Ruthenium(ii) complexes with N-heterocyclic carbene-phosphine ligands for theN-alkylation of amines with alcohols

Article abstract of DOI:10.1039/d1ob00362c

Metal hydride complexes are key intermediates forN-alkylation of amines with alcohols by the borrowing hydrogen/hydrogen autotransfer (BH/HA) strategy. Reactivity tuning of metal hydride complexes could adjust the dehydrogenation of alcohols and the hydrogenation of imines. Herein we report ruthenium(ii) complexes with hetero-bidentate N-heterocyclic carbene (NHC)-phosphine ligands, which realize smart pathway selection in theN-alkylated reactionviareactivity tuning of [Ru-H] species by hetero-bidentate ligands. In particular, complex6cbwith a phenyl wingtip group and BArF^?counter anion, is shown to be one of the most efficient pre-catalysts for this transformation (temperature is as low as 70 °C, neat conditions and catalyst loading is as low as 0.25 mol%). A large variety of (hetero)aromatic amines and primary alcohols were efficiently converted into mono-N-alkylated amines in good to excellent isolated yields. Notably, aliphatic amines, challenging methanol and diamines could also be transformed into the desired products. Detailed control experiments and density functional theory (DFT) calculations provide insights to understand the mechanism and the smart pathway selectionvia[Ru-H] species in this process.

Full text of DOI:10.1039/d1ob00362c

Organic &
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PAPER
Ruthenium(II) complexes with N-heterocyclic
carbene–phosphine ligands for the N-alkylation
of amines with alcohols†
Cite this: Org. Biomol. Chem., 2021,
19, 3451
Ming Huang,
*
a,b Yinwu Li,b Xiao-Bing Lan, b Jiahao Liu, b Cunyuan Zhao,b
b
Yan Liu *c and Zhuofeng Ke
*
Metal hydride complexes are key intermediates for N-alkylation of amines with alcohols by the borrowing
hydrogen/hydrogen autotransfer (BH/HA) strategy. Reactivity tuning of metal hydride complexes could
adjust the dehydrogenation of alcohols and the hydrogenation of imines. Herein we report ruthenium(II)
complexes with hetero-bidentate N-heterocyclic carbene (NHC)-phosphine ligands, which realize smart
pathway selection in the N-alkylated reaction via reactivity tuning of [Ru–H] species by hetero-bidentate
ligands. In particular, complex 6cb with a phenyl wingtip group and BArF− counter anion, is shown to be
one of the most efficient pre-catalysts for this transformation (temperature is as low as 70 °C, neat con-
ditions and catalyst loading is as low as 0.25 mol%). A large variety of (hetero)aromatic amines and primary
alcohols were efficiently converted into mono-N-alkylated amines in good to excellent isolated yields.
Notably, aliphatic amines, challenging methanol and diamines could also be transformed into the desired
products. Detailed control experiments and density functional theory (DFT) calculations provide insights
to understand the mechanism and the smart pathway selection via [Ru–H] species in this process.
Received 25th February 2021,
Accepted 19th March 2021
DOI: 10.1039/d1ob00362c
rsc.li/obc
active for this transformation, since the seminal work of the
groups of Grigg32 and Watanabe33 in the early 1980s. In particu-
Introduction
N-Alkylated amines are widely used compounds that have lar, the Ru-based systems, mainly Ru(II) complexes, are among
numerous applications in pharmaceuticals, agrochemicals, the most active catalysts in those fields.9,10,34–39 The electronic
polymer materials, and synthetic industries.1–4 One of the and steric properties of the ancillary ligands are essential for
most appealing synthetic approaches for their preparation is the high performance of Ru(II) catalysts. For example, Williams
the BH/HA methodology, in which the N-alkylated amines are et al. reported the use of [Ru(p-cymene)Cl2]2 with either the
furnished by using sustainable and abundant alcohols as bidentate phosphine ligand Dppf or DPEphos for the
coupling reagents.5–7 Notably, these transformations are not N-alkylation of amines with alcohols.9 Those systems are toler-
only environmentally benign, allowing alcohols to replace the ant to a large amount alcohols and amines and have been
toxic alkyl halides as the alkylating agents, but also atom econ- applied to the synthesis of some pharmaceutical drugs, as well
omical, eliminating only water as the byproduct.
as to the N-alkylation of sulfonamides and cyclization reactions.
More and more homogeneous transition metal (TM) Recently, Takacs et al. developed a Ru(II) complex with a biden-
complexes,5–12 and even those based on non-noble metals tate phosphine-dihydrooxazole ligand, which is capable of alky-
(Co,13–15 Fe,16–18 Ni,19–27 and Mn28–31), have been shown to be lating amines with primary and secondary alcohols and the
regioselective mono- and sequential diamination of diols.35
This system has also been applied to the synthesis of hetero-
aClinical Pharmacy of The First Affiliated Hospital, School of clinical pharmacy,
cyclic rings including indoles, piperazines, and pyrrolidines.
Guangdong Pharmaceutical University, Guangzhou 510006, P. R. China.
Shortly afterward, Williams et al. reported a Ru(II) catalyst with a
E-mail: 1529236883@qq.com
bSchool of Materials Science & Engineering, PCFM Lab, School of Chemistry, Sun
bidentate phosphine-pyridyl ligand, which could realize chemo-
selective benzylic N-alkylation of amines under mild con-
ditions.36 This system works without solvents and additives and
is compatible with unprotected phenols and anilines. Despite
numerous efforts, high temperatures (above 100 °C), or high
catalyst loadings (above 1 mol%) are usually required to obtain
satisfactory yields.40,41
Yat-sen University, Guangzhou 510275, P. R. China.
E-mail: kezhf3@mail.sysu.edu.cn
cSchool of Chemical Engineering and Light Industry, Guangdong University of
Technology, Guangzhou 510006, P. R. China. E-mail: yanliu@gdut.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1830666, 1911586
and 1912108. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d1ob00362c
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The BH/HA strategy for the TM-catalyzed N-alkylation reac- via a classical d → π* back-donation.49,50 Therefore, NHC is
tions included three key steps: (i) the acceptorless dehydro- usually described as a class of strong σ-basic/weak π-acidic
genation (AD) of alcohols to aldehydes, accompanied by the ligands. For the PR3 ligands, the lone pair of the P atoms
formation of the metal hydride ([M − H]) species; (ii) the serves as an electron donator, while the σ* orbitals of the P–R
in situ condensation of aldehydes with amines to imines; and bonds play the role of an acceptor. As compared with NHC,
(iii) the hydrogenation of imines by the [M − H] species the phosphine ligand is a relatively weaker donor, and a stron-
(Scheme 1a). Thus, it is essential to tune the stability and the ger back-donation acceptor.51 We assumed that the diversity of
activity of the [M − H] species for the design of efficient BH/ the hetero-bidentate NHC-phosphine ligands could stabilize or
HA catalysts. If the [M − H] species are too active and less activate the hydride in [Ru–H] species via different coordi-
stable, the dehydrogenation of alcohols to [M − H] species nation geometries, in which the hydride could locate trans to
may be suppressed. However, if the ligand makes the [M − H] either the phosphine ligand or the NHC ligand (Scheme 1c).
species too stable, the successive hydrogenation of imines Inspired by this possible hetero-mixed ligand strategy, we are
would be inhibited. We envisioned that hetero-bidentate looking forward to developing a Ru(II) catalyst system with the
ligands bearing different binding characters, enabling the hetero-bidentate NHC-phosphine ligands for realizing the
[M − H] species to be adaptable to both stability and activity, smart pathway selection via the [M − H] species in the
which should be advantageous for the design of BH/HA cata- N-alkylation reaction.
lysts. However, the specific role of hetero-bidentate ligands in
Herein, we describe the development of a Ru(II)-catalyzed
tuning or accelerating chemical reactions has not been well protocol enabling the smart pathway selection for the syn-
elucidated for Ru-catalyzed N-alkylation. Therefore, we are thesis of N-alkylated amines from alcohols and amines. As a
focusing on the development of hetero-bidentate ligands special highlight, this catalytic system is applicable even for
towards smart pathway selection, which not only guarantees the less active aliphatic alcohols including methanol.
[M − H] stability, but also achieves high activity.
Moreover, experiments and DFT calculations were carried out
Recently, the combination of phosphine and N-heterocyclic to understand the mechanism and the smart pathway selec-
carbene (NHC) ligands has resulted in the improvement of tion of the [Ru–H] species in this process. These results imply
several important catalytic processes.42–45 Both the phosphine the potential of the smart pathway selection strategy using
and NHC ligands are strong σ-donating ligands, which are hetero-bidentate ligands in BA/HA or other tandem catalytic
beneficial for the TM-catalyzed BH/HA reactions.9,10,34,46–48 reactions.
However, there are electronic and steric diversities between the
phosphine and NHC ligands (Scheme 1b). NHC ligands have
the sp2 lone pair electrons on the central carbon atom that can
coordinate to a TM, which confers strong σ-donation behavior.
Meanwhile, the π* molecular orbital (MO) of the NHC ligands
Results and discussion
Screening of the ligands
can accept electron density from the filled d orbitals of the TM We initially prepared three types of bidentate NHC ligands
including hetero-bidentate NHC-phosphine ligands (L1–L4),52
bis-NHC ligands (L5–L8)53 and hetero-bidentate NHC/pyridine
ligand (L9–L10)54,55 motifs (Table 1). All these ligands can be
prepared in good yields in few steps starting from commer-
cially available reagents (see the ESI† for more details). It
should be noted that the steric environment of these hetero-
bidentate ligands can be tuned modularly through the modifi-
cation of the N-substituents of the imidazole. With these
bidentate NHC ligands (L1–L10) and the bidentate phosphine
ligands Dppf (L11) and DPEphos (L12), the N-alkylation of
aniline with benzyl alcohol was performed via the catalytic
systems formed in situ, which were derived from a mixture of
ligands, different Ru resources, and KOtBu in toluene at
110 °C (Table 1). Trace amounts of products were observed in
the absence of the Ru source (entry 1), whereas a control
experiment in the absence of the ligand resulted in a poor
yield (entry 2). The reactions were conducted with various Ru
precursors and L1, in which good yields were obtained with all
of the precursors [Ru(p-cymene)Cl2]2, RuCl3·3H2O, Ru(COD)
Cl2 and RuCl2(DMSO)4 (entries 3–6), demonstrating the great
potential of the hetero-bidentate NHC-phosphine ligand in
Scheme 1 (a) BH/HA strategy for the N-alkylation of amines with alco-
hols; (b) molecular orbitals of the NHC and phosphine ligands with the
this transformation. Selecting [Ru(p-cymene)Cl2]2 for further
study, the effects of various ligands were evaluated (entries
metal; (c) the isomerization of the hetero-bidentate NHC-phosphine Ru
hydrides intermediates.
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Table 1 Effects of ligands on the N-alkylation of aniline with benzyl
alcohol catalyzed by Rua,b
Scheme 2 Synthesis of complexes 6a–d, 6aa, and 6ba–be.
and trans-metalation of the resulting silver carbene to [Ru(p-
cymene)Cl2]2, afforded the new complexes 6a–d in high
yields.10 The analogues 6aa and 6ca–ce were prepared by the
addition of AgX (X = PF6, OTf, and BF4 for complexes 6aa or
6ca, 6cc and 6cd, respectively) or NaX (X = BArF and BPh4 for
complexes 6cb and 6ce, respectively) to a solution of 6a or 6c
in CH2Cl2.35 The ruthenium complexes 6a–d, 6aa and 6ca–6ce
were all separated by column chromatography as air and
moisture stable yellow solids. In their 1H NMR spectra, the
signals of the imidazole proton at the C-2 position, appearing
for compounds L1–L4, completely disappeared. The character-
istic signals of the carbene carbons in their 13C NMR spectra
[165.4 ppm (6a), 165.7 ppm (6b), 166.9 ppm (6c), and
171.5 ppm (6d)] are comparable to those of the previously
reported ruthenium NHC complexes.57,58
Crystals suitable for X-ray diffraction of 6d, 6aa, and 6ca
were obtained by slow evaporation of their concentrated solu-
tions in CH2Cl2/hexane at room temperature. ORTEP diagrams
of 6d, 6aa, and 6ca are displayed in Fig. 1. These complexes
adopt a three-legged piano stool geometry with the facial
planar p-cymene representing the “seat”, and the chlorido and
the hetero-bidentate NHC-phosphine ligands forming the
three “legs”. The Ru–Ccarbene distances in 6d and 6aa (2.076(2)
and 2.079(3) Å, respectively) are slightly longer than that in 6ca
Entrya
Ligand (0.5 mol%)
Ru (0.5 mol% [Ru])
Yieldb (%)
1
2
3
4
5
6
7
8
L1
—
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
Dppf
DPEphos
—
—
23
93
90
83
85
91
77
49
58
27
33
28
30
22
27
35
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
RuCl3·3H2O
Ru(COD)Cl2
RuCl2(DMSO)4
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
9
10
11
12
13
14
15
16
17
a N-Alkylation reaction conditions: 1.0 mmol 7a, 1.0 mmol 8a,
0.5 mol% L, 0.5 mol% [Ru], 1.0 mmol KOtBu, 2.0 mL toluene, 110 °C,
2 h. b GC yields.
7–15). The wingtip substituents at the hetero-bidentate NHC-
phosphine ligands were found to have an impact on their per-
formance. The best pre-catalysts were formed from methyl-sub-
stituted (L1, entry 3) and isopropyl-substituted (L2, entry 7)
ligands, while the ligands with a phenyl group (L3, entry 8) or
a mesityl-substituent (L4, entry 9) resulted in moderate
activity. The use of bis-NHC ligands (L5–L8, entries 10–13),
hetero-bidentate NHC/pyridine (L9–L10, entries 14 and 15)
and bidentate phosphine ligands (entries 16 and 17) gave
inferior results compared with hetero-bidentate NHC-phos-
phine ligands under identical conditions. Those results indi-
cated that the hetero-bidentate NHC-phosphine ligands played
a pivotal role in the Ru catalyzed the N-alkylation reactions.
Synthesis and characterization
Inspired by the promising performance of precatalysts formed
from L1–L4/[Ru(p-cymene)Cl2]2, we sought to isolate the
corresponding well-defined Ru-complexes. Complexes 6a–d,
6aa,56 and 6ca–6ce were synthesized by following the reaction
Fig. 1 ORTEP diagrams for complexes 6d, 6aa and 6ca with thermal
ellipsoids drawn at the 50% probability level. Hydrogen atoms and
sequence depicted in Scheme 2. Treatment of L1–L4 with Ag2O counter anions are omitted for clarity.
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(2.066(4) Å). The Ru–P distance in 6d (2.3394 (6) Å) is slightly obtain sufficient yields (Table S2,† entries 1–5). Gratifyingly,
shorter than those in 6aa and 6ca (2.3528(7) and 2.3495(11) Å, the yield could reach 91% within 30 min (entry 12). An
respectively). These differences may result from the different attempt to lower the catalyst loading to 0.25 mol% resulted in
steric environments of the N-substituents of the imidazole.
a slight decrease in the yield (entry 13). The temperature of the
reaction was found to have a strong impact on the reaction
rate (entries 14–16). The temperature could be lowered to
50 °C, but a longer reaction time was needed to obtain a high
yield (24 h, 92% yield, entry 15). However, a lower yield was
obtained when the reaction was performed at 30 °C or under
an air atmosphere (entries 16 and 17). When the reaction was
run in H2O, the catalytic activity of 6cb almost disappeared
(entry 18). Gratifyingly, under neat conditions, the reaction
could also successfully occur, and the yield was up to 97%
(entry 19). Furthermore, a good yield was obtained, when the
reaction was carried out without using the glovebox (entry 20).
Optimization of the N-alkylation of amines with alcohols
A screening of the Ru complexes was carried out (Table 2).
Interestingly, the ruthenium complex 6c containing phenyl as
the wingtip substituent (entry 4) led to a higher yield (92%
yield) than those containing methyl, isopropyl, or mesityl
groups (entries 2, 3 and 5). This behavior is in conformity with
the performance of precatalysts in situ formed from L1–L4/[Ru
(p-cymene)Cl2]2, which may result from the different coordi-
nation ability and stability of the free NHC. After these optimi-
zations, we were interested in studying the analogs of 6c in
which one chloride ligand was replaced by a weaker coordinat-
ing counter-anion (entries 6–11). To our delight, complex 6cb
(entry 8) with the BArF− anion is more effective than the
corresponding complex 6c, which could improve the yield to
N-Alkylation of aniline with alcohols
Encouraged by these results, we further investigated the sub-
strate scopes of our catalyst system under neat conditions,
which is more environmentally friendly. Firstly, we focused on
the alkylation of aniline with various alcohol derivatives. As
shown in Table 3, both electron-rich and electron-deficient
benzylic alcohols could be employed efficiently in our process,
and provided alkylated aniline derivatives 9b–l in 55–94%
yields. A series of functional groups, such as halide groups
(9e–g), thioether group (9d), and trifluoromethyl group (9i),
were compatible with the present catalytic system for alcohols.
As for 4-bromobenzyl alcohol, the reaction suffered from de-
bromination, and the product 9f was isolated in moderate yield
(55% at 90 °C). The sterically hindered ortho-methyl benzylic
alcohol could provide the corresponding monoalkylated amine
9j in 86% yield at 90 °C. When heterocylic alcohols, such as
2-pyridinemethanol, 2-furylmethanol, and 2-thiophenemetha-
−
97%. In contrast, the other anions such as PF6 (6ca, entry 7),
OTf− (6cc, entry 9), BF4 (6cd, entry 10), and BPh4 (6ce, entry
11) led to a moderate decrease in the catalytic activity.
Subsequently, complex 6cb was chosen for further optimiz-
ation studies including the base, catalyst loading, reaction
time, and temperature. It was found that KOtBu is an effective
base to obtain high yields. However, replacing KOtBu with
other bases resulted in decreased yields, and even the weaker
bases, such as K2CO3 and Na2CO3, were ineffective (Table S2,†
entries 6–10). In addition, nearly 75 mol% KOtBu is needed to
−
−
Table 2 Optimization of the N-alkylation of aniline with benzyl alcohol
Entrya
Catalyst
R1
X
Yieldb (%)
1
2
3
4
None
6a
6b
—
—
Cl
Cl
Cl
6
76
71
92
Table 3 Alkylation of aniline with various primary alcoholsa,b
Me
i-Pr
Ph
6c
5
6
7
8
9
10
11
6d
Mesityl
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Cl
PF6
PF6
BArF
CF3SO3
BF4
BPh4
BArF
BArF
BArF
BArF
BArF
BArF
BArF
BArF
BArF
54
74
90
97
90
92
87
91
91
98
92
61
6aa
6ca
6cb
6cc
6cd
6ce
6cb
6cb
6cb
6cb
6cb
6cb
6cb
6cb
6cb
12c,d
13d,e
14d,e, f
15d,g
16d,h
17d,i
18d, j
19d,e, f,k
20d,e, f,k,l
25
Trace
97 (95)
95
a N-Alkylation reaction conditions: 1.0 mmol 8a, 1.0 mmol 7a,
1.0 mmol KOtBu, 0.5 mol% 6, 2.0 mL of toluene, 110 °C, 2 h. b GC
yields, isolated yields in parentheses. c Time (0.5 h). d 0.75 mmol
KOtBu. e Catalyst loading (0.25 mol%). f Temperature (70 °C), time
(12 h). g Temperature (50 °C), time (24 h). h Temperature (30 °C), time
(24 h). i Air atmosphere. j 2.0 mL H2O instead of toluene. k Neat con- a N-Alkylation reaction conditions: 0.5 mmol 7a, 0.5 mmol 8, 75 mol%
ditions. l Without using the glovebox.
KOtBu, 0.25 mol% 6cb, 70 °C, 12 h. b Isolated yields. c 90 °C.
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nol were used as the substrates, the corresponding products N-alkylation of p-toluenesulfonamide with benzyl alcohol
(9m and 9r–s) were isolated in 42–78% yields at 90 °C. To our (Scheme S4c†), N-alkylation of p-nitroaniline with benzyl
delight, aliphatic alcohols, such as isobutanol, phenylpropa- alcohol (Scheme S4d†), N-alkylation of aniline with 4-nitro-
nol, and the chain-containing aliphatic alcohols, could benzyl alcohol (Scheme S4e†), and N-alkylation of aniline with
efficiently convert to monosubstituted aniline derivatives 9n–q methyl 4-(hydroxymethyl)benzoate (Scheme S4f†). However,
in 66–88% isolated yields. However, attempts at the these reactions were unsuccessful, even at a higher catalyst
N-alkylation of aniline with secondary alcohols, such as 1-phe- loading (1 mol%) and a higher temperature of 110 °C.
nethyl alcohol, cyclohexanol, and isopropyl alcohol, were
N-Methylation of anilines
unsuccessful, yielding only trace amounts of products.
N-Methylamines are also widely used as key intermediates and
building blocks for the synthesis of bulk and fine chemicals as
N-Alkylation of amines with benzyl alcohol
well as materials.59,60 However, methanol is still a challenging
Next, the scope of the amines was investigated (Table 4).
Substrates bearing either electron-donating or electron-with-
drawing substituents on the aryl ring of aniline were selectively
alkylated to afford the N-monoalkylated anilines 10a–h in
substrate for the N-alkylation of amines, due to the higher acti-
vation barrier (ΔH = 21 kcal mol−1) of the dehydrogenation step
compared to that of higher alcohols, such as ethanol (ΔH =
16 kcal mol−1).61 To further expand the generality of the cata-
good yields (54–92%). In the cases of ortho-bromine aniline,
lytic system, the N-methylation of amines with methanol was
debromination was also observed, and product 10g was iso-
lated in moderate yield (54%). Even sterically hindered, ortho-
phenyl aniline could smoothly convert to the corresponding
product 10h with excellent selectivity (83%). Treatment of the
then investigated. To our delight, the N-methylation of anilines
with methanol was successfully accomplished in the presence
of 0.5 mol% 6cb at 110 °C (Table S3†). As shown in Table 5,
most of the catalytic reactions showed unprecedented efficiency,
bulky amines, such as 1,4-benzodioxan-6-amine and
reaching at least 80% yields (11a–o: 40–94%). Again, a notable
2-naphthylamine, with benzyl alcohol resulted in desired pro-
functional group tolerance was observed. Employing 2-iodoani-
ducts 10i–j in very good yields (85–92%). Advantageously, het-
eroaromatic amines, such as 2-aminopyridine and 3-amino-
line led to 11i in moderate isolated yields (40%), and the reac-
tion also suffered from dehalogenation. Furthermore, important
pyridine, were successfully transformed into the desired pro-
biologically relevant motifs, such as 3-trifluoromethylaniline
ducts 10k–l in good yields (83–86%). Furthermore, aliphatic
and 1,3-benzodioxol-5-amine, were effectively transformed
amines, such as benzylamine, n-hexylamine, and 4-methyl-
(11m–n). Remarkably, we did not observe dialkylation products
phenethylamine could also be converted to the desired pro-
in all the cases, although excess MeOH and high temperature
ducts 10m–o in 43–51% yields. However, the secondary amine,
were used. However, attempts at the N-methylation of aliphatic
such as morpholine (10p), was not tolerated. Furthermore, we
amines, such as benzylamine and n-hexylamine, were unsuc-
have tested the more challenging reactions including the
cessful, yielding only traces of products.
N-alkylation of diamine with dialcohols (Scheme S4a and b†),
N-Alkylation of diamines
Encouraged by the promising results of N-alkylation of
amines, we were interested in the sequential alkylation of di-
Table 4 N-Alkylation of amines using benzyl alcohola,b
Table 5 N-Alkylation of amines with MeOHa,b
a N-Alkylation reaction conditions: 0.5 mmol 7, 0.5 mmol 8a, 75 mol%
KOtBu, 0.25 mol% 6cb, 70 °C, 12 h. b Isolated yields. c 100 mol%
KOtBu, 0.5 mol% 6cb, 110 °C, 24 h.
a General reaction conditions: 7 (0.5 mmol), MeOH (0.2 mL), 6cb
(0.5 mol%), KOtBu (75 mol%), 110 °C, 12 h. b Isolated yield. c GC yield.
d MeOH (0.5 mL) and toluene (1.0 mL).
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Table 6 N-Alkylation of diaminesa,b
a N-Alkylation reaction conditions: 0.5 mmol 12, 0.5 mmol 8, 75 mol%
KOtBu, 0.25 mol% 6cb, 110 °C, 12 h. b Isolated yields. c Conditions:
0.5 mmol 4-methoxybenzyl alcohol,
2 mmol benzenediamine,
0.25 mol% 6cb, 75 mol% KOtBu, 110 °C, 12 h.
amines with two different alcohols (Table 6), which is undoubt-
edly a valuable synthetic tool to obtain compounds with
desired diversity.13,62 Firstly, the diamine was selectively mono-
alkylated to form compound 12 in 83% yield at 110 °C. Then,
we were pleased to note that 12 can be alkylated with different
alcohols to afford the corresponding unsymmetrically functio-
nalized diamines (13a–d) in good yields (65–88%).
Gram-scale synthesis of bioactive intermediates
Scheme 4 Preliminary mechanistic studies.
Next, the synthetic application was also demonstrated for the
gram-scale transformation of 2-aminopyridine into the inter-
mediates of bioactive drugs mepyramine (10q, Scheme 3a),
and chloropyramine (10r, Scheme 3b), which are extensively
used as antihistaminics.19 Gratifyingly, with 2-aminopyridine
as a substrate in 10 mmol scale reactions, N-alkylated deriva-
tives 10q and 10r were obtained in 85% and 91% yields,
respectively.
transfer hydrogenation of the CvN bond, supporting the BH/
HA mechanism (Scheme 4a).63 Moreover, the kinetic isotope
effect (KIE) studies (Scheme 4b and c) were carried out to
obtain more information concerning the reaction pathway.19,64
The reaction of 8a-d2 (97% D) with 7a under standard con-
ditions gave a mixture of N-alkylated products 9a (17%), 9a-d1
(52%) and 9a-d2 (31%) in 87% yield (Scheme 4b), which is
indicative of the reversible alcohol dehydrogenation step and
the existence of D/H exchange.9 Both the intermolecular com-
petition and the parallel reactions of 8a and 8a-d2 with 7a
showed a low KIE value (KIE = 1.66 and 1.27, respectively),
suggesting that the alcohol oxidation step should probably not
be involved in the rate-determining step (rds.) of the reac-
tion.64 In addition, the production of hydrogen gas was
detected from the head gas of the reaction of 7a with 8a under
the standard conditions (Fig. S6†). We further evaluated the
ability of 6cb to hydrogenate the intermediate imine 9aa
(Scheme 4d).65 Under the standard conditions, using toluene
as the solvent, and the hydrogen bag with extra 700 pa
pressure, product 9a was obtained in 36% yield. This result
indicated the potential of 6cb to hydrogenate the imine with
hydrogen gas.
Mechanistic studies
To gain insight into the N-alkylation process, several control
experiments were performed. Firstly, the dehydrogenation
reaction of benzyl alcohol, and the N-alkylation of aniline with
benzyl alcohol were monitored by 1H NMR spectroscopy.
However, the benzaldehyde was not observed, which indicated
that the aldehyde should be a short-lived intermediate or it
does not dissociate from the metal center in the N-alkylation
reaction.10 Additionally, the reaction of imine 9aa with benzyl
alcohol 8a under the optimal conditions gave 9a (98%) via
To investigate the real catalytic species, the reaction
between benzyl alcohol and aniline in toluene-d8 with high
1
catalyst loadings (20 mol% of 6cb) was monitored by H and
31P NMR spectroscopy.10,46,66 Immediately, hydrido signals
were detected in the range from −3 to −11 ppm (Fig. 2a) after
the addition of substrates and the base. This indicates a quick
exchange of the chlorido ligand with the alkoxide, as an initial
Scheme 3 Gram-scale synthesis of bioactive compounds.
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Fig. 3 The selection of the reaction pathways in the dehydrogenation
of alcohol by the hetero-bidentate NHC-phosphine Ru catalyst (A → B).
The dehydrogenation of alcohol step occurs via the β-H
elimination on the Ru center from complex A1 or A2 (Fig. 3).
Because the hydride could be trans to either the phosphine or
the NHC arm, the β-H elimination step diverges into two path-
ways (A1 → B1 and A2 → B2, respectively). The β-C–H agostic
intermediate A1 with the hydride to be eliminated trans to the
phosphine arm is 2.9 kcal mol−1 more stable than A2 with the
hydride to be eliminated trans to the NHC ligand. With A1 as
the reference point, the overall barriers for these two pathways
are 11.1 kcal mol−1 and 11.8 kcal mol−1, respectively, which
are comparable. However, the intermediate B2 is more ender-
gonic by 7.6 kcal mol−1 than B1, indicating that the P ligand is
beneficial for stabilizing the Ru hydride.
Similarly, the insertion of imine step (Fig. 4, C → D) is also
divided into two different pathways (Fig. 4, C1 → D1 and C2 →
D2, respectively). Imine complex C1 with the hydride trans to
the phosphine arm is 2.2 kcal mol−1 more stable than C2 with
the hydride trans to the NHC arm. However, the overall free
energy barrier from C1 to D1 (21.2 kcal mol−1) is higher than
that from C2 to D2 (9.5 kcal mol−1). These results suggest that
the NHC arm significantly favors the insertion of imine step
over the phosphine arm. Therefore, these DFT calculations
Fig. 2 (a) 1H NMR (400 MHz, toluene-d8) spectrum of reaction mixtures
for amination at 0 min of the hydride region; (b) 1H NMR (400 MHz,
toluene-d8) spectrum of the free p-cymene and reaction mixtures for
amination (0 min and 60 min) in the range of 0–2 ppm.
step that does not require heating, in contrast to results
reported by Valerga and co-workers.10 In particular, a high-
intensity doublet at −10.07 ppm with a coupling constant of
2J(P, H) = 40 Hz, is indicative of the existence of a cis co-
ordinated [RuH(PPh2NHC)] species.46,66 Furthermore, the
proof for the existence of [RuH(PPh2NHC)] species could also
be found in the 31P NMR spectrum (Fig. S8†), as the single
signal of complex 6cb at 23.95 ppm has been replaced by
several new downfield signals ranging from 32 to 72 ppm.46,66
In addition, the signal of dissociated p-cymene ligand (50% at
0 min and 80% at 60 min) could be found in the crude 1H
NMR spectra (Fig. 2b) at 110 °C, indicating that the p-cymene
could be dissociated into the active species.46,66
Theoretical investigations
Density functional theory (DFT) calculations (see the ESI† for
computational details) were used to investigate the unique role
of the hetero-bidentate NHC-phosphine ligands in this
process.64,67 Herein, we are mainly focused on the dehydro-
genation of alcohol and the insertion of imine steps involving
the key intermediate, the metal hydride. In computational
studies, the structure of the NHC ligand was simplified by
replacing the phenyl group with a methyl substituent and the
vacant site generated by the dissociation of p-cymene was occu-
pied by the tert-butoxy groups. No further simplifications of
the catalyst structure were introduced.
Fig. 4 The selection of reaction pathways in the insertion of imine by
the hetero-bidentate NHC-phosphine Ru catalyst (C → D).
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Organic & Biomolecular Chemistry
plexes were found to be highly effective catalysts for the selec-
tive monoalkylation of aromatic amines through a BH/HA
mechanism. In particular, complex 6cb is one of the most
active ruthenium catalysts known to date; it can be used to cat-
alyze the reaction at temperatures as low as 70 °C with a very
low catalyst loading (0.25 mol%) under neat conditions. A
large variety of (hetero)aromatic amines, aliphatic amines and
primary alcohols including biologically relevant motifs and
the challenging methanol, were efficiently converted into
mono-N-alkylated amines in good to excellent isolated yields.
Detailed control experiments and DFT calculations were
carried out to understand the mechanism of this process and
the smart pathway selection via tuning the stability and activity
of the [Ru–H] species through the hetero-bidentate NHC-phos-
phine ligands. These results imply the potential of the
pathway selection strategy by hetero-bidentate ligands in BA/
HA or other tandem catalytic reactions.
Scheme 5 Proposed catalytic cycle for the N-alkylation of amines with
alcohols by the hetero-bidentate NHC-phosphine Ru catalyst.
Experimental section
General procedures and materials
Unless otherwise stated, all manipulations were carried out
under dry argon using conventional Schlenk and glove box
techniques. Non-halogenated solvents were dried over sodium
benzophenone ketyl and halogenated solvents over CaH2. All
other commercial reagents were used without further purifi-
cation. Detailed experimental procedures, characterization
provide clues to explain the importance of the hetero-bidentate
NHC-phosphine ligands, which could realize the smart
pathway selection for adjusting the dehydrogenation of alcohol
and the insertion of imine steps via tuning the stability and
activity of the [Ru–H] species.
On the basis of these observations and previous studies,9,10
1
data, computational details and structures, copies of H NMR
a
possible mechanism for the N-alkylation reaction is
and 13C NMR spectra for all isolated compounds are available
in the ESI.†
suggested (Scheme 5). At the initial stage, the alkoxy ruthe-
nium species A0 is generated by the dissociation of p-cymene
and the coordination of the alcohol to the ruthenium center
under the acceleration of the base. The phosphine arm is
more prone to stabilize the Ru hydride. The dehydrogenation
step would begin with the formation of an agostic intermedi-
ate A1 on the trans position to the phosphine arm.
Accompanied by its β-hydride elimination (TS-A1-B1), the
ruthenium hydride species B1 coordinated with the aldehyde
is generated. Subsequently, the condensation between the
aldehyde and amine would occur on the metal center to give
the imine complex C1. C1 would isomerize to C2 with the
hydride trans to the NHC arm, which will promote the inser-
tion of imine step. From C2, the hydride transfer (TS-C2-D2)
takes place to afford amido complex D2. Finally, the catalyti-
cally active alkoxy ruthenium species A0 will be regenerated by
releasing the N-alkylated amine as the product by the reaction
of species D2 with alcohol.
NMR spectra were recorded using a Bruker 400 MHz
spectrometer, and chemical shifts are reported relative to TMS
1
for H and 13C. ESI-MS spectra were recorded on a Shimadzu
LCMS-2010 instrument. GC analyses were performed on a
Shimadzu GC-2014C device equipped with a Wondacap 1
column. High resolution mass spectrometric (HRMS) data
were obtained using an LTQ Orbitrap Elite instrument, using a
sample concentration of approximately 1 ppm.
General method for the preparation of ruthenium complexes
6a–d
A
suspension of appropriate imidazolium salts (L1–L4,
0.1 mmol) and silver oxide (0.5 equiv.) in CH2Cl2 was stirred at
room temperature in the dark for 24 h. The mixture was then
filtered through a pad of Celite into a solution of [(p-cymene)
RuCl2]2 (0.5 equiv.) in CH2Cl2 and stirred at room temperature
for 24 h. Then the organic solvent was removed by evaporation
and the crude product was purified by column chromato-
graphy (CH2Cl2 : MeOH = 20 : 1).
Conclusions
General method for the preparation of ruthenium complexes
6aa and 6ca–ce
In summary, we have reported the synthesis and characteriz-
ation of a series of air-stable ruthenium complexes (6a–d, 6aa,
and 6ca–6ce) bearing
a hetero-bidentate NHC-phosphine To a solution of NaX (0.1 mmol; X = BArF, BPh4; for complexes
ligand, in which the substituents on the NHC wingtip and the 6cb and 6ce, respectively) or appropriate AgX (0.20 mmol; X =
coordinating counter-anions have been modified. These com- PF6, OTf and BF4 for complexes 6ca, 6cc and 6cd, respectively)
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in CH2Cl2 (2 mL) was added complex 6a or 6c (0.1 mmol) and
the resulting mixture was stirred at rt for 2 h. Then products
Acknowledgements
6aa and 6ca–ce were obtained directly by silica gel column This study was supported by the 12th Five-Year Plan Key
chromatography (CH2Cl2 : MeOH = 100 : 1 for 6aa; CH2Cl2 : n- Discipline of Clinical Pharmacy, High Level Clinical Key
hexane = 2 : 1 for 6cb; CH2Cl2 : MeOH = 40 : 1 for 6ca, 6cc and Specialty in Guangdong Province, the NSFC (22002023,
6cd; CH2Cl2 : n-hexane = 5 : 1 for 6ce).
21973113, and 21773312), the Guangdong Natural Science
Funds (no. 2015A030306027 for Distinguished Young Scholar),
the Tip-Top Youth Talents of Guangdong Special Support
Program (no. 20153100042090537) and the Fundamental
Research Funds for the Central Universities.
General method for the N-alkylation of amines with alcohols
To a 15 mL reaction tube in a glovebox, was added complex
6cb (0.25 mol%), KOtBu (75 mol%), alcohols (0.5 mmol), and
amine (0.5 mmol) at room temperature. Then the tube was
closed and removed from the glovebox. The reaction mixture
was stirred at 70 °C for 12 h. After being cooled to rt, the reac-
tion mixture was diluted with ethyl acetate, filtered and dried
under vacuum. The product was purified by column chromato-
graphy over silica-gel (300–400 mesh) with an appropriate
mixture of petroleum ether and ethyl acetate (80 : 1).
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Conflicts of interest
There are no conflicts to declare.
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