Polyhedron
Effect of the ancillary ligand in N-heterocyclic carbene iridium(III)
catalyzed N-alkylation of amines with alcohols
⇑
Xinshu Feng, Ming Huang
School of Clinical Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of air-stable N-heterocyclic carbene (NHC) Ir(III) complexes (Ir1-6), bearing various combinations
of chlorine, pyridine and NHC ligands, were assayed for the N-alkylation of amines with alcohols. It was
found that Ir3, with two monodentate 1,3-bis-methyl-imidazolylidene (IMe) ligands, emerged as the
most active complex. A large variety of amines and primary alcohols were efficiently converted into
mono-N-alkylated amines in 53–96% yields. As a special highlight, for the challenging MeOH, selective
N-monomethylation could be achieved using KOH as a base under an air atmosphere. Moreover, this cat-
alytic system was successfully applied to the gram-scale synthesis of some valuable compounds.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 6 April 2021
Accepted 15 May 2021
Available online 26 May 2021
Keywords:
N-heterocyclic carbene
Iridium
N-alkylation of amines with alcohols
Methanol
1. Introduction
tate phosphine-NHC-Ir(I) complex B (Scheme 1b) and realized the
N-alkylation of anilines with alcohols at room temperature [33]. In
N-Alkylated amines are one of the most valuable types of com-
pounds, having versatile applications in polymer materials, phar-
maceutical and synthetic industries [1–3]. The conventional
method for the preparation of N-alkylated amines involves a nucle-
ophilic substitution reaction of amines with an alkylating agent,
such as an alkyl halide. However, this procedure suffers from some
draw-backs, such as overalkylation, using toxic alkylating agents,
low atom economy and the generation of harmful by-products.
Alternatively, the hydrogen auto-transfer (HA) or borrowing
hydrogen (BH) strategy (Scheme 1a) is one of the most appealing
synthetic approaches for the synthesis of selective N-alkylated
amines [4–6]. Notably, this transformation is a green and sustain-
able reaction, using abundant alcohols as coupling reagents and
producing water as the only by-product.
To date, various transition metal (TM) catalyst systems based
on noble metals, such as Ru [7–10] and Ir [11–13], or non-noble
metals, such as Co [14–16], Fe [17–20], Ni [21–23] and Mn [24–
26], as well as TM-free catalyst systems [27–30] have been devel-
oped in these fields. Especially, Ir complexes with NHC ligands
have emerged as one of the most effective and practical catalysts
[31]. For instance, in 2012, Martín-Matute et al. developed the
Cp*Ir(III) complex A (Scheme 1b), bearing a functional alcohol/
alkoxide-tethered-NHC ligand, which exhibited highly catalytic
activity for the N-alkylation of anilines with alcohols under base-
free conditions [32]. In 2013, Andersson et al. developed the biden-
2017, Royo et al. reported the amide-functionalized NHC-Cp*Ir(III)
complex C (Scheme 1b), which exhibited high activity for the
N-alkylation of amines with alcohols in aqueous media and under
base-free conditions [34]. In 2019, Ke et al. demonstrated that
NHC-Ir(III) complex D (Scheme 1b), with a 2-hydroxypyridine
ligand, acted as a metal–ligand bifunctional catalyst for the N-alky-
lation of aromatic amines and poor nucleophilic sulfonamides with
alcohols in aqueous media [11]. Additionally, NHC-Ir complexes
have been developed for more challenging reactions, such as the
N-alkylation of amines with methanol, the N-alkylation of amides
with alcohols and the N-alkylation of aqueous ammonia with alco-
hols [12,35–38]. In 2017, Tu et al. reported the NHC-Ir coordination
polymer E (Scheme 1b) for the selective N-methylation of anilines
with methanol at 130 °C [36]. In 2018, Fujita et al. developed the
NHC-Ir complex F (Scheme 1b), which exhibited high catalytic per-
formance for the N-alkylation of aqueous ammonia with alcohols
at 150 °C [12]. Despite these great efforts, high temperature (above
100 °C) or high catalyst loadings (above 2 mol%) are usually
required to obtained a satisfactory yield. In addition, the effect of
the NHC ligands on the activity of Ir compounds has not been stud-
ied systematically. Therefore, the development of NHC-Ir catalysts
remains a major driving force in these fields.
Very recently, our group has developed a bis-NHC-Mn complex,
which provided the first example of a room temperature non-noble
metal homogeneous system that catalyzes the selective N-alkyla-
tion of anilines with alcohols [26]. Continuing in this field, we
became interested in a systematic study of the effects of the NHC
ligands of Cp*Ir(III) complexes on the reaction of the N-alkylation
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0277-5387/Ó 2021 Elsevier Ltd. All rights reserved.