Dimethylamination of Primary Alcohols Using a Homogeneous Iridium Catalyst: A Synthetic Method for N, N-Dimethylamine Derivatives

Article abstract of DOI:10.1021/acs.joc.0c02896

A new catalytic system for N,N-dimethylamination of primary alcohols using aqueous dimethylamine in the absence of additional organic solvents has been developed. The reaction proceeds via borrowing hydrogen processes, which are atom-efficient and environmentally benign. An iridium catalyst bearing an N-heterocyclic carbene (NHC) ligand exhibited high performance, without showing any deactivation under aqueous conditions. In addition, valuable N,N-dimethylamine derivatives, including biologically active and pharmaceutical molecules, were synthesized. The practical application of this methodology was demonstrated by a gram-scale reaction.

Full text of DOI:10.1021/acs.joc.0c02896

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Article
Dimethylamination of Primary Alcohols Using a Homogeneous
Iridium Catalyst: A Synthetic Method for N,N‑Dimethylamine
Derivatives
Jaeyoung Jeong and Ken-ichi Fujita*
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ABSTRACT: A new catalytic system for N,N-dimethylamination of
primary alcohols using aqueous dimethylamine in the absence of
additional organic solvents has been developed. The reaction proceeds
via borrowing hydrogen processes, which are atom-efficient and
environmentally benign. An iridium catalyst bearing an N-heterocyclic
carbene (NHC) ligand exhibited high performance, without showing
any deactivation under aqueous conditions. In addition, valuable N,N-
dimethylamine derivatives, including biologically active and pharma-
ceutical molecules, were synthesized. The practical application of this
methodology was demonstrated by a gram-scale reaction.
Scheme 1. Synthetic Method for N,N-Dimethylamine
Compounds
INTRODUCTION
■
N,N-Dimethylamine derivatives are a representative building
block of bioactive compounds and natural products that are
applied in various fields such as agrochemicals, materials, and
pharmaceuticals (Figure 1).1 Therefore, the synthesis of
valuable N,N-dimethylamine compounds has attracted much
attention.
The Eschweiler−Clarke reaction, which achieves N-methyl-
ation using amine and formaldehyde, has been established as a
conventional synthetic method in the industry (Scheme 1,
(1)).2 Furthermore, nucleophilic substitution using methyl
halide3 or dimethyl sulfate4 is well known (Scheme 1, (2)).
However, these reactions have significant disadvantages as they
Received: December 7, 2020
Published: February 19, 2021
Figure 1. Representative drugs containing the N,N-dimethylamine
moiety.
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use toxic reagents, as well as because of producing a large
amount of waste, in many cases, these reactions suffer from low
selectivity.
benign synthetic method was developed based on organic-
solvent-free reaction system. Based on this, we examined
synthetic methods for obtaining valuable dimethylamine
derivatives with important applications.
To overcome these drawbacks, transition-metal-catalyzed N-
methylation of amines utilizing methyl reagents5 such as
carbon dioxide,6 paraformaldehyde,7 or formic acid8 has been
successfully developed (Scheme 1, (3)). However, these
reactions require a reductant, are performed under harsh
conditions (high temperature and pressure), and have low
selectivity. Thus, the construction of a C−N bond through a
catalytic “borrowing hydrogen strategy,” using amines and
alcohols, has been regarded as a clean and atom-efficient
method.9 The overall reaction consists of several consecutive
processes including dehydrogenation, imine formation, and
transfer hydrogenation. The only generated byproduct, H2O, is
harmless. Based on this protocol, there have been many reports
of catalytic N-methylation using methanol to obtain N,N-
dimethylamine derivatives.10 However, for dehydrogenation,
compared to other alcohols, methanol demands that a higher
activation energy barrier should be overcome. Furthermore,
selectivity for N,N-dimethylation over N-methylation is poor.
Moreover, amines used as raw materials are usually synthesized
from nitrogen compounds such as ammonia, imines, and
amides, which are relatively expensive substrates.1g,11
RESULTS AND DISCUSSION
■
To obtain dimethylamine derivatives, we examined efficient
and environmentally benign iridium catalytic N,N-dimethyla-
mination of a range of primary alcohols, using aqueous
dimethylamine in the absence of additional organic solvents.
First, optimization studies were carried out with aqueous
dimethylamine and 1-octanol as a model reaction in the
presence of an iridium catalyst (1.0 mol %) and K2CO3. All
reactions were conducted in a sealed stainless tube, and the
results are summarized in Table 1. First of all, catalysts
Table 1. Optimization of Conditions for N,N-
Dimethylamination of 1-Octanol with Aqueous
a
Dimethylamine
By contrast, N,N-dimethylamination utilizing alcohols, via
borrowing hydrogen processes, is an efficient method to obtain
dimethylamine derivatives (Scheme 1, (4)).12 Alcohols are
good alkylating reagents considering their low toxicity, price,
and availability. Therefore, N,N-dimethylamination using
alcohol and dimethylamine has the advantage of being more
efficient than methylation of amines using methylation
reagents. Nevertheless, there are few examples using dimethyl-
amine for the synthesis of N,N-dimethylamine derivatives.
Since dimethylamine is gaseous at room temperature, it is
difficult to handle without special instrumentation. For this
reason, only a few methods using a mixture of organic solvents
or using dimethylammonium salts have been reported.13
In general, commercially available N,N-dimethylamine
derivatives are more expensive than the corresponding alcohols
with the same skeletons, although there are some exceptions.
Thus, the development of a new method for dimethylamina-
tion of alcohols is important because it would provide a means
of producing valuable compounds starting from inexpensive
raw materials. Thus, such a method has the potential to
become an important protocol in the field of synthetic organic
chemistry. In addition, N,N-dimethylamine compounds can be
simply synthesized using an aqueous dimethylamine solution.
The reaction using methylating agents requires relatively costly
amines and two cycles of methylation. Therefore, any synthetic
method using aqueous dimethylamine is a simpler and more
economically favorable process. However, in the absence of
additional organic solvents, catalytic N,N-dimethylamination of
alcohols using commercial aqueous dimethylamine via a
borrowing hydrogen strategy has so far remained a challenge.
In particular, in aqueous conditions, reactions using a metal
catalyst are rare because of the ease of deactivation and low
solubility.14
b
b
entry
catalyst
base (mol %)
conv. (%)
yield (%)
1
2
3
4
5
6
7
8
9
[Cp*IrCl2]2
[IrCl(cod)]2
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
K2CO3 (5)
none
18
8
13
8
1
2
3
4
5
5
5
5
24
35
82
92
92
63
86
90
15
35
77
85
91
62
83
89
K2CO3 (2.5)
K2CO3 (10)
10
a
Reaction was carried out with 1-octanol (1.0 mmol), dimethylamine
(6.0 mmol), K2CO3 (0−10 mol %), and the catalyst (1.0 mol % Ir) at
120 °C for 40 h. Determined by GC analysis using biphenyl as an
b
internal standard.
previously demonstrated as effective for the N-alkylation of
alcohols were investigated. When iridium catalysts without an
NHC ligandsuch as [Cp*IrCl2]2, [IrCl(cod)]2, and a water-
soluble triammine catalyst 1were used, N,N-dimethyloctyl-
amine was obtained with low yield under aqueous conditions
(Table 1, entries 1−3).
However, in the presence of catalyst 2, which has an NHC
ligand with methyl substituents, catalytic activity slightly
increased to give 35% yield (Table 1, entry 4). Therefore,
we expected that an iridium catalyst including an NHC ligand
would be effective for N,N-dimethylamination by aqueous
We have previously developed and reported N-alkylation
using alcohols and a series of efficient catalysts.15 In this study,
we discovered that an iridium catalyst with an N-heterocyclic
carbene (NHC) ligand exhibited good catalytic activity in the
N,N-dimethylamination of alcohols using commercially avail-
able aqueous dimethylamine. Moreover, an environmentally
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dimethylamine. The yield was improved to 77% when catalyst
3, bearing NHC ligands with ethyl groups was used (Table 1,
entry 5). Among all of the catalysts examined, catalysts 4 and 5,
having NHC ligands with isopropyl substituents on nitrogen,
demonstrated the highest activity, with the greatest conversion
and yield percentages being achieved using these catalysts
(Table 1, entries 6 and 7). In particular, NHC catalyst 5, which
has dichloride ligand, exhibited the best performance and
resulted in a 91% (Table 1, entry 7). We also optimized the
amount of a base (Table 1, entries 8−10). In the absence of a
base, the yield was reduced to 62% (entry 8). When a 2.5 or 10
mol % amount of K2CO3 was added, the yield was increased
(entries 9 and 10), but a 5 mol % amount of K2CO3 gave the
best results. In addition to this, other bases, catalysts,
temperatures, reaction times, and the dimethylamine amounts
were explored (see the Supporting Information, Tables S1−
S3). After identifying suitable conditions for the reaction, we
investigated the substrate scope for this reaction.
Scheme 2. N,N-Dimethylamination of Various Primary
Alcohols
a
N,N-Dimethylamination with aqueous dimethylamine of
various primary alcohols was conducted under the optimized
conditions (5 mol % K2CO3, 1.0 mol % catalyst 5, 120 °C, 40
h). The obtained dimethylamine derivatives are illustrated in
Scheme 2. Good yields were obtained for these derivatives.
Interestingly, trace amounts of monomethylamine byproducts
were confirmed by nuclear magnetic resonance (NMR)
spectroscopy in some cases. N,N-Dimethylamine derivatives
having various alkyl chains, such as octyl, hexyl, and decyl, were
observed in good yields (7a−7c). N,N-Dimethylbenzylamine
products with methyl or methoxy aromatic substituents (7d−
7g) were also obtained in good yields. In addition, we
attempted to synthesize some of the expensive N,N-
dimethylphenethylamines used in various fields, including as
supplements and flavorings (7h−7p).16 Phenethylalcohol gave
the corresponding dimethylamine product with an isolated
yield of 84% (7h). Although a meta-methyl substituent on
phenethylalcohol resulted in the slightly reduced yield (7k),
ortho- or para-methyl phenethylalcohols also produced N,N-
dimethylaminated derivatives in good yields (7i, 7j). More-
over, phenethylalcohol with an electron-withdrawing group
such as a halogen and phenethylalcohol with an electron-
donating methoxy or dimethylamino group afforded the
desired products (7l−7p). Interestingly, saturated cyclic
alcohol (2-cyclohexylethanol) and naphthalene ethanol were
also tolerated as substrates (7q and 7r). 3-Phenyl-1-propyl
alcohol and 4-phenyl-1-butanol, having elongated carbon
chains, resulted in excellent yields for their N,N-dimethylamino
derivatives (7s and 7t). Additionally, the reactions of cinnamyl
alcohol and 3-phenyl-2-propyn-1-ol with dimethylamine were
attempted. However, desired N,N-dimethylamino products
were not detected at all.
a
Reaction was carried out with primary alcohol (1.0 mmol),
dimethylamine (6.0 mmol), catalyst 5 (1.0 mol %), and K2CO3
b
(5.0 mol %) at 120 °C for 40 h. Isolated yields are shown. Yield was
We also conducted N-monomethylamination with aqueous
methylamine and alcohols. Interestingly, N-monomethyl-
amines were obtained. Benzyl alcohol and 1-octanol gave the
corresponding N-monomethylamine products (Scheme 3, 8a
and 8b).
c
determined by GC analysis. Reaction was carried out at 130 °C.
d
e
Reaction was carried out for 20 h. Catalyst 5 (0.5 mol %) was used.
Isolated yields are shown.
To evaluate the practical utility of our reaction scheme, a
gram-scale reaction with phenylbutyl alcohol (10 mmol) and
aqueous dimethylamine was carried out. Catalyst 5 exhibited
good performance and the product was obtained in an
excellent isolated yield (Scheme 4). Finally, we attempted the
synthesis of drugs, including a biologically active compound
containing a dimethylamine moiety, using this methodology
(Scheme 5). Hordenine,17 a natural alkaloid, was obtained in
the form of a precursor with an isolated yield of 75% (7u).
Antergan18 is an antihistamine possessing a dimethylamine
moiety and this was prepared in good yield (77%) (7v).
To compare the reactivity between benzyl alcohol and long-
chained aliphatic alcohol, a reaction using a 1:1 mixture of
benzyl alcohol (0.5 mmol) and 1-octanol (0.5 mmol), aqueous
dimethylamine (6.0 mmol), catalyst 5 (1.0 mol %), and K2CO3
(5.0 mol %) at 120 °C for 0.5 h was carried out. By this
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This result indicates that benzyl alcohol is more reactive
than 1-octanol.
Scheme 3. Investigation of N-Monomethylamination Using
an Aqueous Methylamine Solution
a
Based on a previously reported mechanism for N,N-
dimethylamination using a secondary amine and alcohol,15f,19
a plausible mechanism for the reactions investigated in this
study is described in Scheme 7. Alkoxo-iridium species A is
Scheme 7. Possible Mechanism for the N,N-
Dimethylamination of Primary Alcohols With
Dimethylamine
a
Reaction was carried out with primary alcohol (1.0 mmol),
methylamine (6.0 mmol), catalyst 5 (1.0 mol %), and K2CO3 (5.0
mol %) at 120 °C for 40 h. Yields were determined by GC analysis.
a
Scheme 4. Gram-Scale Reaction
a
Reaction was carried out with phenylbutyl alcohol (10.0 mmol),
dimethylamine (60.0 mmol), catalyst 5 (1.0 mol %), and K2CO3 (5.0
mol %) at 120 °C for 40 h. Isolated yields are shown.
Scheme 5. Synthesis of Pharmaceutical Drugs via N,N-
a
Dimethylation Using Aqueous Dimethylamine
formed by the reaction of alcohol and catalyst 5. Then, an
aldehyde and hydride-iridium species B is formed through β-
hydrogen elimination. The aldehyde is transformed into an
iminium ion by condensation with dimethylamine. Next, the
iminium ion is coordinated to the metal in hydride-iridium
species B and an amino complex C is formed. The product is
released through the recovery of alkoxo-iridium species A and
the catalytic cycle is completed.
a
Reaction was carried out with primary alcohol (1.0 mmol),
dimethylamine (6.0 mmol), catalyst 5 (1.0 mol %), and K2CO3
(5.0 mol %) at 120 °C for 40 h. Isolated yields are shown. Reaction
was carried out at 130 °C.
CONCLUSIONS
b
■
In summary, we developed an efficient and environmentally
benign method for the N,N-dimethylamination of various
primary alcohols using aqueous dimethylamine, without any
additional solvent, via borrowing hydrogen and hydrogen
autotransfer processes. A dichloride iridium catalyst bearing an
N-heterocyclic carbene ligand with isopropyl substitutes
exhibited good performance under aqueous conditions.
Valuable dimethylamine derivatives including a simple
pharmaceutical drug were synthesized from relatively inex-
pensive primary alcohols and aqueous dimethylamine.
competitive experiment, N,N-dimethylbenzylamine was ob-
tained in a higher yield than N,N-dimethyloctylamine (Scheme
6).
a
Scheme 6. Competitive Experiment
EXPERIMENTAL SECTION
■
General Information. All reactions were performed in a sealed
stainless tube. 1H and 13C{1H} NMR spectra were recorded on JEOL
ECX-500 (500 MHz) and ECS-400 (400 MHz) spectrometers. Gas
chromatography (GC) analyses were performed on a GC-4000Plus
with a capillary column (InertCap for Amines and InertCap Pure
a
Reaction was carried out with benzyl alcohol (0.5 mmol) and 1-
WAX). The complexes 1,15c 2,20 3,21 4,15e 5,10h and [Cp*IrCl2]2
22
octanol (0.5 mmol), aqueous dimethylamine (6.0 mmol), catalyst 5
(1.0 mol %), and K2CO3 (5.0 mol %) at 120 °C for 0.5 h. Yield was
determined by GC analysis.
were prepared according to the literature method. 2-(4-Benzylox-
yphenyl) ethanol23 and N-benzyl-2-anilinoethanol24 were prepared
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according to the literature method. An aqueous dimethylamine
solution (50%) and an aqueous methylamine solution (40%) are
commercially available and were used as received. Flash column
chromatography was carried out using a Wako-gel C-200. All other
reagents are commercially available and were used as received from
Tokyo Chemical Industry, Sigma-Aldrich, Acros Organics, BLD
Pharm, FUJIFILM Wako Pure Chemical Corporation, and Oakwood
Chemical.
Procedure for Optimization Under the Various Conditions
Shown in Table 1. In a stainless tube, the catalyst (1.0 mol %),
K2CO3 (0−10 mol %), 1-octanol (1.0 mmol), and a 50% aqueous
solution of dimethylamine (0.66 mL, 6.0 mmol) were added and
sealed. The mixture was stirred for 40 h at 120 °C using an aluminum
block heater. On completion of the reaction, it was cooled to room
temperature. The product was extracted with tetrahydrofuran (THF)
(50 mL). The conversion of 1-octanol and the yield of N,N-
dimethyloctylamine (7a) were determined by GC analysis using
biphenyl as an internal standard.
(50:1) to give 7h as a pale yellow oil, 126.1 mg (0.844 mmol, 84%).
1H NMR (500 MHz, CDCl3, r.t.) δ 7.31−7.28 (m, 2H), 7.23−7.19
(m, 3H), 2.81−2.78 (m, 2H), 2.56−2.53 (m, 2H), 2.31 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 140.4, 128.6, 128.4, 126.0,
61.6, 45.5, 34.5.
2-(2-Methylphenyl)-N,N-dimethylethanamine (Scheme 2, 7i).
The product was isolated by silica gel chromatography eluting with
CHCl3/Et3N (50:1) to give 7i as a pale yellow oil, 137.9 mg (0.847
mmol, 85%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.20−7.10 (m, 4H),
2.81−2.77 (m, 2H), 2.49−2.46 (m, 2H), 2,34 (s, 3H), 2.33(s, 6H).
13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 138.6, 136.1, 130.3, 129.3,
126.3, 126.1, 60.4, 45.6, 31.8, 19.4. Anal. calcd for C11H17N: C, 80.92;
N, 8.58; H, 10.50. Found: C, 80.74; N, 8.49; H, 10.67.
2-(4-Methylphenyl)-N,N-dimethylethanamine (Scheme 2, 7j).26
The product was isolated by silica gel chromatography eluting with
CHCl3/Et3N (50:1) to give 7j as a pale yellow oil, 132.9 mg (0.814
mmol, 82%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.15−7.08 (m, 4H),
2.77−2.73 (m, 2H), 2.53−2.50 (m, 2H), 2.32 (s, 3H), 2.30 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 137.4, 135.5, 129.2, 128.6,
61.9, 45.6, 34.1, 21.1.
N,N-Dimethylamination of Various Primary Alcohols with
Aqueous Dimethylamine Catalyzed by 5 Given Dimethyl-
amine Derivatives Shown in Scheme 2. In a stainless tube, the
iridium catalyst 5 (0.5−1.0 mol %), K2CO3 (5 mol %), primary
alcohol (1.0 mmol), and a 50% aqueous solution of dimethylamine
(0.66 mL, 6.0 mmol) were added and sealed. The mixture was stirred
for 20−40 h at 120−130 °C using an aluminum block heater. On
completion of the reaction, it was cooled to room temperature. The
product was extracted with dichloromethane. After evaporation of the
solution, the product was isolated by silica gel chromatography.
Quantitative analysis of 7b and 7d were carried out by GC using
biphenyl as an internal standard. Identification of 7b and 7d was done
by comparison of retention time with commercially available
standards.
2-(3-Methylphenyl)-N,N-dimethylethanamine (Scheme 2, 7k).
The product was isolated by silica gel chromatography eluting with
CHCl3/Et3N (50:1) to give 7k as a pale yellow oil, 109.7 mg (0.672
mmol, 67%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.21−7.17 (m, 1H),
7.02−7.01 (m, 3H), 2.77−2.73 (m, 2H), 2.54−2.51 (m, 2H), 2.33 (s,
3H), 2.30 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 140.4,
138.1, 129.6, 128.4, 126.9, 125.8, 61.8, 45.6, 34.4, 21.5. Anal. calcd for
C11H17N: C, 80.92; N, 8.58; H, 10.50. Found: C, 80.68; N, 8.34; H,
10.71.
2-(4-Fluorophenyl)-N,N-dimethylethanamine (Scheme 2, 7l).27
The product was isolated by silica gel chromatography eluting with
CHCl3/Et2NH (50:1) to give 7l as a pale yellow oil, 151.8 mg (0.908
N,N-Dimethyloctylamine (Scheme 2, 7a).10h The product was
isolated by silica gel chromatography eluting with CHCl3/Et3N
(50:1) to give 7a as a pale yellow oil, 130.0 mg (0.826 mmol, 83%).
1H NMR (500 MHz, CDCl3, r.t.) δ 2.20−2.09 (m, 8H), 1.43−1.37
1
mmol, 91%). H NMR (500 MHz, CDCl3, r.t.) 7.16−7.13 (m, 2H),
6.99−6.94 (m, 2H), 2.76−2.73 (m, 2H), 2.51−2.48 (m, 2H), 2.28 (s,
6H). 13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 161.5 (d, J = 244.1
Hz), 136.1 (d, J = 2.4 Hz), 130.1 (d, J = 7.1 Hz), 115.3 (d, J = 20.4
Hz), 61.7, 45.6, 33.7.
(m, 2H), 1.28−1.10 (m, 10H), 0.84−0.81 (t, 3H, J = 7.0 Hz).
13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 60.1, 45.6, 31.9, 29.7, 29.4,
27.9, 27.6, 22.8, 14.2.
2-(4-Chlorophenyl)-N,N-dimethylethanamine (Scheme 2, 7m).
The product was isolated by silica gel chromatography eluting with
CHCl3/Et2NH (50:1) to give 7m as a pale yellow oil, 147.8 mg
(0.805 mmol, 80%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.23 (d, 2H,
J = 8.6 Hz), 7.12 (d, 2H, J = 8.3 Hz), 2.75−2.72 (m, 2H), 2.51−2.47
(m, 2H), 2.27 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3, r.t.) δ
138.9, 131.8, 130.1, 128.6, 61.4, 45.6, 33.8. Anal. calcd for
C10H14NCl: C, 65.29; N, 7.63; H, 7.68. Found: C, 64.99; N, 7.50;
H, 7.66.
N,N-Dimethyldecylamine (Scheme 2, 7c).25 The product was
isolated by silica gel chromatography eluting with CHCl3/Et3N
(50:1) to give 7c as a pale yellow oil, 129.2 mg (0.699 mmol, 70%).
1H NMR (500 MHz, CDCl3, r.t.) δ 2.27−2.17 (m, 8H), 1.45−1.42
(m, 2H), 1.31−1.18 (m, 14H), 0.87 (t, 3H, J = 6.9 Hz) 13C{1H}
NMR (126 MHz, CDCl3, r.t.) δ 60.2, 45.7, 32.1, 29.79, 29.77, 29.75,
29.5, 28.0, 27.7, 22.8, 14.3.
N,N-Dimethyl(3-methylphenyl)methanamine (Scheme 2, 7e).10h
The product was isolated by silica gel chromatography eluting with an
organic solvent (EtOAc/hexane/Et3N = 1:50:1 to CHCl3/Et3N =
30:1) to give 7e as a pale yellow oil, 87.0 mg (0.583 mmol, 58%). 1H
NMR (500 MHz, CDCl3, r.t.) δ 7.21 (t, 1H, J = 8.0 Hz), 7.14 (s, 1H),
7.08 (t, 2H, J = 7.5 Hz), 3.38 (s, 2H). 2.35 (s, 3H), 2.24 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 138.9, 138.0, 129.9, 128.2,
127.9, 126.3, 64.6, 45.6, 21.5.
2-(4-Bromophenyl)-N,N-dimethylethanamine (Scheme 2, 7n).28
The product was isolated by silica gel chromatography eluting with
CHCl3/Et2NH (50:1) to give 7n as a pale yellow oil, 176.4 mg (0.773
mmol, 77%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.39 (d, 2H, J = 8.5
Hz), 7.07 (d, 2H, J = 8.5 Hz), 2.74−2.71 (m, 2H), 2.51−2.48 (m,
2H), 2.28 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 139.5,
131.5, 130.5, 119.9, 61.4, 45.6, 33.9.
2-(4-Methoxyphenyl)-N,N-dimethylethanamine (Scheme 2,
7o).29 The product was isolated by silica gel chromatography eluting
with CHCl3/Et3N (100:1) to give 7o as a pale yellow oil, 164.1 mg
(0.915 mmol, 92%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.2 (d, 2H, J
= 8.5 Hz), 6.82 (d, 2H, J = 8.5 Hz), 3.78 (s, 3H) 2.74−2.70 (m, 2H),
2.51−2.47 (m, 2H), 2.29 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3,
r.t.) δ 158.0, 132.6, 129.6, 113.9, 62.0, 55.4, 45.6, 33.6.
N,N-Dimethyl(4-methylphenyl)methanamine (Scheme 2, 7f).10h
The product was isolated by silica gel chromatography eluting with
CHCl3/Et3N = 30:1 to give 7f as a pale yellow oil, 128.4 mg (0.860
mmol, 86%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.19 (d, 2H, J = 7.5
Hz), 7.13 (d, 2H, J = 8 Hz), 3.38 (s, 2H), 2.34 (s, 3H), 2.23 (s, 6H).
13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 136.7, 135.9, 129.2, 129.0,
64.2, 45.4, 21.2.
2-(4-Dimethylaminophenyl)-N,N-dimethylethanamine (Scheme
2, 7p). The product was isolated by silica gel chromatography eluting
with CHCl3/Et3N (100:3) to give 7p as a pale yellow oil, 185.8 mg
(0.966 mmol, 97%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.08 (d, 2H,
J = 8.5 Hz), 6.70 (d, 2H, J = 8.5 Hz), 2.91 (s, 6H), 2.71−2.68 (m,
2H), 2.51−2.47 (m, 2H), 2.29 (s, 6H). 13C{1H} NMR (126 MHz,
CDCl3, r.t.) δ 149.3, 129.3, 128.6, 62.1, 45.6, 41.0, 33.5. Anal. calcd
for C12H20N2: C, 74.95; N, 14.57; H, 10.48. Found: C, 74.74; N,
14.35; H, 10.59.
N,N-Dimethyl(4-methoxylphenyl)methanamine (Scheme 2,
7g).10h The product was isolated by silica gel chromatography eluting
with an organic solvent (EtOAc/hexane = 1:50 to CHCl3/Et3N =
50:1) to give 7g as a pale yellow oil, 150.2 mg (0.919 mmol, 92%). 1H
NMR (500 MHz, CDCl3, r.t.) δ 7.21 (d, 2H, J = 9 Hz), 6.85 (d, 2H, J
= 9 Hz), 3.80 (s, 3H), 3.35 (s, 2H), 2.22 (s, 6H). 13C{1H} NMR (126
MHz, CDCl3, r.t.) δ 158.8, 131.1, 130.4, 113.7, 63.9, 55.4, 45.3.
N,N-Dimethylphenethylamine (Scheme 2, 7h).13b The product
was isolated by silica gel chromatography eluting with CHCl3/Et3N
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J. Org. Chem. 2021, 86, 4053−4060

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Article
2-Cyclohexyl-N,N-dimethylethanamine (Scheme 2, 7q).30 The
product was isolated by silica gel chromatography eluting with
CHCl3/Et2NH (100:1) to give 7q as a pale yellow oil, 145.9 mg
Antergan (Scheme 5, 7v).13e In a stainless tube, the iridium
catalyst 5 (5.6 mg (1.0 mol %)), K2CO3 (7.1 mg (5 mol %)), N-
benzyl-2-anilinoethanol (227.9 mg (1.0 mmol)), and a 50% aqueous
solution of dimethylamine (537.4 mg (0.66 mL, 6.0 mmol)) were
added and sealed. The mixture was stirred for 40 h at 130 °C using an
aluminum block heater. On completion of the reaction, it was cooled
to room temperature. The product was extracted with dichloro-
methane. After evaporation of the solution, the product was isolated
by silica gel chromatography eluting with CHCl3/Et3N (50:1) to give
7v as a pale yellow oil, 195.2 mg (0.767 mmol, 77%). 1H NMR (400.0
MHz, CDCl3, r.t.) δ 7.31−7.29 (m, 2H), 7.25−7.16 (m, 5H), 6.71−
6.66 (m, 3H), 4.57 (s, 2H), 3.55 (t, 2H, J = 7.6 Hz), 2.55 (t, 2H, J =
8.0 Hz), 2.28 (s, 6H). 13C{1H} NMR (100.5 MHz, CDCl3, r.t.) δ
148.5, 139.0, 129.4, 128.7, 126.9, 126.7, 116.4, 112.2, 56.5, 54.9, 49.7,
46.1.
Competitive Experiment (Scheme 6). In a stainless tube, the
iridium catalyst 5 (1.0 mol %), K2CO3 (5 mol %), benzyl alcohol (0.5
mmol), 1-octanol, and a 50% aqueous solution of dimethylamine (6.0
mmol) were added and sealed. The mixture was stirred for 0.5 h at
120 °C using an aluminum block heater. On completion of the
reaction, it was cooled to room temperature. The product yield was
determined by GC analysis using biphenyl as an internal standard.
1
(0.940 mmol, 94%). H NMR (500 MHz, CDCl3, r.t.) δ 2.25−2.22
(m, 2H), 2.15 (s, 6H), 1.70−0.87 (m, 13H). 13C{1H} NMR (126
MHz, CDCl3, r.t.) δ 57.8, 45.7, 36.1, 35.6, 33.6, 26.8, 26.4.
N,N-Dimethyl-2-Naphthaleneethanamine (Scheme 2, 7r). The
product was isolated by silica gel chromatography eluting with
CHCl3/Et2NH (50:1) to give 7r as a pale yellow oil, 171.2 mg (0.859
mmol, 86%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.82−7.78 (m, 3H),
7.66 (s, 1H), 7.48−7.35 (m, 3H), 2.98−2.92 (m, 2H), 2.65−2.62 (m,
2H), 2.34 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3, r.t.) δ 138.1,
133.7, 132.2, 128.0, 127.7, 127.53 (two peaks may be overlapped),
126.9, 126.0, 125.3, 61.6, 45.7, 34.7. Anal. calcd for C14H17N: C,
84.37; N, 7.03; H, 8.60. Found: C, 84.22; N, 6.88; H, 8.80.
N,N-Dimethyl-3-phenylpropan-1-amine (Scheme 2, 7s).13e The
product was isolated by silica gel chromatography eluting with
CHCl3/Et3N (50:1) to give 7s as a pale yellow oil, 150.2 mg (0.920
mmol, 92%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.3−7.26 (m, 2H),
7.21−7.17 (m, 3H), 2.64 (t, 2H, J = 7.9 Hz), 2.30 (t, 6H, J = 7.4 Hz),
2.23 (s, 6H), 1.80 (q, 2H, J = 7.5 Hz). 13C{1H} NMR (126 MHz,
CDCl3) δ 142.4, 128.5, 128.4, 125.8, 59.4, 45.6, 33.8, 29.6.
N,N-Dimethyl-3-phenylbutan-1-amine (Scheme 2, 7t).31 The
product was isolated by silica gel chromatography eluting with
CHCl3/Et3N (50:1) to give 7t as a pale yellow oil, 167.7 mg (0.946
mmol, 94%). 1H NMR (500 MHz, CDCl3, r.t.) δ 7.30−7.26 (m, 2H),
7.19−7.16 (m, 3H), 2.63 (t, 2H, J = 7.7 Hz), 2.27 (t, 2H, J = 7.6 Hz),
2.21 (s, 6H), 1.68−1.62 (m, 2H), 1.54−1.48 (m, 2H). 13C{1H} NMR
(126 MHz, CDCl3, r.t.) δ 142.6, 128.5, 128.3, 125.7, 59.8, 45.7, 36.0,
29.4, 27.6.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02896.
■
sı
Investigation of additional conditions such as catalysts,
bases, temperature, reaction times, and the amount of
1
Investigation of N-Monomethylamination Using an Aque-
ous Methylamine Solution (Scheme 3). In a stainless tube, the
iridium catalyst 5 (1.0 mol %), K2CO3 (5 mol %), primary alcohol
(1.0 mmol), and a 40% aqueous solution of methylamine (0.50 mL,
6.0 mmol) were added and sealed. The mixture was stirred for 40 h at
120 °C using an aluminum block heater. On completion of the
reaction, it was cooled to room temperature. The product yield was
determined by GC analysis using biphenyl as an internal standard.
Gram-Scale Reaction to Synthesize N,N-Dimethyl-3-phenyl-
butan-1-amine (Scheme 4). In a stainless tube, the iridium catalyst
5 (55.1 mg (1.0 mol %)), K2CO3 (69.2 mg (5 mol %)), 4-phenyl-1-
butanol (1501.1 mg (10.0 mmol)), and a 50% aqueous solution of
dimethylamine (5403.7 mg (6.60 mL, 60.0 mmol)) were added and
sealed. The mixture was stirred for 40 h at 120 °C using an aluminum
block heater. On completion of the reaction, it was cooled to room
temperature. The product was extracted with dichloromethane. After
evaporation of the solution, the product was isolated by silica gel
chromatography eluting with CHCl3/Et3N (50:1) to give 7t as a pale
yellow oil, 1742.9 mg (9.83 mmol, 98%). 1H NMR (400 MHz,
CDCl3, r.t.) δ 7.30−7.25 (m, 2H), 7.19−7.15 (m, 3H), 2.63 (t, 2H, J
= 7.2 Hz), 2.27 (t, 2H, J = 7.2 Hz), 2.20 (s, 6H), 1.70−1.60 (m, 2H),
1.54−1.47 (m, 2H). 13C{1H} NMR (100.5 MHz, CDCl3, r.t.) δ 142.7,
128.5, 128.4, 125.8, 59.9, 45.7, 36.0, 29.4, 27.6.
the aqueous dimethylamine solution and copies of H
and 13C{1H} NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Ken-ichi Fujita − Graduate School of Human and
Environmental Studies, Kyoto University, Kyoto 606-8501,
Japan; orcid.org/0000-0002-8362-2694;
Email: fujita.kenichi.6a@kyoto-u.ac.jp
Author
Jaeyoung Jeong − Graduate School of Human and
Environmental Studies, Kyoto University, Kyoto 606-8501,
Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02896
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
2-(4-Benzyloxyphenyl)-N,N-dimethylethanamine (Scheme
5, 7u). In a stainless tube, the iridium catalyst 5 (5.5 mg (1.0 mol
%)), K2CO3 (7.1 mg (5 mol %)), 2-(4-benzyloxyphenyl) ethanol
(227.8 mg (1.0 mmol)), and a 50% aqueous solution of dimethyl-
amine (543.6 mg (0.66 mL, 6.0 mmol)) were added and sealed. The
mixture was stirred for 40 h at 120 °C using an aluminum block
heater. On completion of the reaction, it was cooled to room
temperature. The product was extracted with dichloromethane. After
evaporation of the solution, the product was isolated by silica gel
chromatography eluting with CHCl3/Et3N (100:1) to give 7u as a
■
This work was financially supported by the JSPS KAKENHI
(JP19H02715 and JP19H05053). The authors thank Dr. T.
Shimbayashi and M. Shimizu for their helpful suggestions and
comments. The authors also thank S. Furukawa for his valuable
technical assistance.
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J. Org. Chem. 2021, 86, 4053−4060