Mechanistic investigation of imine formation in ruthenium-catalyzed N-alkylation of amines with alcohols

Article abstract of DOI:10.1002/aoc.4277

Imines are observed frequently in ruthenium-catalyzed N-alkylation of amines with alcohols. Herein, nitrogen–phosphine functionalized carbene ligands were developed and used in ruthenium-catalyzed N-alkylation to explore the mechanism of imine formation. The results showed that strongly electron-donating ligands were beneficial for imine formation and alcohol dehydrogenation to generate acid. In addition, with an increase of electron density of nitrogen atom in substituted amines, the yield of imines in N-alkylation was improved. At the same time, with electron-rich imines as substrates, the transfer hydrogenation of imines became difficult. It is suggested that strongly electron-donating ligands and substrates caused an increase of electron density on the ruthenium center, which resulted in the elimination of hydrogen atoms in active species [LRuH₂] as hydrogen gas rather than transfer onto the imine coordinated with the ruthenium center.

Full text of DOI:10.1002/aoc.4277

Received: 15 October 2017
DOI: 10.1002/aoc.4277
Revised: 19 December 2017
Accepted: 24 December 2017
F U L L P A P E R
Mechanistic investigation of imine formation in ruthenium‐
catalyzed N‐alkylation of amines with alcohols
Xiaojun Yu | Yaqiu Li | Haiyan Fu | Xueli Zheng | Hua Chen | Ruixiang Li
Key Laboratory of Green Chemistry and
Imines are observed frequently in ruthenium‐catalyzed N‐alkylation of amines
Technology, Ministry of Education,
College of Chemistry, Sichuan University,
with alcohols. Herein, nitrogen–phosphine functionalized carbene ligands were
Chengdu 610064, China
developed and used in ruthenium‐catalyzed N‐alkylation to explore the mech-
anism of imine formation. The results showed that strongly electron‐donating
Correspondence
Ruixiang Li, Key Laboratory of Green
ligands were beneficial for imine formation and alcohol dehydrogenation to
Chemistry and Technology, Ministry of
generate acid. In addition, with an increase of electron density of nitrogen atom
Education, College of Chemistry, Sichuan
University, Chengdu, 610064, China.
Email: sculiruixiang@163.com
in substituted amines, the yield of imines in N‐alkylation was improved. At the
same time, with electron‐rich imines as substrates, the transfer hydrogenation
of imines became difficult. It is suggested that strongly electron‐donating
ligands and substrates caused an increase of electron density on the ruthenium
center, which resulted in the elimination of hydrogen atoms in active species
[LRuH2] as hydrogen gas rather than transfer onto the imine coordinated with
the ruthenium center.
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21572137
KEYWORDS
dehydrogenation, imine, N‐alkylation, ruthenium
1 | INTRODUCTION
active species bearing this chelating and hemilabile
ligand.[23] However, imine formation was also observed
in reaction condition screening. Especially, when
alkylamines were used as substrates, imines were
obtained as main products. Similarly, functionalized
carbene in ruthenium‐catalyzed N‐alkylation systems also
led to imines as main products.[13,14,19] Nevertheless, the
reason for imine formation was undefined in the reported
N‐alkylation mechanisms.
In general, transition metal‐catalyzed N‐alkylation
includes inter‐ and intramolecular mechanisms[1,2]
(Figure 2). In the intramolecular mechanism, after an
imine is generated on the active center (D), it does not
depart from the metal center, and it subsequently accepts
hydrogen atoms from the metal center to give a sec‐amine.
In this mechanism, the key point is that the imine does
not depart from the metal center and no imine is detected
at the end of the reaction. In the intermolecular mecha-
nism, after an alcohol molecule is dehydrogenated to form
an aldehyde (B), the aldehyde is immediately eliminated
Transition metal‐catalyzed N‐alkylation is an environ-
mentally friendly method for providing primary, second-
ary and tertiary amines, and thus a plethora of Ru, Ir,
Pd, Co, Pt, Fe and Mn complexes have been developed
and used as catalysts for this reaction.[1–9] Among them,
inexpensive ruthenium complexes show high reactivity
and are widely applied in N‐alkylation of amines with
alcohols.[10–14] However, a ruthenium loading of 5% or
more is usually required to achieve satisfactory yields.
Recently, the catalyst loading has been significantly
reduced (Figure 1) while ruthenium complexes bearing
chelating ligands[15–18] and phosphine‐functionalized
carbene ligands[19–22] have been utilized in N‐alkylation.
Based on these results, a nitrogen–phosphine functional-
ized carbene ligand (L1; Figure 1) was developed and used
in N‐alkylation to achieve excellent conversion of amines
when the catalyst loading was as low as 0.01%. This good
result was attributed to the long lifetime of the catalytic
Appl Organometal Chem. 2018;e4277.
wileyonlinelibrary.com/journal/aoc
Copyright © 2018 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4277

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2 | EXPERIMENTAL
2.1 | General
All reactions were conducted under nitrogen atmosphere
unless otherwise stated, and solvents were subjected to
standard purification methods. Commercial reagents
were purchased from suppliers and used as received.
Moisture‐sensitive compounds were stored and used in a
1
glovebox. H NMR, 13C NMR and 31P NMR spectra were
recorded with a Bruker AVANCE III HD‐400 MHz. GC
analysis was performed with an Agilent 6890 N and
Agilent 6890‐GC/MSD (GC‐MS). High‐resolution MS
was conducted with a Shimadzu LCMS‐IT‐TOF mass
spectrometer. [Ru(COD)Cl2]n and ligand L1 were pre-
pared using reported protocols.[23]
FIGURE 1 Ligands and their complexes for highly efficient N‐
alkylation of amines with alcohols
2.2 | Synthesis of Ligand L2
2.2.1 | Synthesis of 3‐(4‐chlorobutyl)‐1‐
methyl‐1H‐imidazol‐3‐ium chloride (1)
1,4‐Dichlorobutane (10 ml) and 1‐methylimidazole (1 ml,
1.1 g) were added into a two‐necked flask under nitrogen,
and then the mixture was heated to 80 °C with stirring
overnight. At the end of the reaction, the mixture was
cooled to room temperature and excessive reagent was
distilled off to give a sticky solid. The solid was washed
with acetone (2 × 5 ml) and dissolved in 60 ml of acetoni-
trile. The acetonitrile solution was cooled to −20 °C,
whereupon some impurity was formed as a precipitate.
The precipitate was filtered off and the filtrate was evapo-
rated to dryness under reduced pressure to afford a light‐
yellow oil (1.0 g, 36% yield). 1H NMR (400.1 MHz, DMSO‐
d6, δ, ppm): 9.39 (s, 1H), 7.85 (t, 1H, J = 1.6 Hz), 7.78 (t,
1H, J = 1.6 Hz), 4.25 (t, 2H, J = 7.2 Hz), 3.87 (s, 3H),
3.69 (t, 2H, J = 6.4 Hz), 1.91 (m, 2H), 1.71 (m, 2H). 13C
NMR (100.6 MHz, DMSO‐d6, δ, ppm): 137.2, 124.1,
122.7, 48.4, 45.1, 36.2, 29.0, 27.4.
FIGURE 2 Mechanism of transition metal‐catalyzed N‐alkylation
of amines
from the metal center and reacts with an amine to form
an imine. And then the imine combines with metal spe-
cies [LRuH2] (E) and transfer hydrogenation occurs to
give a sec‐amine. For this mechanism, imines are often
observed after the reaction is completed. Therefore, Ru–
L1 mediated N‐alkylation was judged to progress via the
intermolecular mechanism and electronic factors of sub-
strates showed a marked influence on imine forma-
tion.[23] However, to the best of our knowledge, the
detailed mechanism of imine formation has not been pro-
posed for the reported transition metal‐catalyzed N‐
alkylation.
In order to explore the mechanism of imine formation
in N‐alkylation, Ru–L1 promoted N‐alkylation of amines
with alcohols and transfer hydrogenation of imines with
various substituents were conducted in the work reported
here. In addition, an electron‐donating phosphine‐func-
tionalized carbene ligand (L2), having similar chelating
effect and hemilability, was synthesized to investigate
the effect of ligand structure on N‐alkylation. The reaction
results proved that electronic factors were vital for imine
formation in N‐alkylation and the mechanism of imine
formation is proposed.
2.2.2 | Synthesis of 3‐[4‐
(diphenylphosphino)butyl]‐1‐methyl‐1H‐
imidazol‐3‐ium chloride (L2)
Triphenylphosphine (5 mmol, 1.31 g) and lithium
(20 mmol, 0.12 g) were added into a 100 ml two‐necked
flask under nitrogen atmosphere. Then 20 ml of tetrahy-
drofuran (THF) was added with a syringe and the mixture
solution was stirred at room temperature for 5 h. At the
end of the reaction, the unreacted lithium was filtered
off and tert‐butyl chloride (5 mmol, 0.465 g) was added
to the filtrate. The solution was stirred at room tempera-
ture for 30 min, and then an acetonitrile (5 ml) solution

YU ET AL.
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of compound 1 (5.5 mmol, 1.15 g) was added into it in an
ice bath. The resulting mixture was further stirred at room
temperature overnight. After the reaction ended, all sol-
vents were removed under reduced pressure and the
residual solid was added to 10 ml of water. The aqueous
solution was extracted with 30 ml of dichloromethane.
The organic phase was separated, dried over MgSO4 and
filtered. The filtrate was evaporated to ca 5 ml under
reduced pressure and 20 ml of ether was added to form
an oil product. The product was separated, washed with
ether (2 × 10 ml) and dried under vacuum to afford a pale
yellow viscous liquid (0.56 g, 31% yield). 1H NMR
(400.1 MHz, DMSO‐d6, δ, ppm): 9.28 (s, 1H), 7.77 (s,
1H), 7.72 (s, 1H), 7.3–7.5 (m, 10H), 4.19 (t, 2H, J =
7.2 Hz), 3.84 (s, 3H), 2.12 (m, 2H), 1.91 (m, 2H), 1.31 (m,
2H). 13C NMR (100.6 MHz, DMSO‐d6, δ, ppm): 138.7 (d,
J = 13.3 Hz), 137.1, 132.8 (d, J = 18.4 Hz), 129.2, 129.0
(d, J = 6.6 Hz), 124.0, 122.7, 48.6, 36.2, 31.1 (d, J =
13.3 Hz), 26.3 (d, J = 11.1 Hz), 22.5 (d, J = 16.8 Hz). 31P
NMR (161.9 MHz, DMSO‐d6, δ, ppm): −17.8. High‐resolu-
tion MS (ESI‐TOF) m/z: [M − Cl]+; calcd for C20H24N2P
323.1677, found 323.1679.
3 | RESULTS AND DISCUSSION
3.1 | Ligand Synthesis
Ligand L1 was prepared using a reported method.[23]
Ligand L2 was prepared by reacting PPh2Li with com-
pound 1 (Scheme 1), which was formed by reacting 1‐
methylimidazole with 1,4‐dicholobutane in refluxing ace-
tone. L2 was obtained as an oily liquid and was very sen-
sitive to air.
3.2 | Imine Formation in N‐alkylation
With ligands L1 and L2 in hand, we subsequently evalu-
ated the catalytic reactivity of corresponding ruthenium
complexes, formed in situ, for N‐alkylation of benzyl alco-
hol with substituted amines. Firstly, it was found that L1
and L2 led to a marked difference in conversions (95
and 83%, respectively) when the ratio of aniline to benzyl
alcohol was 1:1 (Table 1, entries 1 and 2). At the same
time, the residual benzyl alcohol was not detected in GC
analysis in both samples, so we suggest that some benzyl
alcohol was transformed into other substances in the N‐
alkylation process. Obviously, this result may be attrib-
uted to be structural difference between ligands L2 and
L1. Although ligand L1 contained C, P, P coordination
atoms, the key catalytic species should be κ2‐C,P–Ru com-
plex as two singlets, not doublets, were observed in the 31P
NMR spectrum in situ (Figure S1)[23] and coordination
vacant site was necessary as well in N‐alkylation. More-
over, both diphosphine (dppe) and N‐heterocyclic carbene
(MI) resulted in a worse result (Table 1, entries 11 and 12).
2.3 | Typical Procedure for N‐alkylation
and Transfer Hydrogenation
[Ru(COD)Cl2]n (0.01 mmol Ru, 2.8 mg), ligand L1
(0.01 mmol, 5.6 mg) and KOtBu (1 mmol, 112 mg) were
added into a dried reaction tube in a glovebox. Then,
benzyl alcohol (1 mmol, 108 mg), aniline (1 mmol,
93 mg) and toluene (4 ml) were added into it succes-
sively and the mixture reacted at 100°C under stirring
for 24 h. After the reaction ended, the mixture was
cooled to room temperature and quenched with water
(4 ml). Product was extracted with EtOAc (3 × 5 ml)
and the combined organic phase was washed with satu-
rated saline (3 × 25 ml), dried with MgSO4 and ana-
lyzed using GC and GC‐MS. Further purification was
performed with column chromatography to give the cor-
responding pure product. The procedure for transfer
hydrogenation of imines was the same as for N‐alkyl-
ation, except for imines being used as substrates and
alcohols as hydrogen sources.
These
results
implied
both
carbene
and
biphenylphoshpino moieties of ligand L2 might coordi-
nate with the ruthenium center in N‐alkylation. Hence,
the active Ru intermediate bearing ligand L1 or L2 should
be κ2‐C,P type Ru complex. Compared with the electron‐
rich alkyl linker in ligand L2, ligand L1 containing an
electron‐deficient N‐containing alkyl linker showed a pos-
itive effect on the reaction.
Next, the amount of benzyl alcohol was increased to
2 eq. to exclude the effect of deficient alcohol as the side
reaction of benzyl alcohol occurring. As expected, after
the amount of alcohol was increased to 2 eq. (Table 1,
SCHEME 1 Synthesis of ligand L2

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YU ET AL.
TABLE 1 Effect of ligand and substrate structure on imine formation of N‐alkylationa
Entry
Ligand
Substrate (R)
Time (h)
Conv. (%)
Imine/amine (%)
1
L1/1%
Phenyl‐
24
95
<1:99
2
L2/1%
Phenyl‐
24
24
24
24
24
24
24
6
83
>99
>99
92
<1:99
<1:99
<1:99
>99:1
>99:1
>99:1
83:17
5:95
3b
L1/1%
Phenyl‐
4b
L2/1%
Phenyl‐
5b,c
6b,c
7b,c
8b,c
9b
L1/1%
hexyl‐
L1/1%
Cyclohexyl‐
Dodecyl‐
Benzyl‐
98
L1/1%
77
L1/1%
>99
98
L1/1%
Phenyl‐
10b
11b
12b
13b
14b
15b
16b
17b
L2/1%
Phenyl‐
6
74
24:76
64:36
71:29
62:38
3:97
dppe/1%
MI/2%
No ligand
L1/0.1%
L1/0.1%
L1/0.1%
L1/0.1%
Phenyl‐
6
71
Phenyl‐
6
44
Phenyl‐
6
56
4‐Pyridyl‐
4‐Fluorophenyl‐
Phenyl‐
24
24
24
24
96
96
15:86
19:81
66:34
93
4‐Methoxylphenyl‐
96
aReaction conditions: benzyl alcohol (1 mmol, 108 mg), amine (1 mmol), KOtBu (1 mmol, 112 mg), ligand (0.01 mmol), [Ru(COD)Cl2]n (0.01 mmol, 2.8 mg),
toluene (4 ml), temperature 100 °C, time 24 h. GC and GC‐MS analysis. dppe = 1,2‐bis(diphenylphosphino)ethane; MI = 1,3‐bis(2,4,6‐trimethylphenyl)
imidazolinium chloride.
b2 eq. of benzyl alcohol.
c120°C. Conversion was determined by GC with N‐methylaniline as internal standard.
entries 3 and 4), both Ru–L1 and Ru–L2 catalytic systems
gave excellent conversion (>99%) and selectivity to sec‐
amine (>99%). Interestingly, when the reaction time was
shortened to 6 h, the conversion of aniline and selectivity
to sec‐amine for the Ru–L2 system were lower than those
for the Ru–L1 system (Table 1, entries 9 and 10), which
indicated that an increase of the electron‐donating ability
of the ligand caused a decrease in conversion of aniline
and increase in selectivity of imine.
In addition, the electronic nature of substituents on
aromatic amine also showed a significant influence on
N‐alkylation in the presence of 0.1% Ru–L1 (Table 1,
entries 14–17). With an increase of the electron‐donating
ability of substituents, the selectivity to imines increased,
but the conversions of substrates did not show any signif-
icant change. This suggested that the electronic nature of
substituted aromatic amines only changed the selectivity
to imines. And this result also indicated that the reaction
progressed via the intermolecular mechanism. Moreover,
when benzylamine and alkylamines were utilized as
substrates, the conversions were satisfactory, but
benzylamine only gave 17% sec‐amine and all alkylamines
gave imines as main products (Table 1, entries 5–7). Also,
reacting alkyl alcohols with alkylamines containing O,S
heterocycles gave low yields of products for the same con-
ditions (Table S1). And all arylamines gave excellent
yields of sec‐amines in the presence of ligand L1 when
the reaction time was extended to 48 h.[23] Interestingly,
in the reported transition metal‐catalyzed imine forma-
tion by reacting amines with alcohols,[24,25] the authors
only used alkylamines as substrates rather than
arylamines. Therefore, we suggest that the selectivity to
imines is determined by the electron‐donating ability of
amines and both electron‐rich ligands and amines are
favorable for the formation of imines.
3.3 | Transfer Hydrogenation of Imines
In order to clarify why electron‐rich amines gave imines
as major products and electron‐poor amines gave sec‐
amines as major products, we tried to explore the reason
with transfer hydrogenation of substituted imines as it is
a key step in N‐alkylation according to the intermolecular
mechanism (Figure 2). The results showed that the

YU ET AL.
5 of 7
weakly electron‐donating N‐benzylidenebenzylamine
only gave a low conversion of 34% (Table 2, entry 2).
0.6 eq. of benzoic acid. This result evidenced the dehydro-
genation oxidation of alcohol occurring in the N‐alkyl-
ation, which was further supported by the formation of
ca 1 mmol of hydrogen gas in parallel experiment
(Scheme 2). Therefore, the low conversion of aniline
(Table 1, entry 2) was attributed to the dehydrogenation
oxidation of benzyl alcohol, which caused the consump-
tion of benzyl alcohol and led to deficient alcohol in the
For
the
strongly
electron‐donating
N‐
benzylidenecyclohexylamine, transfer hydrogenation did
not occur (Table 2, entry 4). It is noteworthy that when
10 eq. of iPrOH was used as the hydrogen source, the con-
version of N‐benzylidenebenzylamine increased to 99%
(Table 2, entry 3), but there was still no reaction for N‐
benzylidenecyclohexylamine (Table 2, entry 5). Therefore,
these results further confirmed that the existence of
strongly electron‐donating substituents on nitrogen atom
was beneficial for the formation of imines. Moreover, if
transfer hydrogenation of imines was able to occur, excess
alcohol would be favorable for obtaining sec‐amines in
high yields. In fact, in the presence of sufficient benzyl
alcohol, these substituted anilines (Table 1, entries 14–
17) could undergo N‐alkylation to form sec‐amines in
high yields after the reaction time was extended to
48 h.[23] Consequently, we inferred that the formation of
sec‐amines and imines followed different and competing
routes after the imines were formed by reacting aldehyde
with amines. Meanwhile, the competing result was
mainly determined by the electron‐donating ability of
substituents in different substrates. Obviously, this cata-
lytic system showed a high selectivity to imines with
alkylamines or electron‐rich arylamines as substrates
while sec‐amines were formed with electron‐poor
arylamines as substrates.
N‐alkylation. Interestingly,
a controlled experiment
without addition of N‐benzylenecyclohexylamine
showed the dehydrogenation oxidation of benzyl alcohol
was not obvious. This means that the addition of an
electron‐rich imine accelerated the dehydrogenation oxi-
dation of benzyl alcohol. In fact, it proved that the
dehydrogenation of alcohol would generate the key
intermediate RuLH2 in our previous work.[23] Hence,
the generation of hydrogen gas was ascribed to hydro-
gen elimination from Ru–dihydride intermediate and
hydrogen elimination was promoted by adding an elec-
tron‐rich imine.
3.5 | Mechanism of Imine Formation in N‐
alkylation
According to the intermolecular mechanism of N‐alkyl-
ation[1,2] and our previous results, in which we had con-
firmed the presence of aldehyde, Ru–OR complex (I),
RuH2 intermediate (II) and amine–RuH2 complex (V)
from NMR spectra in situ,[23] it is suggested that as soon
3.4 | Dehydrogenation Oxidation of
Alcohol
In
the
transfer
hydrogenation
of
N‐
benzylenecyclohexylamine, NMR and GC analyses dem-
onstrated that the imine was not hydrogenated, but most
of the benzyl alcohol was consumed. After the resulting
mixture was isolated and purified, we obtained about
SCHEME
dehydrogenation of benzyl alcohol
2
N‐benzylidenecyclohexanamine‐promoted
TABLE 2 Transfer hydrogenation of iminesa
Entry
Substrate (R)
Alcohol
Conv. (%)
1
Phenyl
2 eq. BnOH
>99
2
3
4
5
Benzyl
2 eq. BnOH
34
>99
0
i
Benzyl
10 eq. PrOH
Cylcohexyl
Cylcohexyl
2 eq. BnOH
i
10 eq. PrOH
0
aReaction conditions: imine (1 mmol), KOtBu (1 mmol, 112 mg), ligand L1 (0.01 mmol, 5.6 mg), [Ru(COD)Cl2]n (0.01 mmol, 2.8 mg), toluene (4 ml), reaction
stirred at 100 °C for 24 h under nitrogen. Reaction analyzed using GC.

6 of 7
YU ET AL.
as aldehyde was formed by the dehydrogenation of alco-
hol, it could not only react intermediately with amines
to form imines, but it could also be dehydrogenated to
produce acids as byproducts. At the same time, if an
electron‐poor imine coordinated with active LRuH2 spe-
cies to give the imine–LRuH2 species, the coordinated
imine would easily accept the hydrogen atoms from
Ru–dihydride species to produce corresponding sec‐
amine. If the Ru species bears an electron‐rich ligand
and/or imine, the coordinated imine would with diffi-
culty accept the hydrogen atoms from the ruthenium
center and cause the decomposition of the imine–
LRuH2 species to release hydrogen gas and an imine.
Similarly, when an electron‐rich imine was used in the
transfer hydrogenation, no sec‐amine was detected, with
a lot of hydrogen gas being released. Also, different
ligands exhibited similar electronic effects. In a word,
with an increase of electron‐donating strength of sub-
strates or ligands, the intermediate III was quickly
decomposed.
4 | CONCLUSIONS
Phosphine‐functionalized carbene ligands L1 and L2 were
used to examine imine formation in Ru‐catalyzed N‐alkyl-
ation of alcohols with amines. Electron‐rich alkylamines
produced imines as main products due to decomposition
of imine–RuLH2 species. When arylamines and
benzylamines were used as substrates, competitive trans-
fer hydrogenation of imines and decomposition of
imine–RuLH2 intermediate determined the formation
ratio of imines to sec‐amines. With an increase of elec-
tron‐donating ability of ligands and substrates, the selec-
tivity to imines was improved.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21572137).
ORCID
Therefore, a detailed mechanism of imine formation
in N‐alkylation is proposed, as shown in Figure 3.
(Catalyst activation and intermediate configuration are
omitted for clarity. For related information, see Figure
S2.) For an alkylamine, the formed imine would coordi-
nate with RuLH2 intermediate II to form active species
III, and then it decomposes and releases hydrogen gas.
After the alkylamine is completely transformed into the
corresponding imine, the excess alcohol would be
dehydrogenated into acid continuously. In the presence
of an arylamine or benzylamine, the transfer hydrogena-
tion from intermediate III to V is a key step to produce
the corresponding sec‐amine. An electron‐donating sub-
stituent on imine would decrease the stability and lead
to a fast decomposition of intermediate III, so that the
hydrogenation transfer becomes difficult and a low yield
of sec‐amine is obtained.
Ruixiang Li http://orcid.org/0000-0003-2358-1226
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FIGURE 3 Mechanism of imine formation in N‐alkylation
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