Use of a Cyclometalated Iridium(III) Complex Containing a N∧C∧N-Coordinating Terdentate Ligand as a Catalyst for the α-Alkylation of Ketones and N-Alkylation of Amines with Alcohols

Article abstract of DOI:10.1021/acs.joc.6b02758

A cyclometalated iridium(III) complex containing a N^∧C^∧N-coordinating terdentate ligand [Ir(dpyx-N,C,N)Cl(μ-Cl)]₂ was found to be a general and highly effective catalyst for the α-alkylation of ketones and N-alkylation of amines with alcohols. In the presence of catalyst (1 mol % Ir) and base (0.2-0.5 equiv), a variety of desirable products were obtained in good yields under an air atmosphere. Notably, this research exhibited the new potential of Ir(III) complexes bearing non-Cp? ligand and will facilitate the progress of the hydrogen autotransfer process.

Full text of DOI:10.1021/acs.joc.6b02758

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Article
Use of a Cyclometalated Iridium(III) Complex Containing a
N^C^N-Coordinating Terdentate Ligand as Catalyst for the #-
Alkylation of Ketones and N-Alkylation of Amines with Alcohols
Pengcheng Liu, Ran Liang, Lei Lu, Zhentao Yu, and Feng Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02758 • Publication Date (Web): 05 Jan 2017
Downloaded from http://pubs.acs.org on January 5, 2017
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Use of a Cyclometalated Iridium(III) Complex
Containing a N^C^N-Coordinating Terdentate
Ligand as Catalyst for the α-Alkylation of Ketones
and N-Alkylation of Amines with Alcohols
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Pengcheng Liu,† Ran Liang,† Lei Lu,† Zhentao Yu,‡ and Feng Li*,†
* E-mail: fengli@njust.edu.cn
†
School of Chemical Engineering, Nanjing University of Science & Technology, Nanjing
210094, People’s Republic of China
‡
Jiangsu Key Laboratory for Nano Technology, College of Engineering and Applied
Science, Nanjing University, Nanjing 210093, People’s Republic of China
Me
Me
N
O
O
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol % Ir)
base (0.2-0.5 equiv)
tert-amyl alcohol, reflux,under air
R1
R2
R1
N
Ir
Cl
H
Cl
Ir
R2
NH2
N
Cl
Cl
N
R1
R1
R2
OH
H2O
N
52 examples
up to 93% yield
mild reaction conditions
high atom efficiency
Me
Me
environmental friendliness
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2
Abstract:
A cyclometalated iridium(III) complex containing a N^C^N-Coordinating terdentate ligand
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 was found to be a general and highly effective catalyst for the α-
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alkylation of ketones and N-alkylation of amines with alcohols. In the presence of catalyst (1 mol
% Ir) and base (0.2-0.5 equiv), a variety of desirable products were obtained in good yields under
air atmosphere. Notably, this research exhibited the new potential of Ir(III) complexes bearing
non-Cp* ligand and would facilitate the progress of hydrogen autotransfer process.
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■ Introduction
Alkylation represents a class of the most important reactions for the construction of C-C and C-N
bond in organic synthesis.1 Traditionally, alkylation is performed with alkyl halides as alkylating
agents in the presence of a stoichiometric or excess amount of bases. In recent years, much
attention has been paid to the alkylation with alcohols as alkylating agents based on transition
metal-catalyzed hydrogen autrotransfer process (or hydrogen-borrowing strategy).2 In this
process, alcohols are first dehydrogenated to form aldehydes, followed by the condensation of
the resulting aldehydes with nucleophilic agents occurs to afford imine intermediates, which are
further hydrogenated by metal hydride species generated in the step of the dehydrogenation of
alcohols to give alkylated products (Scheme 1). Such methodology is attractive because of the
low toxicity of alcohols, high atom efficiency and the formation of water as the only side product.
Over the past decade, ruthenium,3 iridium,4,5 and other transition metal complexes6 have been
developed as catalysts for hydrogen autotransfer process. Especially, the half-sandwich
iridium(III) complexes having pentamethylcyclopentadienyl ligand, e.g. Cp*Ir(III), have
emerged as one of the most effective and promising catalysts. As outlined in Scheme 2, represent
examples included [Cp*IrCl2]2 (Fujita, Yamaguich’s group, 2002),4a-c Cp*Ir(III) complexes
bearing a ligand, such as N-heterocyclic carbene ligands (Peris’s group, 2008; Crabtree’s group,
2009),4d-f
ammonias
(Fujita,
Yamaguchi’s
group,
2010),4g
bis(2,4,6-
2
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trimethylphenyl)formamidine (Peris’s group, 2011),4h carbonato (Limbach, 2013)4i and chelating
ketimine (Xiao’s group, 2014).4j More recently, we demonstrated that Cp*Ir(III) complexes
bearing a functional bihydroxypyridine or bipyridonate ligand are metal-ligand bifunctional
catalysts for the N-alkylation of sulfonamides in water and the α-alkylation of ketones with
alcohols.7,8 In other hand, Ir(III) complexes bearing non-Cp* ligand have obtained a wide
application in recent years. They have been used as efficient catalysts for water oxidation,9 CO2
hydrogenation10 and organic photoredox reactions.11 However, the potential of such complexes
as catalysts for the alkylation with alcohols remains rarely explored. In 2014, Wang and co-
workers reported a class of benzoxazolyl iridium(III) complexes, which exhibited highly
catalytic activities for the α-alkylation of ketones and N-alkylation of amines with alcohols.12
However, it is necessary to add expensive AgNTf2 to activate benzoxazolyl iridium(III)
complexes. Moreover, these reactions required the presence of a stoichiometric amount of base
and nitrogen atmosphere. From both synthetic and environmental point of views, the
development of a new type of Ir(III) complexes bearing a non-Cp* ligand as catalysts for the
alkylation with alcohols under more environmentally benign conditions is apparently highly
desirable.
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Scheme 1. Transition Metal-catalyzed Hydrogen Autotransfer Process.
[M]
R
OH
R
Nuc
[M]
[M-H]
R
R
O
Nuc
Nuc
H2
O
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Scheme 2. Representative Ir(III) Complexes as Catalysts for Hydrogen Autotransfer Process.
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Cl
Cl
Cl
Ir Cl
Cl
N
Ir
Cl
Ir
Ir
N
Cl
Cl
N
N
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Fujita, Yamaguchi's group,2002
Peris's group, 2008
Tejeda, Peris, Royo's group, 2008
2X-
PF6
PF6
Ir
H3
H3
N
N
NH3
Ir Cl
N
Ir Cl
N
N
N
N
N
X = Cl, Br, I
N
N
Crabtree's group, 2009
Fujita, Yamaguchi's group,2010
MeO
Ir Cl
N
H
N
Ir Cl
N
Ir Cl
N
O
H
O
OMe
Peris's group, 2011
Limbach's goup, 2013
Xiao's group, 2015
[OTf]2
Cl
Ir
HO
O
PPh3
Ir H2
N
O
OH
Ir H2
O
O
N
N
O
N
N
2
Wang, Ding's group, 2014
Li' group, 2014
Li' group, 2015
We have reported a series of environmentally friendly reactions based on hydrogen
autotransfer process or dehydrogenation catalyzed by Cp*Ir(III) complexes.7,13 As part of our
continuing effort in this field, we are interesting in exploring the α-alkylation of ketones and N-
alkylation of amines with alcohols catalyzed by air-stable cyclometalated complexes containing
N^C^N-coordinating terdentate ligands. Such complexes were originally developed by Williams
and co-workers14 and were used as organic light-emitting devices,15 organic light-emitting
diodes,16 OLEDs17 and catalysts for water photoreduction.18
Results and Discussion
Our inital investigation focused on the α-alkylation of acetophone (1a) with benzylic alcohol
(2a). As shown in Scheme 3, a range of cyclometalated iridium(III) complexes containing a
N^C^N-coordinating terdentate ligand, were chosen as catalysts for this model reaction. In the
presence of dichlorobridged dimer complex [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (dpyx: 1,3-di(2-pyridyl)-
4,6-dimethylbenzene) (1 mol % Ir) and Cs2CO3 (0.2 equiv), the reaction proceeded in tert-amyl
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alcohol at reflux under air atmosphere for 12 h to afford the desired α-alkylated product 3a in
91% yield. Using netrual bis-terdentate complexes [Ir(dpyx)(ppy)Cl] (ppy: 2-phenylpyridine)
and [Ir(dpyx)(dppy)Cl] (dppy: 2,6-diphenylpyridine) as alternative catalysts, the product 3a was
also obtained in 80% and 83% yields, respectively. When a cationic bis-terdentate complex
[Ir(dpyx)(tpy)][PF6]2 (tpy: 2-(6-(pyridin-2-yl)pyridin-2-yl)pyridine) was examined, the reaction
gave the product 3a in only 60% yield.
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Scheme 3. The α-Alkylation of Acetophenone with Benzyl Alcohol as a Model Reactiona
O
O
Catalyst (1 mol% Ir)
Cs2CO3 (0.2 equiv)
OH
+
tert-amyl alcohol
reflux, under air
1a
2a
Me
3a
Me
Me
N
Me
N
N
Ir
Cl
Cl
Ir
N
Cl
Ir
Cl
N
Cl
N
N
Me
Me
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2, 91% yield
[Ir(dpyx)(ppy)Cl], 80% yield
[PF6
]
2
Me
N
Me
N
Me
Me
N
N
N
N
Ir
Ir
N
N
[Ir(dpyx)(dppy)Cl], 83% yield
[Ir(dpyx)(tpy)][PF6]2, 60% yield
aReactions conditions: 1a (0.5 mmol), 2a (0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2
(1 mol % Ir), Cs2CO3 (0.2 equiv), tert-amyl alcohol (1 mL), reflux, under air, 12 h.
Inspired by above promising results, we examined the scope of α-alkylation with respect to
alcohols catalyzed by [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 and these results are outlined in Scheme 4. The
α-alkylation of 1a with benzylic alcohols bearing an electron-donating substituent, such as
methyl, isopropyl and methoxy group, afforded the corresponding products 3b-f in 80-89%
yields. Similarly, benzylic alcohols bearing an electron-withdrawing group, such as fluoro,
chloro, bromo and trifluoromethyl group, were converted to the desired products 3g-k in 82-88%
yields. Transforamtions of 2-thiophenemethanol, ferrocenemethanol and 2-naphthylmethanol
gave the corresponding products 3l-n in 77-87% yields as well. When aliphatic alcohols, such as
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1-hexanol, 2-methyl-1-butanol, 1-octanol and 2-ethylhexan-1-ol, were utilized, the desired
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products 3o-3r were obtained in 75-78% yields.
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Scheme 4. The α-Alkylation of Acetophone with Various Alcohols.a
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O
O
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol% Ir)
Cs2CO3 (0.2 equiv)
R2
R2
OH
+
tert-amyl alcohol, reflux, under air
1a
2
3
O
O
Me
O
Me
Me
Me
3b, 89% yield
3c, 86% yield
3d, 87% yield
O
O
O
OMe
OMe
F
3e, 80% yield
3f, 87% yield
3g, 86% yield
O
F
O
O
Cl
Br
3h, 88% yield
3i, 82% yield
3j, 83% yield
O
O
O
CF3
S
Fe
3k, 85% yield
3l, 77% yield
3m, 87% yield
O
O
O
3n, 82% yield
3o, 77% yieldb
3p, 75% yieldb
O
O
3q, 76% yieldc
3r, 78% yieldb
a Reactions conditions: 1a (0.5 mmol), 2 (0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1
mol % Ir), Cs2CO3 (0.2 equiv), tert-amyl alcohol (1 mL), reflux, under air, 12 h. b 2 (2 equiv),
Cs2CO3 (0.5 equiv). c 2 (2 equiv), KOH (0.3 equiv).
As shown in Scheme 5, the scope of α-alkylation with respect to ketones was then investigated.
The α-alkylation of acetophones (1) bearing an electron-donating or electron-withdrawing group
with 2a proceeded smoothly to give the corresponding products 4a-g in 83-91% yields. For 1-
indanone and 1-tetralone, reactions afforded the desired products 4h and 4i in 87% and 85%
yields, respectively. In the case of aliphatic ketones, the desired products 4j and 4k were isolated
in 83% and 86% yields, respectively.
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Scheme 5. The α-Alkylation of a Series of Ketones with Benzyl Alcohols.a
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7
O
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol% Ir)
Cs2CO3 (0.2 equiv)
O
OH
R1
+
R1
tert-amyl alcohol, reflux, under air
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1
2a
4
O
O
O
Me
MeO
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Me
4a, 83% yield
4b, 89% yield
4c, 91% yield
O
O
O
Br
F
Cl
4d, 86% yield
4e, 84% yield
4f, 85% yield
O
O
O
Br
4g, 86% yield
4h, 87% yield
4i, 85% yield
O
O
4j, 83% yield
4k, 86% yield
a Reactions conditions: 1 (0.5 mmol), 2a (0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1
mol % Ir), Cs2CO3 (0.2 equiv), tert-amyl alcohol (1 mL), reflux, under air, 12 h.
To further expand the generality of catalytic system, the N-alkylation of amines with alcohols
was then investigated (Scheme 6). Reactions of aniline with benzyl alcohols, and benzylic
alcohols bearing an electron-donating or electron-withdrawing group afforded the desired
products 6a-6g in 82-93% yields. For aliphatic alcohols, the desired products 6h-k were also
obtained in 72%-82% yields. Transformations of anilines bearing a variety of substituents with
2a gave the corresponding products 6l-6s in 79-89% yields. The system was also applied to
naphthylamine and heterocyclic anilines, giving the desired products 6t-6v in 76-86% yields.
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Scheme 6. The N-alkylation of Amines with Alcohols.a
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7
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol% Ir)
Cs2CO3 (0.2 equiv)
R2
R1 NH2
R1 NH
R2
OH
+
tert-amyl alcohol, reflux,under air
5
2
6
8
9
Me
OMe
H
H
N
H
N
N
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6a, 86% yield
6b, 82% yield
6c, 89% yield
Cl
Br
H
N
H
N
H
N
F
6d, 93% yield
6e, 86% yield
6f, 87% yield
H
N
H
N
H
N
CF3
6g, 86% yield
6h, 72% yieldb
6i, 75% yieldb
H
N
H
N
H
N
Me
6j, 82% yieldb
6k, 75% yieldc
6l, 85% yield
H
N
H
N
H
N
Cl
MeO
Cl
6m, 79% yield
6n, 88% yield
6o, 88% yield
Cl
H
N
H
N
H
N
F3
C
Cl
Br
6p, 87% yield
6q, 84% yield
6r, 80% yield
H
N
H
N
F3CO
6s, 83% yield
6t, 86% yield
H
N
H
N
N
N
N
6u, 77% yield
6v, 76% yield
a Reactions conditions: 5 (0.5 mmol), 2 (0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol
% Ir), Cs2CO3 (0.2 equiv), tert-amyl alcohol (1 mL), reflux, under air, 12 h. b 5 (0.5 mmol), 2
(1.0 mmol), KOH (0.3 equiv), 12 h. c 5 (0.5 mmol), 2 (1.0 mmol), KOH (0.3 equiv), 24 h.
A plausible mechanism is proposed to account for the α-alkylation of ketones and N-alkylation
of amines with alcohols catalyzed by [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (Scheme 7). The initial step of
reaction involved the formation of alkoxo iridium species A by the reaction of iridium species
with alcohols under the acceleration of base. Accompanied by the β-hydrogen elimination of
alkoxo iridium species A, the iridium hydride species B coordinated with aldehydes were
generated. Subsequently, the condensation between resulting B and ketones (or amines) occurred
to give iridium hydride species C (or E) coordinated with α,β-unsaturated ketones (or imines).
The addition of iridium hydride into the C=C bond of α,β-unsaturated ketones (or C=N bond of
imines) afforded the carbanion-iridium species D (or amido-iridium species F). Finally, α-
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alkylated ketones (or N-alkylated amines) were released as products and the catalytically active
alkoxo iridium species A were regenerated via the reaction of species D (or F) with alcohols.
Scheme 7. Proposed Reaction Mechanism.
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R1 NH2
R2
OH
[Ir]
H
O
O
R2
R1
R2
O
[Ir]
B
H2O
R1
R2
D
Me
Me
N
R2
,
OH
base
R1
N
R2
[Ir]
H
Ir
O
[Ir]
H
R2
N
[Ir]
O
Cl
R2
R2
Cl
Ir
O
[Ir]
R1
Cl
Cl
A
E
C
A
R2
,
OH
base
N
N
H2O
R1 NH
Me
Me
R1
N
R2
[Ir]
[Ir]
H
O
R2
R2
O
R2
OH
R1
F
B
To support the proposed mechanism shown in Scheme 7, the hydrogen transfer between an
α,β-unsaturated ketone (or an unsaturated imine), which was formed by the condensation
between a ketone (or a amine) and an aldehyde, and an alcohol was conducted (Scheme 8). In the
presence of [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol % Ir) and Cs2CO3 (0.2 equiv), the reaction of (E)-
chalcone (7) with benzyl alcohol (2a) was carried out under reflux for 12 h to give the product 3a
in 88% yield. Similarly, the transformation of (E)-N-benzylidenebenzenamine (8) with 2a gave
the product 6a in 86% yield.
Scheme 8. Transfer Hydrogenation of an Unsaturated Intermediate with an Alcohol.
O
O
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol % Ir)
Cs2CO3 (0.2 equiv)
+
Ph
OH
tert-amyl alcohol, reflux, under air
3a, 88% yield
7
2a
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol % Ir)
Cs2CO3 (0.2 equiv)
H
N
N
+
Ph
OH
tert-amyl alcohol, reflux, under air
6a, 86% yield
8
2a
The present catalytic system was also applied to direct synthesis of a biologically active
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molecule donepezil (a well-known acetylcholinesterase inhibitor used clinically to treat cognitive
dysfunction in Alzheimer’s disease) (Scheme 9).19 In the presence of [Ir(dpyx-N,C,N)Cl(μ-Cl)]2
(1 mol % Ir) and Cs2CO3 (0.2 equiv), the reaction of 5,6-dimethoxy-2,3-dihydroinden-1-one (9)
with 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydroinden-1-one (10) was
performed at reflux for 12 h to give the desired product 11 in 85% yield.
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Scheme 9. Synthesis of a Biologically Active Molecule Donepezil.
O
MeO
Ph
N
MeO
O
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (1 mol % Ir)
Cs2CO3 (0.2 equiv)
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MeO
MeO
+
tert-amyl alcohol, reflux, under air
HO
N
11 (donepezil), 85% yield
Ph
10
■ Conclusion
In summary, we have demonstrated that a cyclometalated iridium(III) complex containing a
N^C^N-coordinating terdentate ligand [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 is a general and highly
effective catalyst for the α-alkylation of ketones and N-alkylation of amines with primary
alcohols. In the presence of catalyst (1 mol % Ir) and base (0.2-0.5 equiv), a variety of desirable
products were obtained in good yields under air atmosphere. Notably, this research exhibited the
new potential of Ir(III) complexes bearing non-Cp* ligand and would facilitate the progress of
hydrogen autotransfer process.
■ Experimental Section
Experimental Details. Proton nuclear magnetic resonance (1H NMR) spectra were recorded at
500 MHz. Chemical shifts are reported in delta (δ) units, parts per million (ppm) downfield from
tetramethylsilane or ppm relative to the center of the singlet at 7.26 ppm for CDCl3. Coupling
constants J values are reported in Hertz (Hz), and the splitting patterns were designated as
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follows: s, singlet; d, doublet; t, triplet; m, multiplet; b, broad. Carbon-13 nuclear magnetic
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resonance (13C NMR) spectra were recorded at 125 MHz. Chemical shifts are reported in delta (δ)
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units, ppm relative to the center of the triplet at 77.0 ppm for CDCl3. C NMR spectra were
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routinely run with broadband decoupling.
[Ir(dpyx-N,C,N)Cl(μ-Cl)]2, [Ir(dpyx)(ppy)Cl], [Ir(dpyx)(dppy)Cl] and [Ir(dpyx)(tpy)][PF6]2
were synthesized according to previous reports.14
General procedure for ɑ-alkylated ketones with Alcohols Catalyzed by [Ir(dpyx-
N,C,N)Cl(μ-Cl)]2 (Schemes 3-4). In a round-bottomed flask with a condenser tube, ketone (0.5
mmol), alcohol (0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (2.6 mg, 0.0025 mmol, 1 mol
% Ir), Cs2CO3 (33 mg, 0.1 mmol, 0.2 equiv), and tert-amyl alcohol (1 mL) were placed under an
air atmosphere. The reaction mixture was heated under reflux in an oil bath for 12 h. The
reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified by flash
column chromatography with hexane/ethyl acetrate to afford the corresponding product.
1,3-Diphenylpropan-1-one (3a).3f White solid; 86% yield (91 mg); mp 69-70 °C; H NMR
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(500 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 6.9 Hz, 1H), 7.45 (t, J = 6.9 Hz, 2H),
7.34-7.23 (m, 4H), 7.20 (t, J = 6.7 Hz, 1H), 3.30 (t, J = 7.3 Hz, 2H), 3.07 (t, J = 7.3 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 199.1, 141.2, 136.8, 133.0, 128.5, 128.5, 128.4, 128.0,
126.1, 40.4, 30.1.
1-Phenyl-3-p-tolylpropan-1-one (3b).3f White solid; 89% yield (100 mg); mp 33-34 C; H
NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz,
2H), 7.15 (d, J = 8.1 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.28 (t, J = 7.7 Hz, 2H), 3.03 (t, J = 7.7 Hz,
2H), 2.32 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.3, 138.2, 136.9, 135.6, 133.0, 129.2,
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128.6, 128.3, 128.0, 40.6, 29.7, 21.0.
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1-Phenyl-3-o-tolylpropan-1-one (3c).6c Pale yellow oil; 86% yield (96 mg); H NMR (500
MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.19-
7.11 (m, 4H) 3.24 (t, J = 7.9 Hz, 2H), 3.05 (t, J = 7.8 Hz, 2H), 2.35 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 199.3, 139.4, 136.9, 136.0, 133.1, 130.4, 128.7，128.6, 128.1, 126.3.126.2, 39.1,
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27.5, 19.3.
3-(4-Isopropylphenyl)-1-phenylpropan-1-one (3d).20 Pale yellow oil; 87% yield (110 mg);
1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.2, 2H), 7.55 (t, J = 7.4, 1H), 7.45 (t, J = 7.7 Hz, 2H),
7.19-7.15 (m, 4H), 3.29 (t, J = 7.8 Hz, 2H), 3.04 (t, J = 7.8 Hz, 2H), 2.91-2.85 (m, 1H), 1.24 (d, J
13
= 6.9 Hz, 6H); C{1H} NMR (125 MHz, CDCl3) δ 199.3, 146.6, 138.5, 136.9, 132.9, 128.5,
128.3, 128.0, 40.5, 33.7, 29.7, 24.0.
3-(4-Methoxyphenyl)-1-phenylpropan-1-one (3e).3f White solid; 80% yield (96 mg); mp 64-
65 oC; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.45 (t, J
= 7.7 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 3.79 (s, 3H), 3.27 (t, J = 7.7 Hz,
13
2H), 3.01 (t, J = 7.7 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 199.3, 157.9, 136.9, 133.2,
132.9, 129.3, 128.5, 128.0, 113.9, 55.2, 40.6, 29.2.
3-(3-Methoxyphenyl)-1-phenylpropan-1-one (3f).21 White solid; 87% yield (104 mg); mp
68-69 oC; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45
(t, J = 7.7 Hz, 2H), 7.22(t, J = 7.9 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.76 (dd, J =
8.2 Hz and 2.2Hz, 1H), 3.80 (s, 3H) 3.30 (t, J = 7.7 Hz, 2H), 3.05 (t, J = 7.7 Hz, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 199.0, 159.7, 142.8, 136.8, 132.9, 129.4, 128.5, 127.9,120.6 , 114.2,
111.3, 55.0, 40.2, 30.1
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3-(4-Fluorophenyl)-1-phenylpropan-1-one (3g).22 White solid; 86% yield (98 mg); mp 65-
66 °C; 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.7 Hz, 2H), 7.20 (dd, J = 8.5 Hz and 5.6 Hz, 2H), 6.97 (t, J = 8.7 Hz, 2H), 3.28 (t, J = 7.6 Hz,
2H), 3.05 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.9, 161.4 (d, JC-F = 243.9
Hz), 136.8, 136.8, 133.0, 129.8 (d, JC-F = 7.7 Hz), 128.6, 128.0, 115.2 (d, JC-F = 21.2 Hz), 40.3,
29.2.
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3-(2-Fluorophenyl)-1-phenylpropan-1-one (3h).23 Pale yellow oil, 88% yield (100 mg); H
NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz,
2H), 7.29-7.25 (m, 1H), 7.21-7.17 (m, 1H), 7.08-7.01 (m, 2H), 3.32 (t, J = 7.6 Hz, 2H), 3.18 (t, J
13
= 7.6 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 199.0, 161.2 (d, JC-F = 243.9 Hz), 136.7,
133.1, 130.9 (d, JC-F =4.8 Hz), 128.6, 128.0, 127.9, 127.9,124.1 (d, JC-F = 3.0Hz), 115.3 (d, JC-F
=
22.1 Hz), 38.8, 23.9
3-(4-chlorophenyl)-1-phenylpropan-1-one (3i).24 White solid; 82% yield (100 mg); mp 52-
53 °C; 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.7 Hz, 2H), 7.21 (dd, J = 8.5 Hz and 5.5 Hz, 2H), 6.97 (t, J = 7.8 Hz, 2H), 3.28 (t, J = 7.6 Hz,
13
2H), 3.05 (t, J = 7.5 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 198.8, 139.7, 136.7, 133.1,
131.8, 129.8, 128.6, 128.6, 128.0, 40.1, 29.3.
3-(4-bromophenyl)-1-phenylpropan-1-one (3j).25 White solid; 83% yield (120 mg); mp 63-
64 °C;1H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J
= 7.7 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 3.28 (t, J = 7.6 Hz, 2H), 3.03 (t,
13
J = 7.5 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 198.7, 140.2, 136.7, 133.1, 131.5, 130.2,
128.6, 127.9, 119.8, 40.0, 29.4.
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1-Phenyl-3-(3-(trifluoromethyl)phenyl)propan-1-one (3k).21 White solid; 85% yield (118
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mg); mp 57-58 C; H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.3 Hz, 2H), 7.56 (t, J = 7.4 Hz,
1H), 7.45 (t, J = 7.7 Hz, 2H), 7.22 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.80 (s, 1H), 6.76
(dd, J = 8.2 Hz and 2.2Hz, 1H), 3.80 (s, 3H), 3.30 (t, J = 7.7 Hz, 2H), 3.05 (t, J = 7.7 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 198.5, 142.2, 136.6, 133.2, 131.9, 130.8 (q, JC−F = 32.0 Hz),
128.9, 128.6,128.0 , 128.6, 128.0, 125.1 (d, JC−F = 3.4 Hz), 124.2 (q, JC−F = 272.1 Hz), 123.0 (d,
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C−F = 3.4 Hz), 39.9, 29.7.
3-(Thiophen-2-yl)-1-phenylpropan-1-one (3l).21 White solid; 77% yield (83 mg); mp 46-47
°C; 1H NMR (500 MHz,CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J =
7.7 Hz, 2H), 7.11 (dd, J = 5.1 Hz and 1.0Hz, 1H), 6.92-6.90 (m, 1H), 6.86-6.85 (m, 1H), 3.35 (t,
13
J = 7.0 Hz, 2H), 3.29 (t, J = 7.0 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 198.5, 143.8,
136.7, 133.1,128.6, 128.0, 126.8, 124.6, 123.3, 40.5, 24.2 .
3-Ferrocenyl-1-phenylpropan-1-one (3m).26 Red solid; 87% yield (138 mg); mp 90-91 C;
o
1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6
Hz, 2H), 4.13 (s, 5H), 4.11 (t, J = 1.7 Hz, 2H), 4.07 (t, J = 1.7 Hz, 2H), 3.20 (t, J = 7.7 Hz, 2H),
2.79 (t, J = 7.7 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.5, 136.9, 133.0, 128.6, 128.0,
88.0, 68.5, 68.1, 67.3, 40.3, 24.1
3-(Naphthalen-2-yl)-1-phenylpropan-1-one (3n).21 White solid; 82% yield (107 mg); mp 65-
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66 °C; H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.2 Hz, 1H), 7.79 (t, J = 8.6 Hz, 3H), 7.68
(s,1H), 7.54 (t, J = 7.3 Hz, 1H), 7.46-7.38 (m, 5H), 3.38 (t, J = 7.7 Hz, 2H), 3.23 (t, J = 7.6 Hz,
2H); 13C{1H} NMR (125MHz, CDCl3) δ 199.1, 138.8, 136.8, 133.6, 133.0, 132.1, 128.6, 128.1,
128.0, 127.6, 127.5, 127.2, 126.5, 126.0, 125.3, 40.3, 30.2.
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1-Phenyloctan-1-one (3o).27 Pale yellow oil; 77% yield (79 mg); 1H NMR (500 MHz, CDCl3)
δ 7.96 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 2.96 (t, J = 7.4 Hz,
2H), 1.76-1.70 (m, 2H), 1.37-1.29 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 200.6, 137.1, 132.8, 128.5, 128.0, 38.6, 31.7, 29.3, 29.1, 24.3, 22.5, 14.0.
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4-Methyl-1-phenylhexan-1-one (3p).3f Pale yellow oil; 75% yield (71 mg); H NMR (500
MHz, CDCl3) δ 7.96 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 3.02-
2.90 (m, 2H), 1.81-1.74 (m, 1H), 1.58-1.51 (m, 1H), 1.46-1.36 (m, 2H), 1.26-1.16 (m, 1H), 0.93-
0.88 (m, 6H); 13C{1H} NMR (125 MHz,CDCl3) δ 200.8, 137.1, 132.8, 128.5, 128.0, 36.3, 34.2,
30.9, 29.3, 19.0, 11.3.
1-phenyldecan-1-one (3q).28 Yellow oil; 76% yield (88 mg); H NMR (500 MHz, CDCl3) δ
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2H), 1.75-1.72 (m, 2H), 1.38-1.27 (m, 12H), 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 200.5, 137.1, 132.8, 128.5, 128.0, 38.6, 31.8, 29.4, 29.2, 24.3, 22.6, 14.0.
4-Ethyl-1-phenyloctan-1-one (3r).5a Yellow oil; 78% yield (90 mg); H NMR (500 MHz,
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7.8 Hz, 2H), 1.72-1.67(m, 2H), 1.35-1.25 (m, 9H), 0.90-0.86 (m, 6H); 13C{1H} NMR (125 MHz,
CDCl3) δ 200.9, 137.1, 132.8, 128.5, 128.0, 38.6, 36.1, 32.7, 28.9, 27.7, 25.7, 23.1,14.1, 10.9.
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3-Phenyl-1-m-tolylpropan-1-one (4a).29 Pale yellow oil; 83% yield (93 mg); H NMR (500
MHz, CDCl3) δ 7.79-7.77 (m, 2H), 7.39-7.35 (m, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.28-7.26 (m,
2H), 7.23 (t, J = 7.1 Hz, 1H), 3.31(t, J = 7.7 Hz, 2H), 3.08 (t, J = 7.7 Hz, 2H), 2.42 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 199.3, 141.3, 138.3, 136.9, 133.7, 128.6, 128.5, 128.4,
128.3, 126.0, 125.2, 40.4, 30.1, 21.3.
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3-Phenyl-1-p-tolylpropan-1-one (4b).29 White solid; 89% yield (100 mg); mp 67-68 C; H
NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.26-7.24 (m, 4H),
7.21 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.7 Hz, 2H), 2.41 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 198.8, 143.8, 141.4, 134.3, 129.2, 128.5, 128.4, 128.1, 126.1, 40.3,
30.2, 21.6.
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1-(3-Methoxyphenyl)-3-phenylpropan-1-one (4c).23 Pale yellow oil, 91% yield (109 mg); 1H
NMR (500 MHz, CDCl3) δ 7.53 (d, J = 7.7 Hz, 2H), 7.49 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H) 7.30
(t, J = 7.4 Hz, 2H), 7.25-7.24 (m, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.09 (dd, J = 8.2 Hz and 2.5Hz,
13
1H), 3.84 (s, 3H), 3.29 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.7 Hz, 2H); C{1H} NMR (125 MHz,
CDCl3) δ 199.0, 159.8, 141.2, 138.2, 129.6, 128.4, 126.1, 120.6, 119.5, 112.3, 55.4, 40.5, 30.2.
1-(4-Fluorophenyl)-3-phenylpropan-1-one (4d).30 Gray solid; 86% yield (98 mg); mp 38-39
oC; H NMR (500 MHz, CDCl3) δ 7.98 (m, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.24 (d, J = 7.1 Hz,
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2H), 7.21 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 8.6 Hz, 2H), 3.27 (t, J = 7.7 Hz, 2H), 3.06 (t, J = 7.7 Hz,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 197.6, 165.7 (d, JC-F = 254.5 Hz), 141.1, 133.3, 130.6
(d, JC-F= 9.3 Hz), 128.5, 128.4, 126.2, 115.6 (d, JC-F = 21.9 Hz), 40.3, 30.1
1-(4-Chlorophenyl)-3-phenylpropan-1-one (4e).24 White solid; 84% yield (103 mg); mp 73-
74 oC; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.30 (t, J
13
= 7.5 Hz, 2H), 7.25-7.20 (m, 3H), 3.27 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H); C{1H}
NMR (125 MHz, CDCl3) δ 197.9, 141.0, 139.4, 135.1, 129.4, 128.9, 128.5, 128.3, 126.2, 40.3,
30.0.
1-(3-Bromophenyl)-3-phenylpropan-1-one (4f).31 Pale yellow oil; 85% yield (122 mg); H
1
NMR (500 MHz, CDCl3) δ 8.08 (t, J = 1.7 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.69-7.67 (m, 1H),
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7.35-7.29 (m, 3H), 7.25-7.20 (m, 3H), 3.27 (t, J = 7.7 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 197.8, 140.9, 138.6, 135.9, 131.1, 130.2, 128.6, 128.4, 126.5, 126.2,
123.0, 40.5, 30.0.
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1-(4-Bromophenyl)-3-phenylpropan-1-one (4g).32 White solid; 86% yield (124 mg); mp 98-
99 oC; 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.30 (t, J
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= 7.5 Hz, 2H), 7.25-7.20 (m, 3H), 3.27 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H); C{1H}
NMR (125 MHz, CDCl3) δ 198.6, 140.4, 136.6, 132.9, 132.7, 130.6, 128.4, 127.9, 127.8, 127.5,
124.2, 38.4.3, 30.6.
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2-Benzyl-2,3-dihydroinden-1-one (4h).33 Yellow oil; 87% yield (97 mg); H NMR (500
MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.40-7.35 (m, 2H), 7.29 (t, J =
7.4 Hz, 2H), 7.25-7.20 (m, 3H), 3.40 (dd, J = 14.0 Hz and 4.2 Hz, 1H), 3.16 (dd, J = 17.1 Hz and
7.3 Hz, 1H), 3.03-2.97 (m, 1H), 2.85 (dd, J = 17.2 Hz and 4.1 Hz, 1H), 2.66 (dd, J = 13.9 and
10.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 207.8, 153.6, 139.6, 136.5, 134.8, 128.9,
128.5, 127.4, 126.5, 126.3, 124.0, 48.9, 37.0, 32.2.
2-Benzyltetralin-1-one (4i).34 Yellow oil; 85% yield (100 mg); 1H NMR (500 MHz, CDCl3) δ
8.07 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.32-7.29 (m, 3H), 7.25-7.20 (m, 4H), 7.25-
7.20 (m, 3H), 3.50 (dd, J = 13.8 Hz and 4.0 Hz, 1H), 3.16 (dd, J = 17.1 Hz and 7.3 Hz, 1H),
3.03-2.97 (m, 1H), 2.85 (dd, J = 17.2 Hz and 4.1 Hz, 1H), 2.97-2.88 (m, 1H), 2.78-2.72 (m, 1H),
2.64 (dd, J = 13.8 Hz and 9.0 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.3, 144.0, 140.0,
133.2, 132.5, 129.2, 128.7, 128.4, 127.5, 126.6, 126.1, 49.4, 35.7, 28.6, 27.7.
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1-Cyclopropyl-3-phenylpropan-1-one (4j).35 Pale yellow oil; 83% yield (72 mg); H NMR
(500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.17 (m, 3H), 2.94-2.85 (m, 4H), 1.92-1.87 (m,
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1H), 1.03-1.00 (m, 2H), 0.86-0.83 (m, 2H); C{1H} NMR (125 MHz, CDCl3) δ 209.9, 141.1,
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128.4, 128.3, 126.0, 44.9, 29.9, 20.5, 10.6.
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4,4-Dimethyl-1-phenylpentan-3-one (4k).3f Pale yellow oil; 86% yield (82 mg); H NMR
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(500 MHz, CDCl3) δ 7.29-7.26 (m, 2H), 7.19-7.18 (m, 3H), 2.87 (t, J = 7.2 Hz, 2H), 2.79 (t, J =
7.1 Hz, 2H), 1.10 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ 214.9, 141.6, 128.4, 128.3, 126.0,
44.1, 38.5, 30.1, 26.3.
General procedure for the N-alkylation of amines with Alcohols Catalyzed by [Ir(dpyx-
N,C,N)Cl(μ-Cl)]2 (Scheme 5). In a round-bottomed flask with a condenser tube, amine (0.5
mmol), alcohol (0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (2.6 mg, 0.0025 mmol, 1 mol
% Ir), Cs2CO3 (33 mg, 0.1 mmol, 0.2 equiv) and tert-amyl alcohol (1 mL) were placed under an
air atmosphere. The reaction mixture was heated under reflux in an oil bath for 12 h. The
reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified by flash
column chromatography with hexane/ethyl acetrate to afford the corresponding product.
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N-benzylaniline (6a).12 Pale yellow oil; 86% yield (79 mg); H NMR (500 MHz, CDCl3) δ
7.38-7.32 (m, 4H), 7.27 (t, J = 7.1 Hz, 1H), 7.17 (t, J = 7.9 Hz, 2H), 6.71 (t, J = 7.3 Hz, 1H),
6.63 (d, J = 7.7 Hz, 2H), 4.33 (s, 2H), 4.01 (brs, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.2,
139.4, 129.3, 128.6, 127.5, 127.2, 117.6, 112.8, 48.3.
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N-(4-methylbenzyl)aniline (6b).12 Pale yellow oil; 82% yield (81 mg); H NMR (500 MHz,
CDCl3) δ 7.26 (d, J = 7.2 Hz, 2H), 7.18-7.14 (m, 4H), 6.71 (t, J = 7.3 Hz, 2H), 6.63 (d, J = 7.8
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Hz, 2H), 4.28 (s, 2H), 3.97 (brs, 1H), 2.34 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 148.2,
136.8, 136.3, 129.3, 129.2, 127.5, 117.4, 112.8, 48.0, 21.1.
o
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N-(4-methoxybenzyl)aniline (6c).12 Pale yellow solid; 89% yield (95 mg); mp 61-62 C; H
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NMR (500 MHz, CDCl3) δ 7.27 (d, J = 7.3 Hz, 2H), 7.17-7.15 (m, 2H), 6.87 (d, J = 6.9 Hz, 2H),
6.70 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 7.5 Hz, 2H), 4.23 (s, 2H), 3.92 (brs, 1H), 3.78 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 158.8, 148.2, 131.4, 129.2, 128.7, 117.4, 114.0, 112.8, 55.2,
47.7.
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N-(3-fluorobenzyl)aniline (6d).36 Pale yellow oil; 93% yield (93 mg); H NMR (500 MHz,
CDCl3) δ 7.29 (dd, J = 13.8 Hz and 7.9 Hz, 1H), 7.19-7.13 (m, 3H), 7.08 (d, J = 9.8 Hz, 1H),
6.95 (td, J = 8.4 Hz and 2.2 Hz, 1H), 6.73 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 2H), 4.34 (s,
2H), 4.09 (brs, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 163.1 (d, JC−F = 246.5 Hz), 147.8,
142.3 (d, JC−F = 6.6Hz), 130.0 (d, JC−F = 8.2Hz), 129.2, 122.7, 114.0 (d, JC−F = 15.7Hz), 113.9 (d,
JC−F = 15.2Hz), 112.8, 47.7.
N-(4-chlorobenzyl)aniline (6e).12 Pale yellow solid; 86% yield (93 mg), mp 50-51 C; H
NMR (500 MHz, CDCl3) δ 7.29 (s, 4H), 7.16 (t, J = 7.9 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 6.60
(d, J =7.7 Hz, 2H), 4.29 (s, 2H), 4.03 (brs, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 147.8,
138.0, 132.8, 129.2, 128.7, 128.6, 117.8, 112.9, 46.60
o
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N-(4-bromobenzyl)aniline (6f).36 Pale yellow solid; 87% yield (114 mg); mp 51-52 C; H
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NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.6 Hz,
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1H), 6.75 (t, J = 7.6 Hz, 1H), 6.62 (d, J = 7.9 Hz, 2H), 4.29 (s, 2H), 4.05 (brs, 1H); C{1H}
NMR (125 MHz, CDCl3) δ 147.7, 138.5, 131.6, 129.2, 129.0, 120.8, 127.70, 117.7, 112.8, 47.6.
N-(3-trifluoromethylbenzyl)aniline (6g).37 Pale yellow oil; 86% yield (108 mg); H NMR
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(500 MHz, CDCl3) δ 7.62 (s, 1H), 7.55-7.51 (m, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.17 (t, J = 8.0 Hz,
2H), 6.73 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 7.7 Hz, 2H), 4.37 (s, 2H), 4.07 (brs, 1H); 13C{1H}
NMR (125 MHz, CDCl3) δ 147.7, 140.6, 130.9 (q, JC−F = 32.2 Hz), 130.6, 129.3, 129.1, 124.1 (q,
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JC−F = 272.3 Hz), 124.1, 118.0, 112.9, 47.9.
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N-hexylaniline (6h).38 Pale yellow oil; 72% yield (64 mg); H NMR (500 MHz, CDCl3) δ
7.17 (t, J = 7.8 Hz, 2H), 6.68 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 8.1 Hz, 2H), 3.58 (brs, 1H), 3.10
(t, J = 7.2 Hz, 2H), 1.61 (p, J = 7.3 Hz, 2H), 1.43-1.37 (m, 2H), 1.33-1.31 (m, 4H), 0.90（t, J =
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6.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.5, 129.2, 117.0, 112.7, 44.0, 31.6, 29.5,
26.8, 22.6, 14.0
N-(2-methylbutyl)aniline (6i).39 Pale yellow oil; 75% yield (61 mg); H NMR (500 MHz,
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CDCl3) δ 7.16 (t, J = 7.9 Hz, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 3.65 (brs,
1H), 3.06-3.02 (m, 1H), 2.90-2.86 (m, 1H), 1.69-1.63 (m, 1H), 1.53-1.45 (m, 1H), 1.25-1.16 (m,
1H), 0.96-0.91 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.6, 129.2, 116.9, 112.6, 49.9,
34.5, 27.3, 17.5, 11.3.
N-octylaniline (6j).40 Yellow oil; 82% yield (84 mg); 1H NMR (500 MHz, CDCl3) δ 7.16 (t, J
= 7.8 Hz, 2H), 6.68 (t, J = 7.3 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 3.58 (brs, 1H), 3.09 (t, J = 7.2
Hz, 2H), 1.62-1.59 (m, 2H), 1.30-1.28 (m, 8H), 0.90-0.87 (m, 3H); C{1H} NMR (125 MHz,
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CDCl3) δ 148.5, 129.2, 117.0, 112.6, 44.0, 31.8, 29.6, 29.4, 29.3, 27.2, 22.6, 14.1.
N-(2-ethylhexyl)aniline (6k).12 Yellow oil; 75% yield (77 mg); 1H NMR (500 MHz, CDCl3) δ
7.16 (t, J = 7.7 Hz, 2H), 6.67 (t, J = 7.8 Hz, 1H), 6.60 (d, J = 8.0 Hz, 2H), 3.60 (brs, 1H), 3.01 (d,
J = 6.8 Hz, 2H), 1.57-1.53 (m, 1H), 1.43-1.38 (m, 2H), 1.35-1.30 (m, 6H), 0.92-0.89 (m, 6H);
13C{1H} NMR (125 MHz, CDCl3) δ 148.7, 129.1, 116.9, 112.6, 47.0, 39.1, 31.3, 29.0, 24.5, 23.2,
14.1, 10.9.
N-benzyl-4-methylaniline (6l).36 Pale yellow oil; 85% yield (84 mg); H NMR (500 MHz,
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CDCl3) δ 7.35-7.30 (m, 4H), 7.25 (t, J = 7.3Hz, 1H), 6.97 (d, J = 8.2 Hz, 2H), 6.54 (d, J = 8.3 Hz,
2H), 4.28 (s, 2H), 3.87 (brs, 1H), 2.22 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 145.9, 139.6,
129.7, 128.6, 127.4, 127.1, 126.7,112.9, 48.9, 20.4
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N-benzyl-4-methoxyaniline (6m).12 Pale yellow oil; 79% yield (84 mg); 1H NMR (500 MHz,
CDCl3) δ 7.36-7.30 (m, 4H), 7.25 (t, J = 7.0 Hz, 1H), 6.76 (d, J = 8.9 Hz, 2H), 6.58 (d, J = 8.9
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Hz, 2H), 4.26 (s, 2H), 3.71 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 152.1, 142.4, 139.6,
128.5, 127.5, 127.1, 114.9, 114.0, 55.7, 49.2
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N-benzyl-3-chloroaniline (6n).12 Pale yellow oil; 88% yield (96 mg); H NMR (500 MHz,
CDCl3) δ 7.33 (d, J = 5.1 Hz, 4H), 7.29-7.26 (m, 1H), 7.04 (t, J = 8.0 Hz, 1H), 6.68 (dd, J = 7.9
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Hz and 1.3Hz, 1H), 6.62 (s, 1H), 6.49 (dd, J = 8.2 Hz and 1.6 Hz, 1H), 4.29 (s, 1H); C{1H}
NMR (125 MHz, CDCl3) δ 148.5, 138.3, 135.0, 130.2, 128.7, 127.6, 127.5, 117.9, 113.0, 112.6,
48.4.
N-benzyl-4-chloroaniline (6o).12 Pale yellow oil; 88% yield (96 mg), mp 46-45 oC; 1H NMR
(500 MHz, CDCl3) δ 7.34 (d, J = 4.3 Hz, 4H), 7.29-7.27 (m, 1H), 7.10 (d, J = 8.3 Hz, 4H), 6.53
(d, J = 8.2 Hz, 4H), 4.29 (s, 2H), 4.07 (brs, 1H); 13C{1H} NMR (125MHz, CDCl3) δ 146.6,
138.9, 129.0, 128.7, 127.4,127.3,122.0, 113.9, 48.3.
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N-benzyl-2,4-dichloroaniline (6p).41 Pale yellow oil; 87% yield (109 mg); H NMR (500
MHz, CDCl3) δ 7.36-7.31 (m, 4H), 7.29-7.25 (m, 2H), 7.02 (dd, J = 8.7 Hz and 2.3Hz, 1H), 6.50
(d, J = 8.3 Hz, 1H), 4.71 (brs, 1H), 4.35 (d, J = 4.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ
142.5, 138.2, 128.7, 128.7, 127.7,127.5,127.1, 121.3, 119.3, 112.0, 47.8.
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N-benzyl-4-bromoaniline (6q).36 Pale yellow oil; 84% yield (110 mg); H NMR (500 MHz,
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Hz, 4H), 4.28 (s, 2H), 4.06 (brs, 1H); C{1H} NMR (125MHz, CDCl3) δ 147.0, 138.8, 131.9,
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128.7, 127.4, 114.4, 109.1, 48.2.
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N-benzyl-4-trifluoromethylaniline (6r).42 White solid; 80% yield (100 mg); mp 53-54 oC; 1H
NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.6Hz, 2H), 7.34-7.31 (m, 4H), 7.29-7.26 (m, 1H), 6.59
(d, J = 8.6Hz, 2H), 4.33 (s, 2H), 4.11 (brs, 1H); 13C{1H} NMR (125MHz, CDCl3) δ 150.4, 138.4,
128.8, 127.5, 127.3, 126.6 (d, JC−F = 3.4 Hz), 124.9 (q, JC−F = 270.2 Hz), 119.0 (q, JC−F = 32.5
Hz), 111.9, 47.8.
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N-benzyl-4-trifluoromethoxyaniline (6s).43 Pale yellow oil; 83% yield (111 mg); H NMR
(500 MHz, CDCl3) δ 7.37-7.29 (m, 5H), 7.02 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 9.0 Hz, 2H), 4.32
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(s, 2H) , 4.11 (brs, 1H); C{1H} NMR (125MHz, CDCl3) δ 146.9, 140.6, 138.9, 128.7, 127.4,
122.4, 120.7(q, JC−F = 255.1 Hz), 113.0, 113.0, 48.4.
o
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N-benzylnaphthalen-1-amine (6t).12 White solid; 86% yield (100 mg); mp 69-70 C; H
NMR (500 MHz, CDCl3) δ 7.85-7.81 (m, 2H), 7.48-7.25 (m, 9H), 6.65 (d, J = 7.4 Hz, 1H), 4.71
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(brs, 1H), 4.52 (s, 2H); C{1H} NMR (125 MHz, CDCl3) δ 143.2, 139.1, 134.2, 128.7, 127.7,
127.3, 126.6, 125.7, 124.7, 123.3, 119.9, 117.6, 104.7, 48.5.
2-Benzylaminopyridine (6u).12 White solid; 77% yield (71 mg); mp 92-93 oC; 1H NMR (500
MHz, CDCl3) δ 8.06 (d, J = 4.9 Hz, 1H), 7.38-7.30 (m, 5H), 7.25(t, J = 7.7 Hz, 1H), 6.55 (dd, J
= 6.9 Hz and 5.7Hz, 1H), 6.34 (d, J = 8.4 Hz,1H), 5.12 (brs, 1H), 4.48 (d, J = 5.9 Hz,
2H); 13C{1H} NMR (125 MHz, CDCl3) δ 158.6, 148.1, 139.1, 137.4, 128.5, 127.3, 127.1, 113.0,
106.7, 46.2.
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N-benzyl-(2-pyrimidyl)amine (6v).44 White solid; 76% yield (70 mg); mp 78-79 C; H
NMR (500 MHz, CDCl3) δ 8.26 (d, J = 4.5 Hz, 2H), 7.37-7.32 (m, 4H), 7.29-7.26 (m, 1H), 6.54
(t, J = 9.7 Hz, 1H), 5.59 (brs, 1H), 4.64 (d, J = 5.9 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
162.3, 158.0, 139.1, 128.6, 127.5, 127.2, 110.7, 45.4.
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Hydrogen Transfer between an α,β-unsaturated ketone and an alcohol (Scheme 7). In a
round-bottomed flask with a condenser tube, (E)-chalcone (7) (104 mg, 0.5 mmol), benzyl
alcohol (2a) (65 mg, 0.6 mmol), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (2.6 mg, 0.0025 mmol, 1 mol % Ir),
Cs2CO3 (33 mg, 0.1 mmol, 0.2 equiv), and tert-amyl alcohol (1 mL) were placed under an air
atmosphere. The resulting mixture was then heated under reflux in an oil bath for 12 h, at which
point the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was
concentrated in vacuo and purified by flash column chromatography with hexanes/ethyl acetate
to afford product 3a in 88% yield (92 mg).
Hydrogen Transfer between an imine and an alcohol (Scheme 8). In a round-bottomed
flask with a condenser tube, N-benzylideneaniline (8) (91 mg, 0.5 mmol), benzyl alcohol (2a)
(65 mg, 0.6 mmol), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2 (2.6 mg, 0.0025 mmol, 1 mol % Ir), Cs2CO3 (33
mg, 0.1 mmol, 0.2 equiv), and tert-amyl alcohol (1 mL) were placed under an air atmosphere.
The resulting mixture was then heated under reflux in an oil bath for 12 h, at which point the
reaction mixture was allowed to cool to ambient temperature. The reaction mixture was heated under
reflux in an oil bath for 12 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo,
and purified by flash column chromatography with hexane/ethyl acetrate to afford product 6a in 86% yield (79
mg).
Procedure for the Synthesis of Donepezil (Scheme 9). In a round-bottomed flask with a
condenser tube, 5,6-dimethoxy-2,3-dihydroinden-1-one (9) (96 mg, 0.5 mmol), (1-
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benzylpiperidin-4-yl)methanol (10) (123 mg, 0.6 mmol, 1.2 equiv), [Ir(dpyx-N,C,N)Cl(μ-Cl)]2
(2.6 mg, 0.0025 mmol, 1 mol % Ir), Cs2CO3 (33 mg, 0.1 mmol, 0.2 equiv), and tert-amyl alcohol
(1 mL) were placed under an air atmosphere. The reaction mixture was heated under reflux in an
oil bath for 12 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo,
and purified by flash column chromatography with hexane/ethyl acetrate to afford the
corresponding product.
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2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydroinden-1-one (11).45 Pale
1
yellow oil; 85% yield (162 mg); H NMR (500 MHz, DMSO-d6) δ 7.32-7.22 (m, 5H), 7.06-7.05
(m, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.42 (s, 2H), 3.22-3.17 (dd, J = 17.6 Hz and 8.1 Hz, 1H),
2.80-2.75 (m, 2H), 2.65-2.62 (m, 2H), 1.91-1.87 (m, 2H), 1.72-1.67 (m 2H), 1.60-1.57 (m, 1H),
1.46-1.38 (m, 1H), 1.26-1.10 (m, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 206.5, 155.2,
149.0, 148.6, 138.6, 128.7, 128.3, 128.0, 126.7, 108.1, 103.9, 62.5, 55.8, 55.5, 53.2, 44.7, 38.2,
33.8, 32.6, 31.4.
Notes
The authors declare no competing financial interest.
Acknowledgments
Financial support by National Natural Science Foundation of China (21272115), the State Key
Laboratory of Fine Chemicals (KF1401) and Natural Science Foundation of Jiangsu Province
(BK20161494) is greatly appreciated.
Supporting Information.
13
1H NMR and C NMR spectra of the products. This material is available free of charge via the
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