Tunable dehydrogenative amidation versus amination using a single ruthenium-NHC catalyst

Article abstract of DOI:10.1021/acscatal.5b00588

Mixed N-heterocyclic carbene (NHC)/phosphine complexes of the type [RuCl(p-cymene)(bimy)(PPh₃)]- PF₆ (bimy = benzimidazolin-2-ylidene) have been synthesized and fully characterized. Complex 1 bearing the 1,3-dibenzylbenzimidazolin-2-ylidene ligand is able to selectively catalyze both dehydrogenative amidation, mono-, and diamination (N-alkylation) through coupling of simple alcohols with amines effectively yielding a range of amides and secondary and tertiary amines. Selectivity is achieved by controlling the fate of the common hemiaminal intermediate, which in turn can be simply influenced by the choice of base and solvent.

Full text of DOI:10.1021/acscatal.5b00588

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Article
Tunable Dehydrogenative Amidation versus
Amination using a single Ruthenium-NHC Catalyst
Xiaoke Xie, and Han Vinh Huynh
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b00588 • Publication Date (Web): 28 May 2015
Downloaded from http://pubs.acs.org on May 29, 2015
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Tunable Dehydrogenative Amidation versus
Amination using a single RutheniumꢀNHC
Catalyst
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Xiaoke Xie and Han Vinh Huynh*
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543, Republic of Singapore
ABSTRACT: Mixed NHC/phosphine complexes of the type [RuCl(pꢀ
cymene)(bimy)(PPh3)]PF6 (bimy = benzimidazolinꢀ2ꢀylidene) have been synthesized and
fully characterized. Complex 1 bearing the 1,3ꢀdibenzylbenzimidazolinꢀ2ꢀylidene ligand
is able to selectively catalyze both dehydrogenative amidation, monoꢀ and diꢀamination
(Nꢀalkylation) through coupling of simple alcohols with amines effectively yielding a
range of amides, secondary and tertiary amines. Selectivity is achieved by controlling the
fate of the common hemiaminal intermediate, which in turn can be simply influenced by
the choice of base and solvent.
KEYWORDS: acceptorless dehydrogenation, borrowing hydrogen, ruthenium, Nꢀ
heterocyclic carbene (NHC), hemiaminal, selectivity
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Introduction
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The transition metal catalyzed dehydrogenation of alcohols followed by further
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nucleophilic functionalizations has attracted much attention.
By using these
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methodologies, amides and amines, which play very important roles in organic chemistry,
pharmaceutical chemistry and biochemistry,2,3 can be directly synthesized from readily
available alcohols and amines. These transformations are not only atom economical, but
also environmentally benign eliminating only nonꢀpolluting hydrogen gas or water as the
sole byproducts. The research on acceptorless dehydrogenation (AD)ꢀtype amidation has
been pioneered by the group of Milstein, who used a dearomatized RuꢀPNN pincer
complex as catalyst.4 Amides, peptides and polyamides can be synthesized in excellent
yields with low catalyst loading.5 Thereafter, many effective catalytic systems based on
ruthenium have been developed.6 Those ligated by Nꢀheterocyclic carbenes (NHCs) have
proven to be especially potent for this process.7,8
On the other hand, the amination of alcohols can be realized by the “borrowing
hydrogen” approach, in which rutheniumꢀ or iridiumꢀbased catalytic systems are usually
involved. 9 , 10 After Fujita and coworkers explored such amination catalyzed by
[Cp*IrCl2]2,11 many successful examples have been reported by other researchers using
iridiumꢀbased systems. 12 Meanwhile, rutheniumꢀcatalyzed amination has also been
developed with either in situ generated or well defined catalysts.13 In particular, great
contributions have been made by Williams,14 and Beller et al.15
According to previous studies, the relationship between ADꢀtype amidation and the
borrowing hydrogen process is proposed to be mechanistically quite close.6a, 16 Both
transformations go through a hemiaminal A that is formed from the initial addition of an
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amine to an aldehyde. Oxidative release of dihydrogen from the hemiaminal generates
amide B. If the hemiaminal eliminates water, and the intermediate imine is further
reduced by the “liberated” or “borrowed” dihydrogen, an amine C is obtained as the
product (Scheme 1). Additionally, a doubly alkylated product D can form if the
secondary amine C reacts with excess alcohol via a second similar process.17
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Scheme 1. Proposed pathways for amidation and amination of alcohols
Although the hemiaminal is the intermediate in the catalytic cycle of both
transformations, its subsequent different (redox) reactions, from which either the amide
or the amine is obtained, have only been affected by using very different catalytic
systems so far.14,18 Good selectivity for both types of products with a single wellꢀdefined
catalyst under baseꢀcontrolled condition is quite challenging, and to the best of our
knowledge, has not been reported yet. Crabtree and coworkers have reported the
possibility that amidation versus amination could be selectively affected by using baseꢀ
controlled conditions. Nevertheless, product control in the actual study was not
satisfactory, as various conditions only favored amide formation.16a Herein, we report our
studies on a baseꢀcontrolled chemoselective dehydrogenative amidation and amination by
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the activation of alcohols with amines catalyzed by a single wellꢀdefined, cationic
benzimidazolinꢀ2ꢀylidene ruthenium complex. The subsequent reactions of the
hemiaminal are tunable, and thus a wide range of amides, secondary and tertiary amines
have been synthesized effectively.
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Results and discussion
Synthesis and characterization of well-defined mixed NHC/phosphine
ruthenium complexes. Previous studies indicated that the presence of both NHC and
phosphine ligands are beneficial in the rutheniumꢀcatalyzed activation of alcohols and
their subsequent reactions with amines.7a–c,8a–c However, wellꢀdefined and structurally
characterized ruthenium complexes bearing a mixed NHC/phosphine donor set have
rarely been studied. Therefore, complexes [RuCl(pꢀcymene)(Bn2ꢀbimy)(PPh3)]PF6 (1)
and [RuCl(pꢀcymene)(iPr,Bnꢀbimy)(PPh3)]PF6 (2) were prepared by treating the
previously reported neutral [RuCl2(pꢀcymene)(bimy)] complexes I and II with PPh3 and
KPF6 in acetone (Scheme 2).19 Chlorido displacement afforded the desired complexes 1
and 2 as yellow solids in good yields (the yield is 97% for complex 1 and 94% for
complex 2 based on 1 mmol of the starting material). The formation of
bis(triphenylphosphine)ruthenium complexes was not observed for both cases, even when
I and II were reacted with two equivalents or excess of PPh3 and KPF6. This can be
explained by the bulkiness of the PPh3 ligand that prevents the coordination of a second
phosphine to the ruthenium(II) center as well as the unfavorable buildꢀup of positive
charge in the hypothetical product. Complexes 1 and 2 are soluble in polar, aprotic
solvents such as DMSO and DMF, sparingly soluble in CH3CN, MeOH and acetone, but
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virtually insoluble in nonpolar solvents including diethyl ether, hexane, and toluene. In
the 1H NMR spectra of both complexes, four doublets for the four aromatic protons in the
pꢀcymene ligand are detected from 4.5–5.5 ppm, indicating their asymmetry after
introduction of the phosphine ligand.20 In their 13C NMR spectra, the carbene carbon
atoms resonate as doublets due to coupling with phosphorus centered at 187.3 and 185.7
ppm for complexes 1 and 2, respectively, which are shifted to higher field by ~4 ppm
compared to those in their precursors I and II. This observation is also indicative of a
greater Lewis acidity of the metal centers as a consequence of the positive charge.
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Scheme 2. Synthesis of Ru-NHC complexes 1 and 2
Single crystals of the cationic RuIIꢀNHC complexes 1 and 2 suitable for Xꢀray
diffraction analyses were obtained by slow evaporation of their concentrated solutions in
CH2Cl2/hexane. The pianoꢀstool geometry is observed for each complex, and their
molecular structures are depicted in figure 1. The pꢀcymene represents the “seat”, and the
chlorido, triphenylphosphine and NHC ligands form the three “legs”. Complex 1
crystallizes in the triclinic crystal system in the P1 space group, while a monoclinic
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crystal system in the Cc space group was found for complex 2. Although both complexes
are chiralꢀatꢀmetal, they expectedly crystalized in racemic forms due to the lack of chiral
induction.
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Fig. 1. ORTEP diagram of the cations of complexes 1 and 2 with thermal ellipsoids
shown at 50% probability level. Hydrogen atoms are omitted for clarity. Selected bond
lengths [Å] and bond angles [deg] for complex 1: Ru1ꢀC1 2.076(4), Ru1ꢀP1 2.3860(10),
Ru1ꢀCl1 2.3828(9); C1ꢀRu1ꢀP1 92.95(10), C1ꢀRu1ꢀCl1 87.89(10). Complex 2: Ru1ꢀC1
2.091(5), Ru1ꢀP1 2.3812(13), Ru1ꢀCl1 2.4138(12); Cl1ꢀRu1ꢀP1 82.28(3), C1ꢀRu1ꢀCl1
92.72(13).
In the molecular structures, the two Nꢀsubstituents are pointing away from the
ruthenium center due to steric repulsion from the triphenylphosphine ligand. The two
benzyl substituents in complex 1 are arranged in an anti arrangement with respect to the
benzimidazolinylidene plane. The Ru–Ccarbene bond lengths of complexes 1 and 2
averaging to 2.083 Å are identical within 3σ. The same was observed for the Ru–P bonds
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with a mean value of 2.3836 Å. However, the Ru–Cl distance of 2.3828(9) Å in complex
1 is slightly shorter than that in the complex 2 {2.4138(12) Å}, making the former
ruthenium center sterically more congested.
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Catalytic Studies
Selective Amidation. With complexes 1 and 2 in hand, we initially studied their
suitability in the rutheniumꢀcatalyzed amidation. In addition, the neutral and phosphineꢀ
free dichlorido complexes I–III were included as well for comparison of in situ generated
catalysts by addition of phosphine into the catalytic mixture. The coupling of 4ꢀ
methoxybenzyl alcohol (3) with benzylamine (4) in toluene under reflux at 125 °C (oil
bath temperature) to afford Nꢀbenzylꢀ4ꢀmethoxybenzamide (5) was chosen as the
benchmark reaction (Table 1). First, the influence of the base was examined in the
presence of complex 1 (entries 1–9). It was found that the desired amide 5 was not
formed under the baseꢀfree condition (entry 1), and only a trace of the Nꢀbenzylꢀ1ꢀ(4ꢀ
methoxyphenyl)methanamine (6) was observed as a monoꢀalkylation product of
benzylamine. Notably, a significant amount of Nꢀbenzylꢀ1ꢀphenylmethanimine was also
observed, indicating that the homocoupling between two molecules of benzylamine had
occurred.21 With the weak bases NaHCO3 and Na2CO3 no improvements in the yields of
5 and 6 were noted, although imine formation was reduced (entries 2 and 3). The use of
stronger bases led to a substantial increase in yields of amide 5 without the formation of 6
(entries 4–7). A particularly high yield of 91% was obtained with NaH (entry 8), which
could be further improved to 95% by increasing its amount to 30 mol% (entry 9).
Notably, no additional hydrogen acceptor is required in this catalytic system.
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Table 1. Catalyst Screening and optimization for the selective amidationa
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Entry
1f,g
2f,g
3f,g
4
5
6
7
8
Complex
1
1
1
1
1
1
1
Base
ꢀ
5 [%]b
N.D.
N.D.
N.D.
85
62
83
69
6 [%]b
Trace
Trace
4
N.D.
N.D.
N.D.
N.D.
N.D.
N.D.
ꢀ
NaHCO3
Na2CO3
NaOH
Cs2CO3
KOH
tꢀBuOK
NaH
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1
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NaHd
NaHd
NaHd
NaHd
NaHd
95/92e
88e
10
11c
12c
13c
I + PPh3
II + PPh3
III + PPh3
81e
ꢀ
ꢀ
ꢀ
79e
82e
a Benzylamine (0.2 mmol), 4ꢀmethoxybenzyl alcohol (0.24 mmol), Ru catalyst (5 mol%), base (20 mol%),
b
125 °C. Yields were determined by GC using hexadecane as the internal standard for an average of two
c
e
runs. 5 mol% of PPh3 were added. d 30 mol% of NaH was added. Isolated yield for an average of two
f
g
runs. NꢀBenzylꢀ1ꢀ(4ꢀmethoxyphenyl)methanimine was detected. NꢀBenzylꢀ1ꢀphenylmethanimine was
detected. N.D. = Not detected.
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Under these conditions, complex 2 was also found to be catalytically active. However,
its performance was slightly lower compared to that of complex 1. The activities of the in
situ generated catalysts similar to 1 and 2 have also been examined by mixing complexes
I–III with equimolar amounts of PPh3 (entries 11–13), but all were found to be less
reactive compared to complex 1.
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Using the optimized conditions, we investigated the substrate scope for the selective
amidation via acceptorless dehydrogenation of alcohols, and the results are summarized
in Table 2. The reaction between benzylic alcohols and benzylamine gave good to
excellent yields (5, 8 and 9). However, electron deficient benzylic alcohols gave a
slightly lower yield of the product (9). Aliphatic or heterocyclic alcohols react with
benzylamine to give the corresponding amides in medium to good yields (products 10ꢀ
13). Notably, there is a drop in yield with increasing length of the alkyl chain. Furyl
alcohol gave only moderate yield, which however, could be significantly improved by
using higher temperatures. Thus, Nꢀbenzylꢀ2ꢀfuramide 13 was isolated in 86% yield by
heating the reactants in pꢀxylene at 150 °C under reflux. Furthermore, the reactions
between benzylalcohol and various cyclic and acyclic amines were examined; the
products 14–18 were generally formed in good yields. It is worth noting that complex 1 is
also applicable in the synthesis of the more challenging sterically hindered amides.
Compound 16 was synthesized in 64% yield from αꢀmethyl benzylamine, while the bulky
tertiary and heterocyclic amides 17 and 18 can also be obtained in good yields at elevated
temperatures. The performance of catalyst 1 in most of the reactions, especially those
giving hindered and bulky amides, compares well to other wellꢀdefined or in situ
generated ruthenium complexes with phosphine ligands.7a,8a,8cꢀe However, the latter
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usually require more elaborate and expensive phosphine ligands (e.g. PCyp3·HBF4) or
bases (e.g. KOtBu).
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Table 2. Substrate scope for the selective amidation b
a R1CH2OH (0.24 mmol), R2NH2 (0.2 mmol), complex 1 (5 mol%), NaH (30 mol%). Isolated yields are
b
c
given for an average of two runs. The yield of the reaction carried out in pꢀxylene at 150 °C are given in
parenthesis.
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Selective mono-alkylation of amines. Having identified complex 1 as the superior
catalyst and the optimal conditions for the preparation of various amides, we further
explored possibilities of varying the conditions for the selective preparation of Nꢀbenzylꢀ
1ꢀ(4ꢀmethoxyphenyl)methanamine (6) from 4ꢀmethoxybenzyl alcohol (3) with
benzylamine (4) using the same catalyst. This reaction may be challenging, since the
formed secondary amine 6, due to its stronger nucleophilicity, could compete with
substrate 4 in the coupling with the alcohol 3, which would afford the doubly alkylated
tertiary amine 7. It has been reported that the addition of weaker bases favors the imine
formation in RuꢀNHC catalyzed reactions.22 Therefore, our experiments were carried out
or with a weak base or without any base. Furthermore, in order to facilitate the hydrogen
transfer process required for this process, all reactions were performed under a solventꢀ
free environment (Table 3).
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Table 3. Optimization for the synthesis of 6 by selective mono-alkylationa
Entry
Base
Temp (°C)
120
Time (h)
6 [%]b
45
7 [%]b
trace
trace
trace
< 5
1
2
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ꢀ
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Na2CO3
NaHCO3
NaHCO3
NaHCO3
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NaHCO3
NaHCO3
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< 5
70c
tracec
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9
b
aBenzylamine (1 mmol), 4ꢀmethoxybenzyl alcohol (1.2 mmol), complex 1 (5 mol%), base (20 mol%).
c
Isolated yields in an average of two runs. 2 mmol of benzylamine and 2.4 mmol of 4ꢀmethoxybenzyl
alcohol was used. The reaction was performed in a Schlenk tube connected to an oil bubbler.
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At 120 °C and without additional base, the desired amine 6 was obtained in a moderate
yield of 45% after 24 h together with some trace amounts of the tertiary amine 7 resulting
from double alkylation (entry 1). In the presence of Na2CO3 and NaHCO3, the yield of
amine 6 increased to 49% and 68%, respectively (entries 2 and 3). Stepwise increase of
the temperature also led to an enhancement of the catalytic performance (entries 4ꢀ5)
with the highest yield of 81% being obtained at 130 °C. On the other hand, shortening of
the reaction time to 18 h led to a slight drop in yield (entry 6). It is noteworthy, that the
aforementioned competing formation of 7 could be successfully suppressed by using
catalyst 1 under the given conditions. Overall, less than 5% of 7 was determined in all
entries. Lastly, the reaction was also performed in an open system with 2 mmol of the
amine and 2.4 mmol of the alcohol. After 24 hours, compound 6 was obtained in a good
yield of 70% (entry 7), which is only slightly lower than that obtained in a closed system
(entry 5). This observation excludes the possibility that the imine was reduced by the
released dihydrogen gas.
The general applicability of the selective amination protocol catalyzed by 1 was tested
for a range of other alcohols and amines (Table 4). In the presence of NaHCO3, benzylic,
aliphatic alcohols can be activated by complex 1 and further couple with benzylamine to
give compounds 6 and 19–21 in moderate to good yields.
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Table 4. Substrate scope for the mono-alkylation of primary and cyclic aminesa,b
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a R1CH2OH (1.2 mmol), R2NH2 (1.0 mmol), complex 1 (5 mol%), NaHCO3 (20 mol%), the reaction was
carried out in a closed vial. b Isolated yields are given in an average of two runs. c The reaction was carried
out for 48h.
Aniline derivatives also underwent smooth alkylations with various alcohols to generate
the corresponding amines in decent yields (22–23 and 25–26). However, product 24
could only be obtained in 20% yield from 1ꢀphenyl ethanol and aniline despite heating
the reaction mixture in pꢀxylene under reflux. Here, significant amount of unreacted
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aniline was observed. The alkylation between the hindered amines and benzylalcohol also
proceeds well yielding 69% of 27. The cyclic tertiary amine 28 was obtained in 73%
yield from a cyclic secondary amine. Finally, 2ꢀaminopyridine was alkylated with octanol
to give Nꢀheterocyclic amine 29 in 77% yield.
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Selective di-alkylation of amines. The selective preparation of tertiary amines from low
cost alcohols and primary amines is also desirable. Therefore, a process involving the
double alkylation of benzylamine with two equivalents of 4ꢀmethoxybenzyl alcohol to
yield tertiary amine 7 by using complex 1 was also sought. Since formation of the tertiary
amine under the monoꢀalkylation conditions described above was insignificant (vide
supra), stoichiometry control and possibly harsher conditions could be applied to drive
this transformation (Table 5).
Table 5. Optimization for the synthesis of 7 by selective di-alkylationa
Entry
n
Temp (°C)
130
130
140
140
Time (h)
6 (%)b
61
39
31
23
7 (%)b
30
56
65
71
1
2.1
2.1
2.1
5.0
5.0
5.0
24
24
24
24
48
48
2c
3c
4c
5c
6
140
140
14
78
9c
71c
a Benzylamine (0.5 mmol), complex 1 (5 mol%), NaHCO3 (20 mol%), the reaction was carried out in a
b
c
c
closed vial Isolated yields in an average of two runs. 250 mg of molecular sieves (4 Å) was added. 1
mmol of benzylamine and 5 mmol of 4ꢀmethoxybenzyl alcohol was used. The reaction was performed in a
Schlenk tube connected to an oil bubbler.
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Thus, benzylamine (3) was reacted with 2.1 equivalents of 4 at 130 °C in a closed vial,
which generated 6 in 61% yield, but also 30% of the tertiary amine 7 (entry 1). The yield
of 7 increased to 56% by adding molecular sieves (4 Å) to absorb water as the formal
condensation product in this reaction (entry 2). Further improvement was realized by
raising the temperature to 140 °C. Finally, a better ratio of 7 to 6 could be realized by
increasing the excess of alcohol 3 to five equivalents. Under these improved conditions, 7
could be isolated in 78% yield accompanied by 14% of intermediate 6. In addition, a
similar yield of 7 was obtained by conducting the reaction in an open system (71%, entry
6).
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Using these final conditions, the generality of the double alkylation of amines catalyzed
by complex 1 was demonstrated by the syntheses of various acyclic tertiary amines
depicted in Table 6. In general, all tertiary amines were isolated in good yields.
Benzylamine was reacted with 4ꢀmethoxybenzyl alcohol or benzyl alcohol to give the
tertiary amines 7 and 31 in yields of 78% and 91%, respectively. Aniline is doubly
alkylated with benzyl alcohol in 62% yield to give compound 32. Substituents on the
aromatic rings are tolerated in this protocol, and the transformations of substituted
anilines and alcohols gave the respective products 33–36 in decent yields, regardless of
the electronic nature of the substituents. In addition, the aliphatic 1ꢀphenyl ethanol can be
employed for a smooth diꢀalkylation of substituted aniline to give compound 36 in 70%
yield. Overall, various tertiary amines were obtained from substituted primary alcohols
and primary amines in good to excellent yields via this simple methodology compared to
only a few previously reported examples with limited substrate scope.23
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Table 6. Scope of the selective di-alkylation of aminesa
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a R1CH2OH (2.5 mmol), R2NH2 (0.5 mmol), complex 1 (5 mol%), NaHCO3 (20 mol%), molecular sieves (4
Å) 250 mg, the reaction was carried out in a closed vial. bIsolated yields are given in an average of two
runs.
Mechanistic proposal. In order to gain better mechanistic insights into the fate of the
ruthenium catalysts precursor, additional solution NMR experiments were carried out to
identify possible intermediates in both amidation and amination processes. The reaction
between 4ꢀmethoxyl benzyl alcohol 3 (0.6 mmol) and benzyl amine 4 (0.5 mmol) was
selected for these studies (see ESI).
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The amidation reaction was carried out in a NMR tube charged with substrates,
complex 1 (0.2 mmol, 20% mol%), NaH (0.36 mmol, 60 mol%) and tolueneꢀd8,
Substoichiometric 1 and base were used in order to obtain higher signalꢀtoꢀnoise ratio in
the spectra. The NMR tube was then immersed in a preꢀheated oil bath at 110 °C for a
certain amount of time before it was cooled down to room temperature. The sample was
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1
then directly analyzed by H NMR spectroscopy. It was found that after 10 min of
heating, 95% of the pꢀcymene had dissociated (with 1,3,5ꢀtrimethoxybenzene as an
internal standard), indicating that the pꢀcymene complexes are not involved in the
catalytic cycle. This is in line with Madsen’s previous report.8b Some hydrido signals
were detected in the range from ꢀ6 ppm to ꢀ14 ppm from another sample, which had been
heated for 1 hour. In particular, a high intensity doublet at – 9.73 ppm is indicative for the
existence of [RuH(PPh3)] species, while the heteronuclear coupling constant of 2J(P,H) =
50 Hz suggests a cis arrangement between triphenylphosphine and hydrido ligand.
31
Furthermore, the P NMR spectrum shows that the initial resonance of the coordinated
triphenylphosphine in complex 1 at 32.54 ppm has been replaced by several new
downfield signals ranging from 45–72 ppm. This provides additional support for the
formation of the [RuH(PPh3)] species as the downfield shifts are in line with a less Lewis
acidic ruthenium center, probably due to coordination of the hydrido ligand. Moreover,
the NHC was found to be still ligated to the [RuH(PPh3)] species as evidenced by a
diagnostic RuꢀCcarbene doublet centered at 196.1 ppm in 13C NMR spectrum. The coupling
2
constant of J(P,C) = 17 Hz is essentially identical to that found in complex 1, while its
chemical shift is more downfield (cf.187.0 ppm for 1), again due to an additional hydrido
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ligand. Accordingly, a [RuH(NHC)(PPh3)]ꢀtype complex could be the catalytically active
intermediate in the amidation process.
7
8
9
For the study of the amination reaction, a different approach was taken. In order to be
consistent with the catalytic runs, a “neat reaction” was carried out in a in a closed vial at
130 °C for 1 h with the same amounts of substrates, catalyst and base (NaHCO3 was the
base in this case) as for the amidation. Upon cooling to ambient temperature, the mixture
was diluted with tolueneꢀd8 for analysis. Similar to the amidation, 96% of the pꢀcymene
was found in free form. A cis coordinated [RuH(PPh3)] species was also observed in the
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1
amination process by H NMR spectroscopy with a diagnostic hydrido doublet at ꢀ9.77
2
31
ppm with a coupling constant of J(P,H) = 50 Hz. In the P spectrum, a resonance for
free triphenylphosphine was observed at ꢀ6.0 ppm together with multiple downfield
signals ranging from 70–45 ppm. Similarly, the proof for the existence of
[RuH(NHC)(PPh3)] complexes can be found in a carbene resonance at 194.71 ppm with a
2
coupling constant of J(P,H) = 17 Hz. Moreover, there are two more carbene signals at
209.5 and 209.3 ppm, which could be assigned to rutheniumꢀNHC dihydrido complexes
due to the significant downfield shifts. In addition, a singlet at 10.17 ppm was detected by
1H NMR spectroscopy, which could be assigned to either the coordinated aldehyde’s
proton from the oxidized alcohol or from the αꢀproton in the coordinated hemiaminalato
species. Finally, in order to observe the formation of imine, which is an important
intermediate in the amination, another closedꢀvial reaction was carried out at a lower
temperature of 100 °C for 1 h. Indeed, the imine was detected in 41% yield by GC
analysis.
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Based on these observations and pioneering previous studies,4,8bꢀc,13c,16a,18,22 two
competing catalytic cycles for the amidation and the amination are proposed in Scheme 3.
Both cycles are initiated by the dissociation of pꢀcymene and baseꢀassisted coordination
of the alcohol to the ruthenium center (E) followed by its internal oxidation to give the
aldehyde and an active hydrido complex F. The aldehyde undergoes an internal addition
reaction with the primary amine, which gives rise to a protonated hemiaminalato complex
G. The subsequent selectivity for amidation versus amination may be highly dependent
on the Nꢀproton transfer.22
3
4
5
6
7
8
9
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Ph
N
NHC =
Ru
Cl
PPh3
NHC
N
Ph
- NaCl
- p-cymene
NaH or NaHCO3
heat
R1
R1
OH
NHC
NHC
H
R1
H2
LnRu NR2
O
LnRu
R1
NHC
H
NHC
PPh3
H
R1
OH
H
PPh3
LnRu
PPh3
LnRu
O
R1
P
L
NHC
LnRu
PPh3
K
NR2
E
R1
NHR2
R1
OH
O
H
PPh3
R2
R1
N
O
H
R1
NHC
R1
NHR2
NHC
R1
LnRu
O
H
O
H
PPh3
LnRu
N
R2
PPh3
F
NHC
LnRu
J
H
NHR2
H
R1
O
PPh3
NHC
LnRu
NH2R2
H
R1
NHC
N
O
H
PPh3
LnRu
PPh3
NHR2
H
NHR2
H
R1
R1
O
NHC
NHC
LnRu
I
G
O
H
PPh3
H
R1
LnRu
R1
H
HO
-H2O
H2
H
PPh3
N
R2
NH
R2
M
H
Scheme 3. Proposed Catalytic Cycle for the Ru-Catalyzed Amidation and
Amination
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With strong base and in nonꢀpolar solvent, the proton transfers to the hydrido (from G
to H), and the “amide catalytic cycle” is initiated via the release of dihydrogen from the
intermediate H to give the hemiaminalato intermediate I. Subsequent internal redox
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reaction of complex I via
βꢀhydride elimination leads to hydrido complex J. Ligand
substitution with an alcohol releases the amide product and a hydrido complex K is
formed. The latter undergoes intramolecular acidꢀbase reaction to give L, which finally
liberates dihydrogen and closes the catalytic cycle to give alkoxido complex E.
On the other hand, in a less basic environment and protic solvent (alcohol), the proton
transfers to the bound oxygen (from G to M) before the free hemiaminal is liberated. The
hemiaminal immediately loses water to form the imine. Then the imine reꢀenters the
“amine catalytic cycle” under formal insertion into the rutheniumꢀhydrido bond of
intermediate O to give an amido complex P. Intermolecular acidꢀbase reaction of
complex P with an external alcohol molecule releases the amine product and reforms
alkoxide complex E closing the cycle.
Overall, we believe that selectivity in the amidation versus amination can be achieved
by the controlling of the Nꢀproton transfer by choosing different bases and solvents. A
strong base in conjunction with a nonꢀpolar solvent favoring the protonꢀtoꢀhydrido
transfer would lead to amide formation, while a weaker base in a polar system results in
protonꢀtoꢀalkoxido transfer to initiate the amination pathway.
Conclusion
In conclusion, we have reported a tunable amidation and amination of alcohols with
amines catalyzed by a single wellꢀdefined ruthenium NHC complex 1. We propose that
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the amide is formed via the acceptorless dehydrogenation process involving a
hemiaminalato complex, while the “borrowing hydrogen” route is operative for the
amination. The selectivity is likely based on the Nꢀproton transfer, which in turn can be
easily tuned by the choice of base and solvent. The protonꢀtoꢀhydrido transfer leads to the
formation of amides, while the protonꢀtoꢀalkoxido transfer results in the formation of an
imine, which is finally reduced by the ruthenium hydride species to give amines. Various
amides, secondary and tertiary amines can be effectively synthesized using a single
catalyst precursor. This study may shine light on the understanding of dehydrogenative
reactions as well as provide the possibility for the design of catalysts suitable for different
types of reactions. Work is in progress to further optimize catalysts for such purposes, to
extend its application to asymmetric catalysis, as well as to provide a better
understanding of the mechanistic details.
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ACKNOWLEDGMENT
The authors thank the National University of Singapore and “GSKꢀEDB Singapore
Partnership for Green and Sustainable manufacturing” for financial support (WBS R143ꢀ
000ꢀ513ꢀ592). Technical support from staff at the CMMAC of our department is
appreciated. We also than Dr. Abdul Majeed Seayad from the Institute of Chemical and
Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR),
Singapore for helpful discussions.
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Supporting Information Available
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Experimental procedures, characterization data of the products, NMR spectra of products,
crystallographic data and CIF files for complex 1 and 2. This information is available free
of charge via the Internet at http://pubs.acs.org/.
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AUTHOR INFORMATION
Corresponding author
*Eꢀmail: chmhhv@nus.edu.sg.
NOTES
The authors declare no competing financial interest.
ABBREVIATIONS
NHC, NꢀHeterocyclic carbene; AD, acceptorless dehydrogenation; N.D. not detected.
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