Hemilabile N-heterocyclic carbene (NHC)-nitrogen-phosphine mediated Ru (II)-catalyzed N-alkylation of aromatic amine with alcohol efficiently

Article abstract of DOI:10.1016/j.catcom.2017.03.007

Based on the hemilability, a novel N-heterocyclic carbene (NHC)-nitrogen-phosphine ligand (1) was synthesized, and the combination of it with [Ru(COD)Cl₂]_n showed the high activity and selectivity with a low Ru loading of 0.1% for the N-alkylation of amine with alcohol. Especially, for these substrates with pyridine backbone, even if the catalyst loading was as low as 0.01%, good yields (81–95%) of the desired products were achieved.

Full text of DOI:10.1016/j.catcom.2017.03.007

Accepted Manuscript
Hemilabile N-heterocyclic carbene (NHC)-nitrogen-phosphine
mediated Ru (II)-catalyzed N-alkylation of aromatic amine with
alcohol efficiently
Xiao-Jun Yu, Hai-Yu He, Lei Yang, Hai-Yan Fu, Xue-Li Zheng,
Hua Chen, Rui-Xiang Li
PII:
S1566-7367(17)30093-6
doi: 10.1016/j.catcom.2017.03.007
CATCOM 4964
DOI:
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
2 February 2017
7 March 2017
10 March 2017
Please cite this article as: Xiao-Jun Yu, Hai-Yu He, Lei Yang, Hai-Yan Fu, Xue-Li Zheng,
Hua Chen, Rui-Xiang Li , Hemilabile N-heterocyclic carbene (NHC)-nitrogen-phosphine
mediated Ru (II)-catalyzed N-alkylation of aromatic amine with alcohol efficiently. The
address for the corresponding author was captured as affiliation for all authors. Please
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ACCEPTED MANUSCRIPT
Hemilabile N-heterocyclic carbene (NHC)-nitrogen-phosphine mediated
Ru (II)-catalyzed N-alkylation of aromatic amine with alcohol efficiently
Xiao-Jun Yu, Hai-Yu He, Lei Yang, Hai-Yan Fu*, Xue-Li Zheng, Hua Chen and Rui-Xiang
Li*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu, 610064, China.
Fax: (+) 86-28-85412904; Email: liruixiang@scu.edu.cn; haijianfu@163.com
Abstract: Based on the hemilability,
a
novel N-heterocyclic carbene
NHC)-nitrogen-phosphine ligand (1) was synthesized, and the combination of it with
Ru(COD)Cl2]n showed the high activity and selectivity with a low Ru loading of 0.1%
(
[
for the N-alkylation of amine with alcohol. Especially, for these substrates with
pyridine backbone, even if the catalyst loading was as low as 0.01%, good yields
(
81-95%) of the desired products were achieved.
Keywords: N-alkylation, N-heterocyclic carbene, phosphine, ruthenium
1. Introduction
Amine or N-containing compounds have versatile applications in the production of
agrochemical, peptide, pharmaceutical and functional materials [1], so the
construction of C-N bond has attracted wide attention and some effectively
[2-4]
synthetic methods
have been developed. Among them, transition metal
catalyzed N-alkylation of amine with alcohol are the most efficient and environment
friendly protocol [5] to construct primary [6], secondary [7] and tertiary amine [8]
[9]
without any waste except water according to “borrowing hydrogen” mechanism .

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Since the transition metal catalyzed N-alkylation was firstly established by Grigg
and Watanabe in 1981 [10, 11], a great number of Ru[12-14], Ir [15-16], Pd [17], Co [18-19], Pt
[20],
and Fe [21] complexes with different ligands have been utilized in this system and
significant progresses have been achieved. Unfortunately, the predominant
combination of phosphine and inexpensive Ru usually required more than 5%
catalyst loading to obtain a high conversion. Latest, some multidentate ligands [22-25]
or functionalized carbene [26-30] were synthesized and applied for promoting the
activity of the transition metals, so that the catalyst loadings could be decreased to
ca. 1-0.5%. It is noteworthy that the anchoring effect and “hemilability” [31] of
functionalized carbene is vital to improve the catalyst efficiency.
Besides, Kempe and Shafir found that the reactivity of transition metal catalyzed
N-alkylation could be improved by the introduction of N atom in phosphine ligand
[32-34]
(
Figure 1). Our previous works also proved that the application of N-containing
tetra-phosphine ligand was highly efficient to Pd-catalyzed C-C coupling [35]. Inspired
by these results, a new ligand including N-heterocyclic carbene, nitrogen and
phosphine scaffold was designed (Figure 1) and synthesized (Scheme 1). As our
expectation, this novel ligand (1) mediated Ru (II) catalyzed N-alkylation of amine
with alcohol showed an excellent activity and the loading of ruthenium could be as
low as 0.01%.

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Figure 1. N-containing (non-coordinated) phosphines in N-alkylation and our design
of hemilabile carbene-nitrogen-phosphine
Scheme 1. Synthesis of N-heterocyclic carbene-nitrogen-phosphine ligand
2. Results and discussions
The catalytic performance of combining Ru precursor with ligand (1) in situ was
examined with N-alkylation of aniline with benzyl alcohol as model reaction. Initially,
the effect of a series of bases on the reaction was tested, and it was found that
t
KO Bu was the best (Table 1, entry 1, more results in supporting information).
Further screening on Ru precursor showed that [Ru(COD)Cl2]n was most effective
(
Table 1, entry 2-3). The effect of temperature and time on the reaction exhibited
that the high conversion of 90% and selectivity of 95% were given at 100 C for 6
hours (Table 1, entry 4-7). At room temperature, the catalyst system still gave a

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satisfying conversion of 83% when the time was extended to 120 hours. These
results implied that the lifetime of the active species was long enough or the stability
of this catalyst system was high enough. In order to shorten the reaction time, we
chose the reaction temperature of 100 C in the following reactions. Meanwhile,
compared with this ligand (1), the introduction of common carbene and biphosphine
ligands gave the low conversion and selectivity (Table 1, entry 8-11). Interestingly,
even if catalyst loading of 0.1% was utilized, the system could result in a complete
conversion when the reaction time was prolonged to 48 h (Table 1, entry 12-13).
According to the previous results, the optimum conditions are 0.1% Ru loading, 2
equiv alcohol, 100 C and 48 h.
Table 1. N-alkylation of aniline with benzyl alcohol a
Entry Variable condition
Conv.(%)
94
Selec.(%)
>99
>99
99
1
Ru(COD)Cl2
2
[Ru(C6H6)Cl2]2
Ru(PPh3)3Cl2
88
3
64
o
4
25 C, 120h
83
91
5
6h
90
95
6
2 equiv. alcohol
80oC
>99(95)
>99
71
>99
>99
36
7 b
8 b
9 b
6h, dppe
6h, dppb
62
34

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1
1
1
1
0 b
1 b
2 b
6h, MI
44
29
95
81
98
6h
97
0.1% catalyst
0.1% catalyst, 48h
93
3 b
>99(96)
a
t
Reaction condition: aniline (1 mmol), benzyl alcohol (1 mmol), KO Bu (1 mmol),
o
[
Ru(COD)Cl2]n (1% mmol Ru), ligand 1 (1% mmol), toluene (4 ml) , 100 C and 24h.
Conversion and selectivity (amine 5a) were determined by GC analysis. Conversion in
parentheses was the isolated yield. dppe, 1,2-(diphenylphosphino)ethane; dppb,
1
,4-(diphenylphosphino)butane; MI, 1,3-dimesityl-imidazolium chloride (0.02 mmol).
b
2
equiv. alcohol.
On the basis of the optimum conditions, the scope of substrates was investigated.
Firstly, the substituents toleration was explored (Table 2). It clearly showed that the
electronic factor (5a-d) of substituents in para-position of amine group didn’t affect
the product yield. However, the methyl group in ortho-position greatly inhibited the
formation rate of corresponding product (5f), but the yield of 80% could be still
obtained when reaction time was extended to 72 h. Encouraged by these results, we
tried to decrease the catalyst loading to 0.01% and got mediate yields (5a, 5d) by
extending reaction time to 120 h. However, for N-containing heterocyclic substrates,
the high yields (5g-m) were obtained, especially, 2-aminopyridine derivatives could
be almost completely converted into the desired products (5g, 5i, 5j) in the catalyst
loading of 0.01% for 24 h. To the best of our knowledge, the high TON (up to 9500) in
this case is unprecedented. The possible coordination of N-atom in pyridine skeleton
with Ru center played a promotional role [32]. Compared with 2-aminopyridine, the
reactivity of 3- and 4-aminopyridines decreased obviously and the reaction time had
to be extended to 48h in order to get satisfactory yields (5l, 5m). However, a
mediate conversion of 59% (5k) was obtained with 0.02% catalyst for

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6-methoxy-2-amino-pyridine, and the inhibition role of the methyl group in
ortho-position of amino group (5h) was in consistent with non-heterocyclic
substrates due to steric hindrance. However, N-alkylation of alkyl amine gave imine
as major products, such as benzyl amine gave only 15% yield of the desired product
besides imine. The result was similar to other functionalized carbene system [26-30]
.
In addition, the reactivity of some diamines, which are difficult to react with
alcohols to give N,N’-dialkylated products [26], was tested (Table 2, 5o-r).Interestingly,
a good yield of 84% was given with 2,6-diaminopyridine (5o) for 72 h. For
phenylenediamines (5p-r), the satisfying yields could be gotten with a catalyst
loading of 1.0%. To date, for the Ru-catalyzed N,N’-dialkylation of diamines with
alcohols, our system was the most efficient and gave the highest TON among a few
reported results [25, 26, 28, 30, 36-38]
.
Table 2. N-alkylation of amines with benzyl alcohol a

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a
t
Reaction condition: amine (1 mmol), benzyl alcohol (2 mmol), KO Bu (1 mmol),
o
[
Ru(COD)Cl ] (0.1% mmol Ru), ligand 1 (0.1% mmol), toluene (4 ml) , 100 C and 48h,
isolated yield in parenthesis (followed bond figures is catalyst loading).
2h.
2
n
b
c
120 h.
d
e
o
f
1
7
24 h. 1% catalyst, 120 C and 24h. Yield was determined by H NMR and
CH2Br2 as internal standard.
Also, the effect of alcohol structure on the N-alkylation was examined (Table 3). All
primary alcohols (6a-f), whether they were aryl or alkyl alcohols, could react with
aniline in the presence of 0.1% catalyst. However, using secondary alcohols (6g-i),
aniline could be not converted completely into the desired products with the catalyst

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o
loading of 0.1% even in reaction temperature of 120 C because of steric hindrance
[24],
but an appropriate increase of catalyst loading (1.0%) improved the yields.
Table 3. N-alkylation of aniline with alcohols a
a
t
Reaction condition: aniline (1 mmol), alcohols (2 mmol), KO Bu (1 mmol),
o
[
Ru(COD)Cl2]n (0.1% mmol Ru), ligand 1 (0.1% mmol), toluene (4 ml) , 100 C and 48h,
isolated yield. 1% mmol catalyst loading, 24 h. All reactions of sec-alcohol were
conducted on 120 C, and yields were determined by GC (N-methylaniline as internal
b
o
standard).
According to the reported mechanism, the transfer hydrogenation of imines was
an important step [9] in this N-alkylation, so imine 7 (N-benzylideneaniline) was used
in transfer hydrogenation and gave 99% GC conversion of corresponding amine
product (5a) with 2 equiv. benzyl alcohol as hydrogen source. Thus, this result
revealed the formation of imine-Ru intermediate was vital in the progress of
N-alkylation. Interestingly, N-benzylidenebenzyl amine (8) finished transfer
hydrogenation to provide amine (5n) with a conversion of 34%, but the transfer
hydrogenation of N-benzylidene cyclohexylamine (9) was completely inhibited.
Obviously, the high electron density on N atom of imine inhibited completely the

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transfer hydrogenation, which indicated the reason why alkyl amines did not give
the desired products in this system.
Further mechanism exploration was performed with NMR in situ (see supporting
1
information). The H NMR spectra (Figure 2) evidenced clearly the formation of [MH2]
3
1
(
(
2 dd signal, J=15.2 Hz and 2.8 Hz.) and aldehyde. Moreover, the splitting of P NMR
Figure 2) at 73 ppm (dd, J = 30.0 Hz, 4.9 Hz) was attributed to the presence of Ru-OR
complex (I). And total proton numbers of 6.32 ppm (coordinated 5a) and 6.39 ppm
1
(
free 5a) on H NMR (see supporting information) was consistent with proton
number of product 5a. Interestingly, at different aniline levels (10 equiv. vs 2 equiv.),
the integral area ratio of coordinated 5a (6.32 ppm) to total product 5a was
approximately equal to the molar ratio of catalyst loading to aniline. The result
revealed that product 5a didn’t intermediately leave form the Ru centre at the end
of N-alkylation reaction and the coordination of benzyl alcohol promoted the
elimination of product 5a from ruthenium center. Furthermore, 2 doublets at 92
3
1
ppm and 73 ppm (J = 30.0 Hz) in P NMR (Figure 2) suggested that ligand (1) in
3
active catalytic species should chelate with ruthenium in κ -C,P,P model and N atom
did not take part in coordination. The addition of substrate led to appearance of the
3
1
broad signal in up-field of P NMR, which implied that the coordinated phosphine
scaffold dissociated from Ru centre to form free phosphine and provide available site
for the activation of substrate. This phenomenon was not only consistent with
“
hemilability” as expectation, but also indicated the reason of high activity and long

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lifetime of this catalyst system. Hence, to combine the reported result and our
evidence, the reaction mechanism was proposed as Figure 3.
Figure 2. NMR spectra of N-alkylation reaction mixture
Figure 3. Proposed mechanism of N-alkylation

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3. Conclusion
In conclusion, a novel hemilabile N-heterocyclic carbene-nitrogen-phosphine (1)
was synthesized conveniently. The combination of this ligand and [Ru(COD)Cl2]n was
used in the N-alkylation of aromatic amine with alcohol to give corresponding
products in good to excellent yields with a low catalyst loading of 0.01-0.1%. NMR
experimental proved the formation of aldehyde and [MH2], and the hemilability of
present catalyst. All results indicated that the introduction of nitrogen atom
between phosphine and carbene was a good strategy for the transition metal
catalyzed N-alkylation.
Acknowledgement
This work was supported by the National Natural Science Foundation of China
(
21572137).
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Graphical abstract and Highlights
Highlights


A mixed tridentate carbene-nitrogen-phosphine was synthesized.
The combination of this ligand with Ru(II) showed an
unprecedented high activity in N-alkylation.

Hemilability of this ligand played a key role for the high activity of
this catalytic system.