H-NMR resonances for the symmetrical
HP
OMe-groups in 3 were observed at δ 3.30 (s, OCH ), with none observed in 4. No
H
3
1
fluxionality in the hemilabile phenoxy moieties were observed in the H-NMR spectra of
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both 3 and 4, which would indicate that hemilability is ligand-induced [7]. The P-NMR
spectrum of 3 revealed a singlet at δ 49.9 for the two equivalent phosphines, which appears
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upfield from the singlet at δ 66.3 observed for 4. The two phenyl substituents of each cis-
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coordinated phosphorous atom contribute to an asymmetric steric environment which renders
the two NH ligands non-equivalent [7]. The non-equivalence of the trans-NH ligands in 4
3
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-1
-1
were confirmed by FTIR (ν(NH) = 3264 and 3155 cm ; δ(NH, asym) = 1580 and 1544 cm ;
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δ(NH, sym) = 1056 and 1026 cm ), and H-NMR (δ 0.91 and 1.89).
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Figure 2: (a) Molecular diagram of the X-ray crystal structure of trans-[Ru(NH ) {PPh (2-
3
2
2
OC H )} ] (4), with thermal ellipsoids drawn at 50% probability level. Hydrogen atoms are
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4
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omitted for clarity. (b) Molecular packing of 4 along the b-axis.
The neutral complex 4 exhibits a distorted octahedral geometry, bearing two Ru-P,O
metallacycles (mean P-Ru-O = 82.87°) with two NH ligands trans to each other in the axial
3
positions (Figure 2) [32]. In each ruthenacycle, the average Ru-P bond distance (2.2438 Å)
was slightly longer than the average Ru-O bond distance (2.1263 Å). Interestingly, the Ru1-
N2 bond is observed to be slightly elongated as compared to the Ru1-N1 bond, with Ru1-N2
= 2.120(2) Å and Ru1-N1 = 2.104(2) Å (Table A, Supplementary Information).
3.2
Reductive amination catalysis
The catalytic activity of complexes 3 and 4 were evaluated in the reductive amination
reaction of different aryl ketones and aldehydes with NH . Our initial attempts were aimed at
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the one-pot conversion of ketones into primary amines through reduction, transfer
hydrogenation, followed by subsequent amination using excess (NH )(OOCCH ) as a major
4
3
NH stock feed. However, neither 3 nor 4 showed any appreciable amination activity with
3
acetophenone, and gave almost exclusively the corresponding alcohols (Table 1). This was
surprising since a moderate transfer hydrogenation activity under the experimental conditions
employed, at the very least, was expected. In the absence of catalyst and reductant almost no
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conversion took place (entry 1). Using complex 4, a higher conversion of ketone was
observed as compared to 3 (entries 2, 3), despite a more sterically congested environment in
4. This is ascribed to the simpler substrate coordination to the vacant coordination site in 3,
and leads to higher transfer hydrogenation activity of the alcoholic species. The blank
experiment with absence of 4, and presence of NaBH was also performed and showed a
4
slight increase in conversion, still with exclusive alcohol formation (entry 2). Despite the
possibility of 4 that could additionally act as an NH reservoir directly in the inner
3
coordination sphere with the bound substrate, 4 failed to exhibit any amination activity with
ketones, even in the presence of NH OH as additive (entry 4). It was initially reasoned that a
4
strong solvent effect might be evident in these reactions, similar to what Schaub et al. [34]
found where less polar solvents (toluene) proved more efficient over polar solvents (THF). If
toluene was used as solvent, solubility and work-up issues hampered the full exploitation of
the catalytic transformation, leading to lower conversions of the ketone species observed.
Separate increases in temperature and reaction times lead to expected increased yields of
alcohol products (entry 7-9). Steric and electronic variations in the ketone moieties also
affected the conversions, a slightly lower conversion was observed for the electron-poor p-
Cl-acetophenone (79%, entry 10), with less conversion for the bulky benzophenone (50%,
entry 11) and 2-isonitrosoacetophenone (43%, entry 12) substrates.
Table 1: Screening of hydrogenation/amination conditions.
Temp (
Cat
Selectivity
(A:B)
Entry
Ketone
Additive Time
Conv. (%)
°
C) (mol%)
a
1
2
acetophenone
acetophenone
-
-
-
24
24
60
60
4 (0)
4 (1)
4
100:0
1
00:0
b
67 (77 )
b
(
100:0 )
100:0
100:0
100:0
100:0
3
4
5
6
acetophenone
acetophenone
acetophenone
acetophenone
24
OH 24
OH 24
60
60
60
60
3 (1)
3 (1)
4 (1)
4 (1)
50
36
69
33
NH
4
4
NH
NH
Cl
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acetophenone
acetophenone
NH
NH
NH
NH
NH
4
4
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OH 24
OH 12
OH 48
OH 18
OH 18
OH 18
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4 (1)
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4 (1)
4 (1)
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91:0:9
100:0
94:0:6
acetophenone
100
79
c
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0
1
2
4-chloro-acetophenone
benzophenone
89:0:11
100:0
1
1
50
2-isonitrosoacetophenone NH
4 (1)
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100:0
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b
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Absence of NaBH and 4. Absence of 4, but with added NaBH . Additional ester-adduct
4
4
products were observed.
A notable increase in selectivity towards the amine-adducts was observed when aldehydes
were employed under the same optimized conditions (Table 2, Figure in Supplementary
Information). Near quantitative conversions of benzaldehyde to its reduced species were
obtained with alcohol:amine ratios of 1:0 with no catalyst present (entry 1), for which the
selectivity increases to 2:3 with 4 (1 mol%) present (entry 2). A final yield of 57% for
benzylamine was achieved, which is comparable to the 68% achieved by Hofmann et al. [33],
considering that they employed 20 mol% of catalyst (20 times more), 20 equivalents of NH3
(two times more), and 145 ºC (55 ºC higher) for similar reaction times. It is important to note
that they added 1-octanol (0.8 equiv) in the reaction mixture, for which they proved that the
alcohol facilitates the reductive amination of the aldehyde.
The latter is in contrast to the recent work of Schaub et al. [28] where they were able to
reductively aminate ketones in high yields using a [Ru(CO)HCl(PPh )] (1 mol%)/dppe (1.1
3
mol%) catalyst system together with Al(OTf) (10 mol%) as an additive that they found to be
3
crucial for amine selectivity. They also found that benzaldehyde could be reductively
aminated using the same catalyst system, employing H (g) (40 bar) as reductant and NH (g)
2
3
(4 bar) as an amine source, giving rise to excellent alcohol:amine selectivity (1:95). They
found that the more electron donating ancillary phosphines decreases the activity of the
resultant Ru(II) complexes, leading to lower substrate conversions. Additionally, they also
observed lowering of alcohol:amine selectivities as the bite angle of the ancillary
diphosphines employed increased. For example, when 1,2-bis(diphenyl)phosphinobenzene (a
ligand closest to our P,O-chelating phosphine) were employed, the selectivity in the
conversion of acetophenone decreased to 1:11 (as compared to their usual 1:99). This drastic
lowering of selectivity could be indicative of induced ligand strain and/or a degree of steric
9

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bulk which in turn limits substrate coordination, and lowers amination activity. Interestingly,
amendment of our protocol to employ H (g) (30 bar) and a methanolic ammonia solution
2
(excess) lead to a slightly lower conversion (92%, entry 1), albeit with a higher alcohol:amine
ratio (1:2) (Supporting Information). The presence of H (g) as opposed to NaBH appears to
2
4
aid in the transfer hydrogenation step to form benzaldehyde, which in turns facilitates the
hydrogenation of the in situ formed imines.
Table 2: Reductive amination of aldehydes with 4
Conv.
Selectivity (%)
Amine
Entry
Aldehyde
(%)
Alcohol
Other
a
1
99
a
a
0
9
8
1
9
9
b
2
3
4
5
(
92 )
b
b
b
6
(20 )
3
7 (24 )
57 (48 )
98
0
0
4
7
9
53
100
100
51
4
c
d
e
2
7
35
38
2
2
2
2
2
50
51
52
53
54
General reaction conditions: aldehyde (0.6 mmol), 4 (1 mol%), NaBH (0.6 mmol),
4
a
NH OOCCH (6 mmol), NH OH (0.3 mmol), EtOH (10 mL), 90°C, 24 hours. Absence of 4,
4
3
4
b
c
but with added NaBH . H (g) (30 bar), NH (2M in MeOH). Bis-alcohol product, ethylene
4
2
3
d
e
glycol. Bis-aminated product, ethylene diamine. Partially aminated product, ethanolamine.
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2
2
2
2
2
2
2
2
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2
2
2
2
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Changes in the electronic and steric substrate environment only slightly affected the
conversions, however, slightly lower alcohol:amine chemoselectivities were observed. The
electron withdrawing 4-NO -benzaldehyde and the less bulky propionaldehyde were gave
2
poor amine to alcohol selectivity (~1:1, entries 3,4). Complex 4 exhibited better stability in
solution, allowing for easier substrate coordination through its hemilabile P,O-metallacycle
ammine ligand system. However, it appears with the more electron-withdrawing substrates,
electron density is perturbed with less stability within the resulting substrate-adduct Ru(II)-
species, leading to catalytically non-active Ru(II)-species. The dialdehyde, glyoxal, were
similarly reductively aminated to give an additional product, the partially aminated
ethanolamine (entry 5). Complex 4 also appears to aid in the reduction of the bis-aldehyde
functionality to give ethylene glycol as an intermediate, followed by the less effective
amination reaction, to give a mono-aminated adduct as main product.
1
3.3
H-NMR study
1
The course of the reductive amination of benzaldehyde was evaluated using H-NMR taken
over a 24 hour period, in order to gain more insight on the intermediate species formed
during the reaction. At time = 0 min (1 in Figure (a)), two signals are observed at δ = 9.1 ppm
(aldehyde) and 7.1 (imine) (Figure 3(a)). Immediate imine formation is expected with high
concentrations of the carbonyl moiety in an ammonia-saturated solution prior to reduction.
Upon addition of NaBH , an (expected) immediate decrease in concentration of the aldehyde
4
is observed, along with an associated increase in corresponding alcohol concentration, and a
decrease in imine concentration (Figure 3(b)). At time = 80 min (4 in Figure (a)), Ru(II)-
catalyzed transfer hydrogenation of the formed alcohol is evident through a decreasing
concentration of the alcohol, and increasing concentrations of the ketone, imine, and amine.
The continued formation of the amine, and low, but noticeable concentrations of the ketone
and imine throughout the course of the reaction is evident of the latter two species acting as
the intermediate species. The absence of acetaldehyde (from the transfer hydrogenation of
ethanol) and ethanamine, follows from the energetically unfavorable transformation of
ethanol (as opposed to the also present benzyl alcohol), into the ketone, followed by the
imine, and finally the amine. This is in accordance with the classical Ru(II)-mediated
reductive amination mechanism proposed [32-34], whereby relatively slowly formed ketone,
is followed by fast imine formation, and even faster reduction to the amine species. In
addition, similar to what Pingen et al. [32] found, under these reaction conditions the
reversible formation of the secondary imine is limited due to the higher nucleophilicity of the
1
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92
93
formed primary amine, and as a result no secondary amine products were observed. The
catalytic transformation of the benzyl alcohol species continues over the period of 24 hours to
1
yield an eventual H-NMR yield of 54% benzylamine.
1
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
94
95
96
97
98
99
00
01
02
03
04
05
06
07
08
09
10
11
12
13
Figure 3: (a) Time-resolved H-NMR of the reductive amination of benzaldehyde; (b)
Corresponding conversion of the reactant and intermediate species involved.
From time = 600 min (8 in Figure (a)) onwards, a gradual decrease in catalyst efficiency is
observed through gradual downturn of amine formation and alcohol consumption. Hofmann
et al. [33] observed a moderate inhibitory effect of the amine product on the reaction rate,
which helps explain the slow, but gradual alcohol transformation. Furthermore, eventual
catalyst decomposition and/or poisoning due to the harsh reducing environment during
reaction are also not excluded. If, however, NaBH is excluded from the reaction, and benzyl
4
alcohol is employed as the reduced form of the substrate, an interesting distribution of
products is observed (Figure 4). The transfer hydrogenation activity of 4 is better
demonstrated with 14% of the alcohol oxidized to benzaldehyde, along with concomitant
1
imine formation (19%). These two species are hardly observed during the H-NMR time-
resolved study, and is reasoned to be less efficiently hydrogenated due to the absence of
NaBH and lower benzyl alcohol concentration. Overall, the absence of NaBH had a minor
4
4
inhibitory effect on amine formation leading to a lower yield of benzyl amine (starting from
benzyl alcohol), but with a higher alcohol:amine selectivity (1:2.2).
1
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Figure 4: Amination of alcohols with NH . General reaction conditions: benzyl alcohol (0.6
3
mmol), 4 (1 mol%), NH OOCCH (6 mmol), NH OH (0.3 mmol), EtOH (10 mL), 90°C, 24
4
3
4
hours.
3.3
Mechanistic considerations
We are in agreement with the thorough experimental and computational findings of Schaub et
al. [34, 35] with respect to the need to include cationic Ru(II) species as the catalytically
active species in the reductive amination transformation. However, for our catalytic system,
we have adapted their mechanism to include neutral Ru(II)-P,O(H) metallacycles bearing a
hydride ligand as the catalytically active species (Figure 5). This mechanism is based on
1
31
experimental ( H- and P-NMR, see Supplementary Information) evidence for partial
conversion of the Ru-P,O bound metallacycle to Ru-P-OH species, along with concomitant
hydride formation. This is inherent of the presence of both cationic and neutral Ru(II)-
hydride species in the reaction mixture.
3
3
30
31
Figure 5: Neutral Ru(II)-hydride alcohol amination mechanism.
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In agreement with both our experimental observations and those of Schaub et al. [34], the
+
active hydride species are formed via protonolysis with NH4 species. This leads to a
coordinatively unsaturated Ru(II) species bearing a hydride, one chelating P,O- phoshine, and
another monodentate (protonated) P-OH ligand. Similar to the common reductive amination
mechanism, a molecule of aldehyde reacts with ammonia to for the corresponding imine,
which coordinates side-on to the 5-coordinate Ru species. Imine reduction via hydride
transfer, followed by coordination of a molecule of alcohol leads to the neutral octahedral Ru
complex bearing a coordinated amine moiety. Cleavage of the α-agostic hydride interaction
of the newly formed Ru-amide species has been proven to be the rate-determining step [34].
Subsequent dissociation of the formed amine, oxidation of the coordinated alcohol to the
corresponding aldehyde via hydride transfer, leads to a neutral octahedral Ru-H complex with
the aldehyde side-bound. Dissociation of the aldehyde and subsequent association of a new
imine molecule completes the cycle. A similar mechanism also exists for cationic Ru species
present, which essentially leads to the same organic products, albeit with possible differences
in the rate-determining step, stability of all the cationic species involved, as well as the
overall efficiency of the transformation.
4. Conclusion
The two novel complexes [RuH{PPh (2-OMeC H )} ]BPh
(3) and trans-
2
6
4
2
4
[Ru(NH ) {PPh (2-OC H )} ] (4) were synthesised from the previously reported complexes
3
2
2
6
4
2
[RuH(1,5-cod)(NH NMe ) ]BPh and [RuCl(1,5-cod)(NH ) (NH NMe )]BPh respectively.
2
2 3
4
3 2
2
2
4
Ligand-assisted bis-demethylation occurs in the reaction mixture of 4 to yield the bis-
ammine, bis-oxo containing ruthenacycles. Complexes 3 and 4 exhibits poor transfer
hydrogenation (and subsequent amination) activity with aryl ketones, while in contrast
performs better (in both transfer hydrogenation and reductive amination) when using aryl
aldehydes. A decent chemoselectivity was observed between ketones and aldehydes, and is
mainly ascribed to associated steric effects, and overall reactivity of aldehydes versus
ketones. The higher overall catalytic activity of 4 (as compared to 3) was attributed to the
higher solution stability of 4, the efficient hemi-labile P,O ligand system, as well as the
presence of the bis-ammine moieties that aided in additional provision of free NH to the
3
catalytic cycle involved.
Acknowledgements
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This work was financially supported by the National Research Foundation of South Africa
(Grant specific unique reference number (UID) 85386), and the New Generation Scholarship
(NGS) of the University of Johannesburg (UJ). Shimadzu South Africa is also acknowledged
for use of their equipment.
Appendix A. Supplementary Information
CCDC numbers 1425248 (4) and 1485450 (benzylaminium cyclohexanoate, Supplementary
Information) contains the supplementary crystallographic data, which can be accessed from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data to this article can be found in the online version.
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Highlights
•
•
•
•
Two novel cationic and neutral chelating phosphine Ru(II) complexes are reported.
X-ray structure of the novel bis-ammine Ru(II) complex reported.
High reductive amination activity for aldehydes.
1
H-NMR study and mechanistic considerations discussed.