Methylation of Amines and Ketones with Methanol Catalyzed by an Iridium Complex Bearing a 2-Hydroxypyridylmethylene Fragment

Article abstract of DOI:10.1021/acs.organomet.8b00575

Reaction of complex [Cp?Ir(HOC₅H₃CH₂C₅H₃OH)Cl][Cl] (1) with AgOTf generated the product [Cp?Ir(HOC₅H₃CH₂C₅H₃OH)(H₂O)][OTf]₂ (2), which was further transformed to the complex [Cp?Ir(OC₅H₃CH₂C₅H₃O)(H₂O)] (3) in the presence of t-BuONa via -OH deprotonation. Complexes 1-3 exhibited high activity for the methylation of amines and ketones. These C-C and C-N coupling reactions proceeded in air with 1 mol % catalyst loading in the presence of K₂CO₃.

Full text of DOI:10.1021/acs.organomet.8b00575

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Methylation of Amines and Ketones with Methanol Catalyzed by an
Iridium Complex Bearing a 2‑Hydroxypyridylmethylene Fragment
†
†
†
,†
Danfeng Deng, Bowen Hu, Min Yang, and Dafa Chen*
†MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemical Engineering
&
Technology, Harbin Institute of Technology, Harbin 150001, People’s Republic of China
*
S Supporting Information
A B S T R A C T : R e a c t i o n o f c o m p l e x [ C p * I r -
(
HOC H CH C H OH)Cl][Cl] (1) with AgOTf generated
5 3 2 5 3
the product [Cp*Ir(HOC H CH C H OH)(H O)][OTf]
5
3
2
5
3
2
2
(
(
2), which was further transformed to the complex [Cp*Ir-
OC H CH C H O)(H O)] (3) in the presence of t-BuONa
5
3
2
5
3
2
via −OH deprotonation. Complexes 1−3 exhibited high
activity for the methylation of amines and ketones. These C−
C and C−N coupling reactions proceeded in air with 1 mol %
catalyst loading in the presence of K CO .
2
3
INTRODUCTION
The borrowing hydrogen (BH) reaction, which is also known
as hydrogen autotransfer, has become an elegant protocol for
the coupling of C−C and C−N bonds during the past years.
Traditional methods for methylation of amines, ketones, or
other methylene compounds are usually dependent on the
utilization of toxic methyl halides and excess base. As
methanol is an abundant, atom-economical and environ-
mentally friendly C1 source, transition-metal-based BH
More recently, our group designed the ruthenium hydride
c o m p l e x b a s e d o n t h e l i g a n d
HOC H NCH C H NC H NOH], which contains one
■
c
[
5
3
2
5
3
5
3
1
−CH C H OH and one −C H OH located at the 6- and 2-
2
5
3
5
3
positions of the middle pyridyl ring. When it was treated with 2
equiv of t-BuOK, c was transformed into d via selective
deprotonation, which means that the −OH group of
2
−
−
C H CH C H OH is more acidic than that of
5 3 2 5 3
7
C H C H OH (Scheme 1). Hence, by the introduction of
5
3
5
3
a methylene group into the 6,6′-dihydroxy-2,2′-bipyridine part
methylation using methanol as a C source for the selective
1
of complex b, the acidity of the resulting complex will increase,
transformation of C−H and N−H bonds to C−CH and N−
3
and it might achieve better catalytic activity for N−CH and
CH bonds has received increasing attention in green
3
3
3
C−CH coupling in the presence of a weaker base (Figure 1,
chemistry. For example, several catalysts have been applied
3
4
right). Herein we report the synthesis and reactivity of the new
to the methylation of ketones to construct C−CH bonds,
and more studies have been reported for N-methylation of
amines to construct N−CH bonds.
Although significant achievements have been made, strong
bases (NaOH, t-BuONa, KOH, t-BuOK, and t-BuOLi) are
usually necessary in two such kinds of reactions. Recently,
the Li group developed a new Cp*Ir complex a bearing a 2,2′-
bibenzimidazole functional ligand with protic hydrogens and
studied its catalytic reactivity for N-methylation of various
amines with methanol in the presence of a weak base
3
Cp*Ir complex [Cp*Ir(HOC H CH C H OH)Cl][Cl] (1),
5
3
2
5
3
5
bearing a 2-hydroxy-6-((6-hydroxypridin-2-yl)methyl)pyridine
ligand (HOC CH OH, L ) (Figure 1, right). In
3
H
C
H
5
5
3
2
3
1
addition, it showed high catalytic efficiency for the methylation
of amines and ketones with methanol, in the presence of
K CO .
2 3
4
,5
RESULTS AND DISCUSSION
■
5g
Synthesis and Characterization of Ligand and
Complexes. As shown in Scheme 2, L was obtained by the
(
Cs CO ) (Figure 1, left). When aniline was used as the
2 3
1
substrate, the yield reached 98% in 12 h with 1 mol % of
catalyst and 0.3 equiv of Cs CO at 120 °C. When Cp*Ir
complexes with 2-hydroxypyridine derivatives, which were
reaction of HBr (40% in water) with 2-methoxy-6-((6-
methoxypyridin-2-yl)methyl)pyridine at reflux for 3 h in 92%
yield. When L1 was treated with [Cp*IrCl2]2 in boiling
2
3
6
reported by Fujita, Yamaguchi, and co-workers, were tried as
CH OH for 6 h, the yellow product [Cp*Ir-
3
catalysts under the same conditions, the results were not very
good. For example, the yield was decreased to 90% when
(
HOC H CH C H OH)(Cl)][Cl] (1) was isolated in 90%
5 3 2 5 3
6
c
complex b was used as the catalyst (Figure 1, middle). When
Cs CO was replaced by a weaker base (K CO ), a relatively
low yield (84%) was obtained.
Received: August 10, 2018
2
3
2
3
5g
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00575
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Figure 1. Li’s iridium complex a (left), Fujita’s iridium complex b (middle), and complex 1 in this work (right).
Scheme 1. Selective Deprotonation from Complex c to d
Scheme 2. Synthesis of Compounds L and 1
1
Figure 2. Molecular structure of complex 1. Hydrogen atoms, solvent,
−
and Cl anion have been omitted for clarity. Selected bond distances
(
2
Å) and angles (deg): Ir(1)−N(1), 2.152(4); Ir(1)−N(1A),
.149(2); Ir(1)−Cl(1), 2.4235(15); Ir(1)−C(7), 2.155(4); Ir(1)−
C(8), 2.178(5); Ir(1)−C(9), 2.164(6); N(1)−Ir(1)−N(1A),
8
8
6.0(2); N(1)−Ir(1)−Cl(1), 86.09(11); N(1A)−Ir(1)−Cl(1),
6.09(11).
1
0
(
H O)] (3) in 80% yield (Scheme 3). No −OH signal is
2
1
shown in the H NMR spectrum of complex 3.
Catalysis. Complexes 1-3 were first tested as catalysts for
the N-methylation of amines. To find the optimal conditions,
the reaction of aniline with methanol was selected as the model
reaction (Table 1). At 120 °C, in the presence of 0.3 equiv of
1
yield. The H NMR spectrum of 1 in d -DMSO exhibits one
6
singlet at 11.60 ppm for its two −OH groups, three signals
between 7.36 and 6.05 ppm for its aromatic protons, one
singlet at 3.66 ppm for its methylene protons, and one singlet
for the Cp* at 1.63 ppm. In principle, the methylene protons
are diastereotopic and should appear as two doublets rather
than one singlet. This phenomenon might be because the
difference in the chemical shifts of these two diastereotopic
protons is zero, resulting in the collapse of two doublets to one
base, with 1 mol % of complexes 1−3 and 2 mL of CH OH,
3
the reactions proceeded well in air. It can be seen that the
catalytic activity of complexes 1−3 was almost identical when
Cs CO was used as the base (Table 1, entries 1−3),
2
3
9
,11
suggesting their similar catalytic processes.
Complex 1
was then selected as the catalyst for such a transformation
because it was more easily synthesized. Two other weak bases,
K CO and Na CO , were then tested. K CO revealed 93%
2
3
2
3
2
3
8
singlet.
conversion, similar to that of Cs CO , while Na CO showed
2 3 2 3
The molecular structure of 1 was further confirmed by X-ray
crystallography (Figure 2). The cation is mirror symmetrical,
with a symmetric Ir(1)−C(6)−Cl(1) plane. The central Ir
atom is coordinated with two pyridyl groups, one Cp* group,
and one Cl atom. The two pyridyl rings are not coplanar, with
an C(5)−C(6)−C(5A) angle of 113.1(6)°. The Ir(1)−N(1)
and Ir(1)−Cl(1) distances are 2.152(4) and 2.4235(15) Å,
respectively, comparable to those of complex b shown in
worse results (Table 1, entries 4 and 5). In comparison to
complex b with 6,6′-dihydroxy-2,2′-bipyridine, 1 exhibited
higher efficiency when K CO was used as the base (93% vs
2
3
5g
84%). In the absence of a base, complex 1 showed no
activity, while complex 3 gave a 31% conversion (Table 1,
entries 6 and 7). The reaction did not proceed without a base
(Table 1, entry 8). When the reactions were carried out with
0.5 mol % catalyst or at 90 °C, the yields were much lower
(Table 1, entries 9 and 10). It should be noted that no N,N-
dimethylated product was detected according to GC analysis.
On the basis of the results above, various aromatic amines
were tested for the methylation reaction and the results are
given in Table 2. Reactions of brominated anilines gave the
corresponding products in 62−90% yields (Table 2, entries 2−
4). It is obvious that ortho-substituted aniline was less active
than meta- and para-substituted anilines due to steric
hindrance. An electron-withdrawing amine, 4-aminobenzoni-
6
c
Figure 1.
Complex 1 was further treated with AgOTf in water at room
temperature, and [Cp*Ir(HOC H CH C H OH)(H O)]-
5
3
2
5
3
2
9
[
OTf] (2) was produced in 82% yield (Scheme 3). The
2
1
H NMR signals for the −OH groups, aromatic protons, and
Cp* protons of 2 are similar to those of 1. Differently, the
−
CH − signals of complex 2 appear as two doublets at 4.52
2
and 3.65 ppm. In the presence of 2 equiv of t-BuONa, 2 was
transformed into the complex [Cp*Ir(OC H CH C H O)-
5
3
2
5
3
B
DOI: 10.1021/acs.organomet.8b00575
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Organometallics
Article
Scheme 3. Synthesis of Complexes 2 and 3
Table 1. Optimization of Reaction Conditions for the
Synthesis of N-Methylaniline
as the catalyst. 4 can also be formed through the loss of the
coordinated water from complex 3. Then the intermediate 4
accepts a proton from methanol to afford the iridium methoxy
species 5, which loses one molecule of formaldehyde to
generate the iridium hydride species 6. The formaldehyde and
amine are condensed into unsaturated imine, accompanied by
the release of one molecule of water. The hydride on iridium
and the proton on the ligand of 6 transfer simultaneously to
the CN bond to give the desired product, and the
unsaturated intermediate 4 is regenerated. A similar mecha-
nism for C-methylation is proposed as well. The nucleophilic
carbon anion of ketone is formed and condensed with
formaldehyde to give an α,β-unsaturated ketone. In a similar
way, the methylated product is produced through hydrogen
transfer from iridium hydride species 6.
a
b
entry
cat.
base
yield (%)
1
2
3
4
5
6
7
8
1
2
3
1
1
1
3
Cs CO
94
92
93
93
79
0
31
0
80
61
2
3
3
3
Cs CO
2
Cs CO
2
K CO
2
3
Na CO
2
3
No base
No base
K CO
No Cat.
1
1
2
3
3
3
c
9
K CO
2
d
CONCLUSIONS
1
0
K CO
2
■
a
Conditions unless specified otherwise: aniline (1 mmol), methanol
2 mL), base (0.3 equiv), air, catalyst (1 mol %), 120 °C, 12 h.
In summary, three iridium complexes bearing a 2-hydroxy-6-
((6-hydroxypridin-2-yl)methyl)pyridine ligand have been
synthesized and applied to the methylation of amines and
ketones using methanol. These iridium complexes were
efficient for such transformations in the presence of a weak
base (0.3 equiv of K CO ) in air. Our current work provides
(
b
Yields determined by GC analysis by using p-xylene as the internal
c
standard. Reaction was carried out with 0.5 mol % of catalyst.
d
Reaction was carried out at 90 °C.
2
3
alternative methods for the coupling of C−C and C−N bonds,
especially when the substrates are sensitive to strong bases.
Other experimental studies are ongoing to explore more active
transition-metal catalysts.
trile, was selectively monomethylated to give the desired
product in 94% yield (Table 2, entry 5). An electron-donating
amine was also selectively monomethylated to form the
corresponding N-methylamine in good yield (Table 2, entry
6
). 2-Aminopyridine, 2-naphthylamine, and benzooxazol-2-
EXPERIMENTAL SECTION
All manipulations were carried out under an atmosphere of dry
nitrogen using vacuum-line and oven-dried standard Schlenk
techniques if not otherwise specified. All solvents were distilled
■
ylamine were also tested, and the corresponding products were
isolated in high yields (Table 2, entries 7−9). In addition, the
catalyst was available for p-toluenesulfonamide and benzene-
sulfonamide, affording the desired products in 93% and 94%
yields, respectively (Table 2, entries 10 and 11). In addition, an
aliphatic amine (phenethylamine) was used with Cs CO to
from the appropriate drying agents under N before use. All reagents
2
were obtained from commercial suppliers and used without further
1
13
2
3
purification. The H and C NMR spectra were recorded on a Bruker
1
give the N,N-dimethylated product in high yield (Table 2,
entry 12).
Avance 400 spectrometer. The H NMR chemical shifts were
5
g
referenced to the residual solvent as determined relative to Me Si (δ 0
4
1
3
ppm). The C{1H} chemical shifts were reported in ppm relative to
Complex 1 was also applied for the methylation of ketones.
The reactions of a series of phenyl ketones with methanol were
conducted, and the results are given in Table 3. Propiophe-
none was converted to the methylation product in high
isolated yield (Table 3, entry 1). Similar to the N-methylation
of amines, electron-withdrawing groups in ortho, meta, and
para positions of propiophenones also decreased the yields
the carbon resonance of CDCl (77.0 ppm) or d -DMSO (39.5 ppm).
3
6
Elemental analyses were performed on a PerkinElmer 240C analyzer.
High-resolution mass spectra (HR-MS) were recorded on a Varian
.0 T FTICR-MS by the ESI technique. IR spectra were recorded on a
Nicolet iS5 FT-IR spectrometer. For single-crystal X-ray diffraction,
suitable crystals were placed in a cooled N stream at 173(2) K on a
7
2
Bruker D8 Quest X-ray diffractometer. Data collections were
performed using four-circle kappa diffractometers equipped with
CCD detectors. Data were reduced and then corrected for
(Table 3, entries 2−4). Electron-donating propiophenones
were selectively monomethylated to form the corresponding
ketones in good yields (Table 3, entries 5 and 6).
Valerophenone was also tested, and the corresponding product
was isolated in 92% yield (Table 3, entry 7).
13
absorption. Solution, refinement, and geometrical calculations for
14
all crystal structures were performed by SHELXTL. All GC
measurements were performed on Agilent GC7890A equipment
using an Agilent 19091B-102 (25 m, 220 μm) column.
Synthesis of 2-Methoxy-6-((6-methoxypyridin-2-yl)methyl)-
pyridine. A solution of n-BuLi (6.5 mL, 2.4 M, 15.6 mmol) in 10 mL
of dry THF was added to 2-methoxy-6-methylpyridine (2.0 g, 15.6
mmol) in THF (25 mL) at −78 °C. When the temperature was raised
The reaction mechanisms of our work might be consistent
4d,g,5a,g,11,12
with relevant literature reports (Scheme 4).
methylation, the first step is to generate the unsaturated
intermediate 4 by a reaction with base when complex 1 is used
For N-
C
DOI: 10.1021/acs.organomet.8b00575
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 2. Ir-Catalyzed Selective Monomethylation of
Anilines or Sulfonamides Using Methanol
Table 3. Ir-Catalyzed Selective Monomethylation of
Propiophenone Derivatives Using Methanol
a
a
a
Conditions: aniline (1 mmol), methanol (2 mL), base (0.3 equiv),
b
air, catalyst (1 mol %), 120 °C, 12 h. Yield of isolated product.
7
.2 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 4.15 (s, 2H), 3.94 (s, 6H). 13
NMR (100 Hz, CDCl , ppm): 163.6, 157.3, 138.9, 116.0, 107.8, 53.3,
C
3
4
6.4.
Synthesis of L . A solution of 2-methoxy-6-((6-methoxypyridin-2-
1
yl)methyl)pyridine (1.3 g, 5.6 mmol) in 10 mL of HBr (40% in
water) was heated at reflux for 3 h. After it was cooled to room
temperature, the yellow solution was neutralized by slow addition of a
saturated aqueous solution of NaOH. The resulting white precipitate
was filtered and then dried to afford L as a white solid (1.1 g, 92%).
1
Mp: 181 °C. HR-MS (ESI, m/z): calcd for C H N O + H,
1
1
10
2
2
2
4
03.0821; found, 203.0820. Anal. Calcd for C H N O : C, 65.34; H,
.98; N, 13.85. Found: C, 65.35; H, 4.94; N, 13.88. H NMR (400
11 10 2 2
1
MHz, d -DMSO, ppm): 11.61 (s, 2H), 7.37 (dd, J = 9.2, 6.8 Hz, 2H),
6
6
.21 (d, J = 9.2 Hz, 2H), 6.06 (d, J = 6.8 Hz, 2H), 3.67 (s, 2H). No
1
3
a
satisfactory C NMR data could be obtained due to low solubility.
Conditions: aniline (1 mmol), methanol (2 mL), base (0.3 equiv),
b
Synthesis of 1. A solution of L1 (0.1 g, 0.5 mmol) and
air, catalyst (1 mol %), 120 °C, 12 h. Yield of isolated product.
c
[Cp*IrCl ] (0.2 g, 0.25 mmol) was refluxed in dried CH OH (30
Reaction was carried out with Cs CO .
2
2
3
2
3
mL) with stirring for 6 h. The mixture was cooled to room
temperature, and the yellow precipitate was collected, washed with
ether, and dried under vacuum to provide 1 (0.26 g, 90%). Single
crystals suitable for X-ray crystallographic determination were grown
with CH Cl /CH OH/n-hexane at ambient temperature. Mp: 203
to −20 °C, 2-bromo-6-methoxypyridine (1.3 g, 7.8 mmol) was added.
The reaction mixture was stirred at −20 °C for 3 h and left at room
temperature overnight. After the addition of 15 mL of water, the water
phase was extracted with CH Cl . The crude product was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate,
v/v 5/1) to give 2-methoxy-6-((6-methoxypyridin-2-yl)methyl)-
pyridine (0.97 g, 56%). HR-MS (ESI, m/z): calcd for C H N O
2
2
3
°C. Anal. Calcd for C H Cl IrN O : C, 42.00; H, 4.20; N, 4.66.
Found: C, 42.13; H, 4.22; N, 4.59. H NMR (400 MHz, d -DMSO,
ppm): 11.60 (s, 2H), 7.36 (dd, J = 6.8, 6.0 Hz, 2H), 6.21 (d, J = 6.8
Hz, 2H), 6.06 (d, J = 6.0 Hz, 2H), 3.66 (s, 2H), 1.63 (s, 15H). No
satisfactory C NMR data could be obtained due to low solubility.
2
2
21 25
2
2
2
1
6
1
3
14
2
2
1
3
+
6
H, 231.1134; found, 231.1137. Anal. Calcd for C H N O : C,
1
3
14
2
2
1
7.81; H, 6.13; N, 12.17. Found: C, 67.84; H, 6.13; N, 12.21. H
Synthesis of 2. AgOTf (0.08 g, 0.32 mmol) was added to a
NMR (400 MHz, CDCl , ppm): 7.52 (t, J = 7.6 Hz, 2H), 6.84 (d, J =
solution of 1 (0.1 g, 0.16 mmol) in H O (10 mL) with stirring for 1 h
3
2
D
DOI: 10.1021/acs.organomet.8b00575
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Organometallics
Article
Scheme 4. Proposed Mechanism of Methylation with Iridium Catalysts
at room temperature. Then the precipitate was filtered and the
solution was concentrated. The crude product was recrystallized with
CH Cl /ether to give 2 as a yellow powder (0.1 g, 82%). Mp: 217 °C.
which was identified by NMR analyses. All analytical data of the
known compounds are consistent with those reported in the
literature.
2
2
5
g
1
Anal. Calcd for C H F IrN O S : C, 32.66; H, 3.22; N, 3.31. Found:
N-Methylbenzenamine.
H NMR (400 MHz, CDCl , ppm):
2
3
27
6
2
9
2
3
1
C, 32.65; H, 3.27; N, 3.28. H NMR (400 MHz, d -DMSO, ppm):
7.17 (t, J = 7.6 Hz, 2H), 6.69 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 7.6 Hz,
6
3.35 (s, 2H), 7.88 (t, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.02
2H), 2.78 (s, 3H).
2-Bromo-N-methylbenzenamine. 1H NMR (400 MHz, CDCl3,
ppm): 7.40 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.61−6.54
(m, 2H), 2.87 (s, 3H).
5l
1
3
14.4 Hz, 1H), 1.58 (s, 15H). C NMR (100 Hz, d -DMSO, ppm):
6
3-Bromo-N-methylbenzenamine. 1H NMR (400 MHz, CDCl
5
k
,
3
Synthesis of 3. t-BuONa (0.023 g, 0.24 mmol) was added to a
ppm): 6.99 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.69 (t, J =
2.0 Hz, 1H), 6.46 (d, J = 8.0 Hz, 1H), 2.75 (s, 3H).
solution of 2 (0.1 g, 0.12 mmol) in H O (10 mL) with stirring for 1 h.
2
5
g
1
Then the precipitate was filtered and the solution was concentrated.
The crude product was recrystallized with CH Cl /ether to give 3 as a
4-Bromo-N-methylbenzenamine. H NMR (400 MHz, CDCl
,
3
ppm): 7.22 (d, J = 8.8 Hz, 2H), 6.42 (d, J = 8.8 Hz, 1H), 2.73 (s, 3H).
2
2
5
g
1
yellow powder (0.05 g, 80%). Mp: 201 °C. Anal. Calcd for
4-(methylamino)benzonitrile.
H NMR (400 MHz, CDCl ,
3
C H IrN O : C, 46.22; H, 4.62; N, 5.13. Found: C, 46.15; H,
ppm): 7.42 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 2.87 (s, 3H).
2
1
25
2
3
1
5k
1
4
6
3
1
1
.61; N, 5.34. H NMR (400 MHz, d -DMSO, ppm): 7.03 (dd, J =
4-Methoxyl-N-methylbenzenamine.
CDCl , ppm): 6.78 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 1H),
3.72 (s, 3H), 2.75 (s, 3H).
N-methylpyridin-2-amine. 1H NMR (400 MHz, CDCl
H NMR (400 MHz,
6
.8, 5.2 Hz, 2H), 6.10 (d, J = 5.2 Hz, 2H), 5.97 (d, J = 6.8 Hz, 2H),
.65 (d, J = 11.6 Hz, 1H), 3.34 (s, 2H), 3.29 (d, J = 11.6 Hz, 1H),
3
.60 (s, 15H). 13C NMR (100 Hz, d -DMSO, ppm): 169.8, 153.6,
5g
, ppm):
6
3
38.1, 114.4, 105.4, 49.1, 9.8.
General Procedure for the Methylation of Amines and
8.07 (d, J = 4.0 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 6.55 (t, J = 5.2 Hz,
1H), 6.37 (d, J = 8.4 Hz, 1H), 2.89 (s, 3H).
N-Methylnaphthalen-2-amine. 1H NMR (400 MHz, CDCl3,
ppm): 7.65−7.56 (m, 3H), 7.33 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 7.2
Hz, 1H), 6.79−6.73 (m, 2H), 2.82 (s, 3H).
5g
Ketones. In air, in a 25 mL Schlenk tube, a mixture of amine or
ketone (1.0 mmol), methanol (2 mL), complex 1 (6 mg, 1 mol %),
and K CO (0.041g, 0.3 equiv) was stirred at 120 °C for 12 h; it was
2
3
5
g
1H NMR (400 MHz,
cooled to room temperature and 0.1 mL of the reaction mixture was
sampled and immediately diluted with 5 mL of CH Cl precooled to 0
N-Methylbenzo[d]oxazol-2-amine.
CDCl , ppm): 7.36 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H),
2
2
3
°
C for GC analysis to calculate the conversion and product selectivity
7.16 (t, J = 8.0 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 3.11 (s, 3H).
5
g
1
of the reaction. After the reaction was completed, the reaction mixture
was condensed under reduced pressure and subjected to purification
by flash silica gel column chromatography to afford the target product,
N,4-Dimethylbenzenesulfonamide.
H NMR (400 MHz,
CDCl , ppm): 7.75 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 1H),
3
2.64 (s, 3H), 2.43 (s, 3H).
E
DOI: 10.1021/acs.organomet.8b00575
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
5g
N-Methylbenzenesulfonamide. 1H NMR (400 MHz, CDCl3,
ppm): 7.87 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.52 (t, J =
REFERENCES
■
(
1) (a) Watson, A. J. A.; Williams, J. M. J. The Give and Take of
8
.0 Hz, 2H), 2.62 (s, 3H).
N,N-Dimethylbenzeneethanamine.
1
5
1H NMR (400 MHz,
Alcohol Activation. Science 2010, 329, 635−636. (b) Gunanathan, C.;
Milstein, D. Applications of Acceptorless Dehydrogenation and
Related Transformations in Chemical Synthesis. Science 2013, 341,
1229712. (c) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J.
Transition Metal Catalysed Reactions of Alcohols Using Borrowing
̈
Hydrogen Methodology. Dalton Trans. 2009, 5, 753−762. (d) Bahn,
S.; Imm, S.; Neubert, L.; Zhang, M.; Neumann, H.; Beller, M. The
CDCl , ppm): 7.26 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H),
3
2
.79−2.75 (m, 2H), 2.54−2.50 (m, 2H), 2.28 (s, 3H).
4d
1
2
-Methyl-1-phenylpropan-1-one. H NMR (400 MHz, CDCl3,
ppm): 7.96 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.46 (t, J =
7
.2 Hz, 2H), 3.56 (m, 1H), 1.22 (d, J = 6.8 Hz, 6H).
4d
1H NMR (400
1
-(2-Fluorophenyl)-2-methylpropan-1-one.
Catalytic Amination of Alcohols. ChemCatChem 2011, 3, 1853−1864.
e) Yang, Q.; Wang, Q.; Yu, Z. Substitution of Alcohols by N-
MHz, CDCl , ppm): 7.77 (t, J = 7.6 Hz, 1H), 7.51−7.46 (m, 1H),
3
(
7
=
.21 (t, J = 8.4 Hz, 1H), 7.14−7.09 (m, 1H), 3.41 (m, 1H), 1.20 (d, J
nucleophiles Via Transition Metal-catalyzed Dehydrogenation. Chem.
Soc. Rev. 2015, 44, 2305−2329. (f) Dobereiner, G. E.; Crabtree, R. H.
Dehydrogenation as a Substrate-Activating Strategy in Homogeneous
Transition-Metal Catalysis. Chem. Rev. 2010, 110, 681−703.
6.8 Hz, 6H).
-(3-Chlorophenyl)-2-methylpropan-1-one.
4
d
1H NMR (400
1
MHz, CDCl , ppm): 7.92 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.52
3
(
=
d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 3.50 (m, 1H), 1.22 (d, J
6.8 Hz, 6H).
-(4-Chlorophenyl)-2-methylpropan-1-one. 1H NMR (400
MHz, CDCl , ppm): 7.89 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz,
(
g) Quintard, A.; Rodriguez, J. A Step into an eco-Compatible
4
d
Future: Iron- and Cobalt- catalyzed Borrowing Hydrogen Trans-
formation. ChemSusChem 2016, 9, 28−30. (h) Pan, S.; Shibata, T.
Recent Advances in Iridium-Catalyzed Alkylation of C−H and N−H
Bonds. ACS Catal. 2013, 3, 704−712. (i) Guillena, G.; Ramn, D. J.;
Yus, M. Alcohols as Electrophiles in C−C Bond-Forming Reactions:
The Hydrogen Autotransfer Process. Angew. Chem., Int. Ed. 2007, 46,
1
3
2
H), 3.50 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H).
4
-Methyl-1-(2-methylphenyl)propan-1-one. 1H NMR (400
MHz, CDCl , ppm): 7.86 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.6 Hz,
4
d
3
2
H), 3.53 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H).
-(4-Methoxyphenyl)-2-methylpropan-1-one. 1H NMR (400
MHz, CDCl , ppm): 7.95 (d, J = 7.2 Hz, 2H), 6.93 (d, J = 8.8 Hz,
4
d
2
358−2364. (j) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J. M. J.
1
Borrowing Hydrogen in the Activation of Alcohols. Adv. Synth. Catal.
2007, 349, 1555−1575. (k) Crabtree, R. H. An Organometallic
Future in Green and Energy Chemistry? Organometallics 2011, 30,
3
2
H), 3.85 (s, 3H), 3.51 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H).
4d
1
2
-Methyl-1-phenylpentan-1-one. H NMR (400 MHz, CDCl3,
17−19. (l) Pen
̃
a-Lopez, M.; Piehl, P.; Elangovan, S.; Neumann, H.;
́
ppm): 7.95 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.46 (t, J =
8
3
.0 Hz, 2H), 3.52−3.44 (m, 1H), 1.83−1.75 (m, 1H), 1.47−1.29 (m,
H), 1.19 (d, J = 6.8 Hz, 6H), 0.90 (d, J = 7.6 Hz, 3H).
Beller, M. Manganese-Catalyzed Hydrogen-Autotransfer C−C Bond
Formation: α-Alkylation of Ketones with Primary Alcohols. Angew.
Chem., Int. Ed. 2016, 55, 14967−14971. (m) Guillena, G.; Ramon, D.
́
J.; Yus, M. Hydrogen Autotransfer in the N-Alkylation of Amines and
Related Compounds using Alcohols and Amines as Electrophiles.
Chem. Rev. 2010, 110, 1611−1641. (n) Corma, A.; Navas, J.; Sabater,
M. J. Advances in One-Pot Synthesis through Borrowing Hydrogen
Catalysis. Chem. Rev. 2018, 118, 1410−1459. (o) Hale, L. V. A.;
Szymczak, N. K. Hydrogen Transfer Catalysis beyond the Primary
Coordination Sphere. ACS Catal. 2018, 8, 6446−6461.
ASSOCIATED CONTENT
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* Supporting Information
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00575.
Crystallographic details and NMR spectra of the new
compounds (PDF)
(2) (a) Yokoyama, Y.; Mochida, K. Et GeNa−YC1 Complex as a
3
3
New Strong Base. J. Organomet. Chem. 1995, 499, C4−C6. (b) Selva,
M.; Bomben, A.; Tundo, P. Selective Mono-N-methylation of Primary
Aromatic Amines by Dimethyl Carbonate over Faujasite X- and Y-
Type Zeolites. J. Chem. Soc., Perkin Trans. 1 1997, 1, 1041−1046.
(c) Lygaitis, R.; Getautis, V.; Grazulevicius, J. V. Hole-transporting
Hydrazones. Chem. Soc. Rev. 2008, 37, 770−788. (d) Szekely, G.;
Amores de Sousa, M. C.; Gil, M.; Castelo Ferreira, F.; Heggie, C.
Genotoxic Impurities in Pharmaceutical Manufacturing: Sources,
Regulations, and Mitigation. Chem. Rev. 2015, 115, 8182−8229.
Accession Codes
CCDC 1859831 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(
e) Caine, D. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I.; Eds.; Pergamon; Oxford, U.K., 1991; Vol. 3, pp 1−63.
f) Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH:
Weinheim, Germany, 2000.
3) (a) Stephan, D. W. A Step Closer to a Methanol Economy.
AUTHOR INFORMATION
(
■
*
Corresponding Author
E-mail for D.C.: dafachen@hit.edu.cn.
(
Nature 2013, 495, 54−55. (b) Olah, G. A. Beyond Oil and Gas: The
Methanol Economy. Angew. Chem., Int. Ed. 2005, 44, 2636−2639.
(c) Natte, K.; Neumann, H.; Beller, M.; Jagadeesh, R. V. Transition-
ORCID
Dafa Chen: 0000-0002-7650-4024
Notes
The authors declare no competing financial interest.
Metal-Catalyzed Utilization of Methanol as a C Source in Organic
1
Synthesis. Angew. Chem., Int. Ed. 2017, 56, 6384−6394.
(4) (a) Li, Y.; Li, H.; Junge, H.; Beller, M. Selective Ruthenium-
catalyzed Methylation of 2-Arylethanols using Methanol as C1
Feedstock. Chem. Commun. 2014, 50, 14991−14994. (b) Ogawa, S.;
Obora, Y. Iridium-catalyzed Selective α-Methylation of Ketones with
Methanol. Chem. Commun. 2014, 50, 2491−2493. (c) Shen, D.;
Poole, D. L.; Shotton, C. C.; Kornahrens, A. F.; Healy, M. P.;
Donohoe, T. J. Hydrogen-Borrowing and Interrupted-Hydrogen-
Borrowing Reactions of Ketones and Methanol Catalyzed by Iridium.
Angew. Chem., Int. Ed. 2015, 54, 1642−1645. (d) Quan, X.;
Kerdphon, S.; Andersson, P. G. C−C Coupling of Ketones with
Methanol Catalyzed by a N-Heterocyclic Carbene−Phosphine
Iridium Complex. Chem. - Eur. J. 2015, 21, 3576−3579. (e) Dang,
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21672045 and 21871068), the
National Science and Technology Pillar Program during the
Twelfth Five-Year Plan Period (2015BAD15B0502), the China
Postdoctoral Science Foundation (2016M591519), the
Heilongjiang Postdoctoral Foundation (LBH-Z16069), and
the National Natural Science Foundation of Heilongjiang
(
Nos. B2018005 and LC2018005).
F
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Article
T. T.; Seayad, A. M. A Convenient Ruthenium-Catalysed α-
Methylation of Carbonyl Compounds using Methanol. Adv. Synth.
Catal. 2016, 358, 3373−3380. (f) Liu, Z.; Yang, Z.; Yu, X.; Zhang, H.;
Functional Bipyridine Ligand. J. Am. Chem. Soc. 2012, 134, 3643−
3646.
(7) Shi, J.; Hu, B.; Ren, P.; Shang, S.; Yang, X.; Chen, D. Synthesis
and Reactivity of Metal−Ligand Cooperative Bifunctional Ruthenium
Hydride Complexes: Active Catalysts for β-Alkylation of Secondary
Alcohols with Primary Alcohols. Organometallics 2018, 37, 2795.
3
2
Yu, B.; Zhao, Y.; Liu, Z. Methylation of C(sp )−H/C(sp )−H Bonds
with Methanol Catalyzed by Cobalt System. Org. Lett. 2017, 19,
5
228−5231. (g) Chakrabarti, K.; Maji, M.; Panja, D.; Paul, B.; Shee,
S.; Das, G. K.; Kundu, S. Utilization of MeOH as a C1 Building Block
(8) Sommerfeld, N. S.; Gulzow, J.; Roller, A.; Cseh, K.; Jakupec, M.
̈
in Tandem Three-Component Coupling Reaction. Org. Lett. 2017,
A.; Grohmann, A.; Galanski, M.; Keppler, B. K. Antiproliferative
Copper (II) and Platinum (II) Complexes with Bidentate N, N-
Donor Ligands. Eur. J. Inorg. Chem. 2017, 2017, 3115−3124.
(9) Fujita, K.; Tamura, R.; Tanaka, Y.; Yoshida, M.; Onoda, M.;
Yamaguchi, R. Dehydrogenative Oxidation of Alcohols in Aqueous
Media Catalyzed by a Water-soluble Dicationic Iridium Complex
bearing a Functional N-heterocyclic Carbene Ligand without using
Base. ACS Catal. 2017, 7, 7226−7230.
19, 4750−4753. (h) Chan, L. K.; Poole, D. L.; Shen, D.; Healy, M. P.;
Donohoe, T. J. Rhodium-Catalyzed Ketone Methylation Using
Methanol Under Mild Conditions: Formation of α-Branched
Products. Angew. Chem., Int. Ed. 2014, 53, 761−765. (i) Li, F.; Ma,
J.; Wang, N. α-Alkylation of Ketones with Primary Alcohols Catalyzed
by a Cp* Ir Complex bearing a Functional Bipyridonate Ligand. J.
Org. Chem. 2014, 79, 10447−10455. (j) Jiang, L.; Guo, F.; Shi, Z.; Li,
Y.; Hou, Z. Syndiotactic Poly (aminostyrene)-Supported Palladium
Catalyst for Ketone Methylation with Methanol. ChemCatChem 2017,
(10) Kawahara, R.; Fujita, K.; Yamaguchi, R. Cooperative Catalysis
by Iridium Complexes with a Bipyridonate Ligand: Versatile
Dehydrogenative Oxidation of Alcohols and Reversible Dehydrogen-
ation-Hydrogenation between 2-Propanol and Acetone. Angew.
Chem., Int. Ed. 2012, 51, 12790−12794.
9
, 3827−3832. (k) Siddiki, S. H.; Touchy, A. S.; Jamil, M. A.; Toyao,
T.; Shimizu, K. I. C-Methylation of Alcohols, Ketones, and Indoles
with Methanol Using Heterogeneous Platinum Catalysts. ACS Catal.
(11) (a) Wang, R.; Fan, H.; Zhao, W.; Li, F. Acceptorless
2
(
018, 8, 3091−3103.
Dehydrogenative Cyclization of o-Aminobenzyl Alcohols with
Ketones to Quinolines in Water Catalyzed by Water-Soluble Metal-
5) (a) Li, F.; Xie, J.; Shan, H.; Sun, C.; Chen, L. General and
Efficient Method for Direct N-monomethylation of Aromatic Primary
Amines with Methanol. RSC Adv. 2012, 2, 8645−8652. (b) Michlik,
S.; Hille, T.; Kempe, R. The Iridium-Catalyzed Synthesis of
Symmetrically and Unsymmetrically Alkylated Diamines under Mild
Reaction Conditions. Adv. Synth. Catal. 2012, 354, 847−862.
Ligand Bifunctional Catalyst [Cp*(6,6′-(OH) bpy)(H O)][OTf] .
2
2
2
Org. Lett. 2016, 18, 3558−3561. (b) Wang, R.; Ma, J.; Li, F. Synthesis
of α-Alkylated Ketones via Tandem Acceptorless Dehydrogenation/
α-Alkylation from Secondary and Primary Alcohols Catalyzed by
Metal-Ligand Bifunctional Iridium Complex [Cp*Ir (2,2′-bpyO)-
(
c) Dang, T. T.; Ramalingam, B.; Seayad, A. M. Efficient
(
H O)]. J. Org. Chem. 2015, 80, 10769−10776. (c) Qu, P.; Sun, C.;
Ruthenium-catalyzed N-methylation of Amines using Methanol.
ACS Catal. 2015, 5, 4082−4088. (d) Campos, J.; Sharninghausen,
L. S.; Manas, M. G.; Crabtree, R. H. Methanol Dehydrogenation by
Iridium N-heterocyclic Carbene Complexes. Inorg. Chem. 2015, 54,
2
Ma, J.; Li, F. The N-Alkylation of Sulfonamides with Alcohols in
Water Catalyzed by the Water-Soluble Iridium Complex {Cp*Ir[6,6′-
(
OH) bpy](H O)}[OTf] . Adv. Synth. Catal. 2014, 356, 447−459.
2
2
2
(
12) Moore, C. M.; Szymczak, N. K. 6,6′-dihydroxy Terpyridine: A
5079−5084. (e) Elangovan, S.; Neumann, J.; Sortais, J. B.; Junge, K.;
Proton-Responsive Bifunctional Ligand and Its Application in
Darcel, C.; Beller, M. Efficient and Selective N-alkylation of Amines
with Alcohols Catalysed by Manganese Pincer Complexes. Nat.
Commun. 2016, 7, 12641−12648. (f) Paul, B.; Shee, S.; Chakrabarti,
K.; Kundu, S. Tandem Transformation of Nitro Compounds into N-
Methylated Amines: Greener Strategy for the Utilization of Methanol
as a Methylating Agent. ChemSusChem 2017, 10, 2370−2374.
Catalytic Transfer Hydrogenation of Ketones. Chem. Commun.
2
013, 49, 400−402.
13) Blessing, R. H. Acta Crystallogr., Sect. A: Found. Crystallogr.
995, 51, 33.
14) Sheldrich, G. M. SHELXTL release 6.1.4 ed; Bruker AXS Inc.,
Madison, WI 53719, USA, 2003.
15) Das, S.; Bobbink, F. D.; Laurenczy, G.; Dyson, P. J. Metal-Free
(
1
(
(g) Liang, R.; Li, S.; Wang, R.; Lu, L.; Li, F. N-Methylation of
(
Amines with Methanol Catalyzed by a Cp*Ir Complex Bearing a
Catalyst for the Chemoselective Methylation of Amines Using Carbon
Functional 2, 2′-Bibenzimidazole Ligand. Org. Lett. 2017, 19, 5790−
Dioxide as a Carbon Source. Angew. Chem., Int. Ed. 2014, 53, 12876−
5793. (h) Bruneau-Voisine, A.; Wang, D.; Dorcet, V.; Roisnel, T.;
12879.
Darcel, C.; Sortais, J. B. Mono-N-methylation of Anilines with
Methanol Catalyzed by a Manganese Pincer-complex. J. Catal. 2017,
347, 57−62. (i) Oikawa, K.; Itoh, S.; Yano, H.; Kawasaki, H.; Obora,
Y. Preparation and Use of DMF-stabilized Iridium Nanoclusters as
Methylation Catalysts using Methanol as the C1 Source. Chem.
Commun. 2017, 53, 1080−1083. (j) Chen, J.; Wu, J.; Tu, T.
Sustainable and Selective Monomethylation of Anilines by Methanol
with Solid Molecular NHC-Ir Catalysts. ACS Sustainable Chem. Eng.
2
017, 5, 11744−11751. (k) Liu, Z.; Yang, Z.; Yu, X.; Zhang, H.; Yu,
B.; Zhao, Y.; Liu, Z. Efficient Cobalt-Catalyzed Methylation of
Amines Using Methanol. Adv. Synth. Catal. 2017, 359, 4278−4283.
(l) Neumann, J.; Elangovan, S.; Spannenberg, A.; Junge, K.; Beller, M.
Improved and General Manganese-Catalyzed N-Methylation of
Aromatic Amines Using Methanol. Chem. - Eur. J. 2017, 23, 5410−
5413. (m) Ogata, O.; Nara, H.; Fujiwhara, M.; Matsumura, K.;
Kayaki, Y. N-Monomethylation of Aromatic Amines with Methanol
H
via PN P-Pincer Ru Catalysts. Org. Lett. 2018, 20, 3866−3870.
(6) (a) Fujita, K.; Tanino, N.; Yamaguchi, R. Ligand-promoted
Dehydrogenation of Alcohols Catalyzed by Cp*Ir Complexes. A New
Catalytic System for Oxidant-free Oxidation of Alcohols. Org. Lett.
2007, 9, 109−111. (b) Fujita, K.; Yoshida, T.; Imori, Y.; Yamaguchi,
R. Dehydrogenative Oxidation of Primary and Secondary Alcohols
Catalyzed by a Cp*Ir Complex having a Functional C, N-chelate
Ligand. Org. Lett. 2011, 13, 2278−2281. (c) Kawahara, R.; Fujita, K.;
Yamaguchi, R. Dehydrogenative Oxidation of Alcohols in Aqueous
Media using Water-soluble and Reusable Cp*Ir Catalysts bearing a
G
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