Synthesis of a-Alkylated Ketones via Tandem Acceptorless Dehydrogenation/a-Alkylation from Secondary and Primary Alcohols Catalyzed by Metal-Ligand Bifunctional Iridium Complex [CpIr(2,2′-bpyO)(H2O)]

Article abstract of DOI:10.1021/acs.joc.5b01975

A new strategy for the synthesis of α-alkylated ketones via tandem acceptorless dehydrogenation/α-alkylation from secondary and primary alcohols was proposed and accomplished. In the presence of metal-ligand bifunctional iridium complex [CpIr(2,2′-bpyO)(H₂O)], various desirable products were obtained in high yields. Compared with previous methods for the direct dehydrogenative coupling of secondary alcohols with primary alcohols to α-alkylated ketones, this protocol has obvious advantages including complete selectivity for α-alkylated ketones and more environmentally benign conditions. Notably, the study also exhibited the potential to develop tandem reactions catalyzed using a metal-ligand bifunctional iridium complex.

Full text of DOI:10.1021/acs.joc.5b01975

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Article
Synthesis of alpha-Alkylated Ketones via Tandem
Acceptorless Dehydrogenation/alpha-Alkylation from
Secondary and Primary Alcohols Catalyzed by a Metal-
Ligand Bifunctional Iridium Complex [Cp*Ir(2,2’-bpyO)(H2O)]
Rongzhou Wang, Juan Ma, and Feng Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01975 • Publication Date (Web): 02 Oct 2015
Downloaded from http://pubs.acs.org on October 12, 2015
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Synthesis of ɑ-Alkylated Ketones via Tandem
Acceptorless Dehydrogenation/ɑ-Alkylation from
Secondary and Primary Alcohols Catalyzed by a
Metal-Ligand Bifunctional Iridium Complex
[Cp*Ir(2,2’-bpyO)(H2O)]
Rongzhou Wang, † Juan Ma, † 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
‡ State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024,
People’s Republic of China
O
O
R2
R1
R3
R1
OH
R2
R2
acceptorless
dedydrogenation
R1
ɑ-alkylation
H2O
O
R2 OH
Ir H2O
O
N
H2
Complete selectivity for α-alkylated ketones
More environmentally benign conditions
Up to 90% yield
N
32 examples
Metal-ligand bifunctional catalyst
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Abstract:
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A new strategy for the synthesis of α-alkylated ketones via tandem acceptorless
dehydrogenation/α-alkylation from secondary and primary alcohols was proposed and
accomplished. In the presence of a metal-ligand bifunctional iridium complex [Cp*Ir(2,2’-
bpyO)(H2O)], various desirable products were obtained in high yields. Compared with previous
methods for the direct dehydrogenative coupling of secondary alcohols with primary alcohols to
α-alkylated ketones, this protocol has obvious advantages, including complete selectivity for α-
alkylated ketones and more environmentally benign conditions. Notably, the study also exhibited
the potential to develop tandem reactions catalyzed using a metal-ligand bifunctional iridium
complex.
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■ Introduction
The development of catalytic transformations using readily available starting materials, high
atom economy and high selectivity is one of the most significant goals of modern organic
synthesis.1 α-Alkylated ketones represent a class of compounds possessing a broad spectrum of
biological activities and are also used as key synthetic intermediates. These compounds are
traditionally synthesized via the α-alkylation of ketones with alkyl halides as alkylating agents in
the presence of inorganic strong base.3 In recent years, significant efforts have been devoted to
the synthesis of α-alkylated ketones via the α-alkylation of ketones with primary alcohols as
alkylating agents. These alkylating agents utilize the “hydrogen autotransfer process”4 and
include ruthenium,5 iridium,6 palladium7 and other transition-metal catalysts.8 This methodology
is very promising because of high atom economy and the generation of water as the sole by-
product. More recently, the direct dehydrogenative coupling of secondary alcohols with primary
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alcohols to α-alkylated ketones has been developed using a heterogeneous γ-alumina-supported
silver subnanocluster,9 a homogeneous Ir-based PC(sp3)P pincer complex,10 and a
bis(benzoxazolyl) iridium complex as catalysts.11,12 In this process, secondary and primary
alcohols are initially dehydrogenated to give the corresponding ketones and aldehydes, thus
generating a metal hydride species. Furthermore, a base-promoted cross-aldol condensation
between the resulting ketones an aldehydes occurs, producing α,β-unsaturated ketones. The C=C
bond of these ketones then undergo the selective transfer hydrogenation to afford α-alkylated
ketones upon liberation of hydrogen gas (Scheme 1). However, it remains extremely challenging
to control reaction selectivity. In the above process, the resulting α,β-unsaturated ketones easily
undergo successive hydrogenation of the C=C and C=O bonds via metal hydride species; thus,
the ß-alkylation of secondary alcohols with primary alcohols inevitably occurs as a side
reaction.13 Moreover, these procedures require a long reaction time (48 h)9 or a stoichiometric
base.10-11 From the sustainable-chemistry standpoint, it is necessary to develop a new strategy
and catalytic system for the preparation of α-alkylated ketones from secondary and primary
alcohols with higher selectivity under more environmentally benign conditions.
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Fujita, Yamaguchi and co-workers recently developed a series of Cp*Ir complexes bearing a
Scheme 1. Direct Coupling of Secondary Alcohols with Primary Alcohols.
OH
O
OH
[M]/Base
[M]
R2
R3 OH
R1
R1
R3
H2
R1
R3
+
R2
R2
or
[M-H]
Base
O
O
R2
R3
O
+
R1
R1
R3
R2
H2O
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hydroxypyridine14 or bipyridonate ligand,15 which exhibits a high activity for the acceptorless
dehydrogenation of alcohols to carbonyl compounds and is based on the concept of “ligand-
promoted dehydrogenation”. More recently, we have demonstrated that such complexes are
highly effective and versatile catalysts for the N-alkylation of sulfonamides with alcohols in
water16 and the α-alkylation of ketones with primary alcohols under extremely environment-
friendly conditions.17-18 A mechanistic investigation revealed that such complexes can be used as
metal-ligand bifunctional catalysts in the “hydrogen autotransfer process”. As our continuing
effort to develop catalytic transformations with alcohols as electrophiles,16-17,19 herein we explore
a new and alternative protocol for synthesizing α-alkylated ketones via iridium-catalyzed tandem
acceptorless dehydrogenation/α-alkylation from secondary and primary alcohols. As outlined in
Scheme 2, the secondary alcohols undergo acceptorless dehydrogenation to form ketones, which
is followed by the conversion of the resulting ketones to α-alkylated ketones via α-alkylation
with alcohols.
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Scheme 2. Proposed Strategy to Synthesize α-Alkylated Ketones.
O
OH
O
R2
R2
R1
R3
R1
R1
R2
acceptorless
dedydrogenation
ɑ-alkylation
H2O
Catalyst
R3 OH
H2
Results and Discussion
In the initial experience, the transformation of 1-phenylethanol (1a) and benzyl alcohol (2a) was
selected as the model reaction. As shown in Scheme 3, a range of Cp*Ir complexes bearing a
hydroxypyridine (Cat. 1-3) and the Cp*Ir complex bearing a bipyridonate ligand (Cat. 4), which
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were originally reported by the group of Fujita and Yamaguchi,14-15 were initially selected as the
catalysts for the acceptorless dehydrogenation of 1a. In the presence of the catalyst (1 mol%), the
reaction of 1a was performed in tert-amyl alcohol at reflux under air for 6 h. The Cp*Ir complex
bearing a bipyridonate ligand (Cat. 4) exhibited higher activity than Cp*Ir complexes bearing a
hydroxypyridine ligand (Cat. 1-3), and the corresponding acetophenone (3a) was produced in
95% yield. Furthermore, low catalytic activity was observed when other Cp*Ir complexes (Cat.
5-9) were evaluated. It is apparent that the hydroxyl or carbonyl groups on the bpy ligand are
critically important for the acceptorless dehydrogenation of 1a. As a result, Cat. 4 was selected
as the catalyst for the proposed tandem reaction. When 1a was completely converted to
Scheme 3. Exploration of the Feasibility of a Model Reaction.
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OH
O
Catalyst (1 mol%)
tert-amyl alcohol
reflux, under air, 6 h
1a
3a
[OTf]2
HO
HO
HO
Ir Cl
Cl
Ir H2O
OH
Ir Cl
N
N
N
N
Cat. 1, 26% yield
Cat. 2, 44% yield
Cat. 3, 81% yield
[OTf]2
Cl-
O
Ir H2O
N
N
Ir H2O
Ir Cl
N
N
O
N
N
Cat. 4, 95% yield
Cat. 5, 25% yield
Cat. 6, n.d.
2Cl-
Cl
Cl
Ir
Ir
Ir Cl
N
Ir
Cl
Cl
H3N
NH3
H3N
Cat. 7, n.d.
Cat. 8, 15% yield
Cat. 9, 10% yield
1) Cat. 4 (1 mol%)
tert-amyl alcohol
reflux, under air, 6 h
OH
O
2) PhCH2OH (2a)
Cs2CO3 (0.1 equiv)
reflux, under air, 6 h
1a
4aa, 90% yield
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intermediate 3a, benzyl alcohol (2a) (1.1 equiv) and Cs2CO3 (0.1 equiv) were added and this
reaction mixture continued to reflux under air for another 6 h to produce 4aa in 90% yield.
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With the optimal reaction conditions established, we investigated the reactions with respect to
primary alcohols, and the results are outlined in Table 1. The transformations of 1a with
electron-rich substituted benzyl alcohols (2b-2e) gave the corresponding products 4ab-4ae in 85-
89% yields (Table 1, entries 1-4). When halogenated benzyl alcohols (2f-2i) were used, the α-
alkylated products 4af-4ai were isolated in 85-90% yields (Table 1, entries 5-8). Stronger
electron-deficient substituted benzyl alcohols (2j and 2k) were also converted to the desired
products 4aj and 4ak in 83% and 80% yields, respectively (Table 1, entries 9 and 10).
Furthermore, 1-naphthylmethanol (2l) and 2-furanmethanol (2m) were also demonstrated to be
suitable substrates, and the α-alkylated products 4al and 4am were obtained in 84% and 83%
yields, respectively (Table 1, entries 11-12). The highly catalytic actitivites was also observed in
aliphatic primary alcohols, such as 1-hexanol (2n), 1-octanol (2o), 2-methylbutan-1-ol (2p) and
cyclohexylmethanol (2q), affording the corresponding products 4an and 4ao in 79%-86% yields,
respectively (Table 1, entries 13-16).
To further expand the reaction generality, the transformations with respect to secondary
alcohols were evaluated (Table 3). Reactions of electron-rich substituted 1-phenylethanols (1b-
1e) afforded the desired products 4ba-4ea in 82-88% yields (Table 3, entries 1-4). For
halogenated 1-phenylethanols (1f-i) and stronger electron-deficient substituted 1-phenylethanols
(1j), the corresponding products 4fa-4ja were isolated in 79-89% yields (Table 2, entries 5-9).
The desired product 4ka was also isolated in high yield when 1-(naphthalen-2-yl)ethanol (1k)
was used as a substrate (Table 2, entry 10). In the case of 1-phenylpropan-1-ol (1l), 1-indanol
(1m) and 1-tetralinol (1n), the reactions afforded the corresponding products 4la-4na in 80-82%
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Table 1. Reactions of 1-Phenylethanol (1a) with Various Primary Alcohols (2).a
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O
OH
1) Cat. 4 (1 mol%), tert-amyl alcohol
reflux, under air, 6 h
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R
2) RCH2OH (2), Cs2CO3 (0.1 equiv)
reflux, under air, 6 h
4
1a
Entry
1
Primary Alcohol
Me
Product
O
Yield (%)
Me
OH
86
2b
2c
4ab
O
Me
Me
Me
Me
OH
OH
2
3
85
4ac
O
87
Me
Me
Me
Me
OMe
F
2d
2e
4ad
O
OH
OH
4
5
89
85
MeO
4ae
O
F
2f
4af
O
OH
OH
6
7
88
90
Cl
Cl
Cl
Cl
2g
4ag
Cl
O
Cl
2h
2i
4ah
O
OH
OH
8
9
89
83
Br
Br
4ai
O
F3C
CF3
2j
4aj
O
OH
10
80
F3CO
OCF3
2k
4ak
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Table 1. (Continued)
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Entry
11
Primary Alcohol
Product
O
Yield (%)
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.
OH
84
2l
4al
O
O
OH
12
13
83
79
O
2m
4am
O
OH
OH
2n
4an
O
85
14
2o
4ao
O
OH
OH
83
86
15
16
2p
2q
4ap
O
4aq
a Reaction conditions: 1) 1a (1 mmol), Cat. 4 (1 mol %), tert-amyl alcohol
(1 mL), reflux, under air, 6 h; 2) 2 (1.1 mmol), Cs2CO3 (0.1 equiv), reflux,
under air, 6 h.
yields (Table 2, entries 11-13). Aliphatic secondary alcohols such as 1-cyclopropylethanol (1o)
and 3-methylbutan-2-ol (1p) were converted to the desired products 4na and 4oa in 84% and
82% yields, respectively; although 2 equiv of secondary alcohol was required (Table 2, entries
14-15).
A plausible mechanism for this tandem acceptorless dehydrogenation/α-alkylation from
secondary and primary alcohols to α-alkylated ketones is shown in Scheme 4. This mechanism is
closely related to the proposed mechanism of Fujita and Yamaguchi for the dehydrogenative
oxidation of secondary alcohols to ketones15 and our proposed mechanism for the α-alkylation of
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Table 2. Reactions of a Range of Secondary Alcohols (1) with Benzyl Alcohol (2a).a
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9
1) Cat. 4 (1 mol%), tert-amyl alcohol,
reflux, under air, 6 h
O
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11
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OH
R2
R
2) PhCH2OH (2a), Cs2CO3 (0.1 equiv)
reflux, under air, 6 h
R1
R2
1
4
Entry
Secondary Alcohol
OH
Product
O
Yield (%)
Me
Me
1
88
1b
4ba
OH
O
2
3
4
82
87
88
Me
Me
1c
4ca
OH
O
1d
4da
OH
O
MeO
F
MeO
F
1e
4ea
OH
O
5
79
83
1f
4fa
OH
O
Cl
Cl
6
7
8
1g
4ga
OH
O
82
89
81
84
Cl
Br
Cl
Br
1h
OH
4ha
O
1i
4ia
OH
O
9
F3C
F3C
1j
4ja
OH
O
10
1k
4ka
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Table 2. (Continued)
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Entry
11
Secondary Alcohol
Product
Yield (%)
10
11
12
13
14
15
16
17
18
19
20
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OH
O
80b
1l
4la
OH
O
12
82
1m
4ma
OH
O
13
14
80
1n
4na
O
OH
84c
1o
4oa
OH
OH
82c
15
1p
4pa
a Reaction conditions: 1) 1 (1 mmol), Cat. 4 (1 mol %), tert-amyl alcohol (1
mL), reflux, under air, 6 h; 2) 2a (1.1 mmol), Cs2CO3 (0.1 equiv), reflux,
under air, 6 h. b Cs2CO3 (0.3 equiv), 20 h. c 1 (2.0 mmol), 2a (1.0 mmol).
The yield is based on the amount of 2a.
ketones with primary alcohols, which is catalyzed by the metal-ligand bifunctional Cp*Ir
complex [Cp*Ir(2,2’-bpyO)(H2O)].17 In cycle I, the bipyridonate ligand of iridium species A
accepted a proton from the secondary alcohol to afford alkoxy iridium species B, which
underwent ß-hydrogen elimination to produce iridium hydride species C and a ketone. The
ligand-promoted hydrogen transfer from the hydride hydroxyl proton on the bpy ligand and the
hydride on the iridium then occurred, releasing hydrogen gas and regenerating catalytic species
A.20 In the initial stage of cycle II, similar to the case of secondary alcohols, the primary alcohols
were initially converted to aldehydes, generating iridium hydride species C. A base-promoted
cross-aldol condensation between aldehydes and ketones, which were generated in cycle I,
afforded α,ß-unsaturated ketones. The hydride on the iridium and hydroxy proton on the ligand
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of species C were simultaneously transferred to the C=C bond of the α,ß-unsaturated ketones,
resulting in the regeneration of catalytic species A and formation of α-alkylated ketones as final
products.21
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Scheme 4. Proposed Reaction Mechanism.
O
R1
O
Cp*
R3
R2
Cp*
R1
H
O
R1
R3
O
O
Ir
R2
Ir
R2
OH
O
N
R2
N
O
N
R1
OH
R1
H
R3
N
R2
base
C
B
Cp*
H
O
Ir
O
O
O
N
Ir H2O
-H2O
Ir
OH
Ir
N
O
O
O
N
N
O
cycle I
cycle II
N
R2
N
N
N
+ H2O
R1
C
A
Cat.4
A
Cp*
Ir
Cp*
O
H
O
R2
R3
O
O
Ir
N
N
OH
N
R3 OH
H2
O
N
H
B
C
:
vacant site
Furthermore, the direct coupling of a secondary alcohol and a primary alcohol, which was
catalyzed by the present catalytic system, was investigated (Scheme 5). In the presence of Cat. 4,
the reaction of 1a with 2a was performed for 12 h to afford the mixture of 4aa and 5aa in 69%
and 31% yields, respectively. It was apparent that the tandem reaction exhibited advantageous
selectivity for α-alkylated ketones compared with the direct coupling reaction when identical
starting materials were used.
Scheme 5. Direct Coupling of 1a with 2a Catalyzed by Cat. 4.
Cat. 4 (1 mol%)
Cs2CO3 (0.1 equiv)
OH
OH
O
OH
+
+
Ph
Ph
2a
Ph
Ph
Ph
Ph
tert-amyl alcohol
under air, reflux, 12 h
4aa
69% NMR yield
5aa
31% NMR yield
1a
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■ Conclusion
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In summary, we have demonstrated a new strategy to synthesize α-alkylated ketones via the
tandem acceptorless dehydrogenation/α-alkylation from secondary and primary alcohols. In the
presence of a metal-ligand bifunctional iridium complex [Cp*Ir(2,2’-bpyO)(H2O)], various
desirable products were obtained in high yields. Compared with previous methods for the direct
dehydrogenative coupling of secondary alcohols with primary alcohols to α-alkylated ketones,
this protocol has obvious advantages, including complete selectivity for α-alkylated ketones and
more environmentally benign conditions. Notably, the study also exhibited the potential to
develop tandem reactions catalyzed by a metal-ligand bifunctional iridium complex.
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■ 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
follows: s, singlet; d, doublet; t, triplet; m, multiplet; b, broad. Carbon-13 nuclear magnetic
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
routinely run with broadband decoupling.
[Cp*(2-(OH)py)]Cl2 (Cat. 1),14a Cp*Ir[2-(2-(2-(OH)py)phenyl]Cl (Cat. 2),14b [Cp*(6,6’-
(OH)2bpy)][OTf]2 (Cat. 3),14c [Cp*Ir(2,2′-bpyO)(H2O)] (Cat. 4),15 [Cp*Ir(bpy)(H2O)][OTf]2 (Cat.
5),22 [Cp*Ir(bpy)Cl)][Cl] (Cat. 6),23 [Cp*Ir(2-phenylpyridine-kC,N)]Cl (Cat. 7),24
[Cp*Ir(NH3)3][Cl]2 (Cat. 8)25 and [Cp*IrCl2]2 (Cat. 9)26 were synthesized according to previous
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General procedure for the synthesis of α-alkylated ketones via tandem acceptorless
dehydrogenation/α-alkylation from secondary alcohols and primary alcohols catalyzed by
[Cp*Ir(2,2’-bpyO)(H2O)] (Tables 1-2). In a round-bottomed flask with a condenser tube,
secondary alcohol (1 mmol), Cat. 4 (5.3 mg, 0.01 mmol, 1 mol %), tert-amyl alcohol (1 mL),
were placed under an air atmosphere. The reaction mixture was heated under reflux in an oil bath
for 6 h and was then cooled to ambient temperature. Primary alcohol (1.1 mmol, 1.1 equiv),
Cs2CO3 (33 mg, 0.1 mmol, 0.1 equiv) were added and the mixture was heated under reflux for 6
h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo, and purified
by flash column chromatography with hexane/ethyl acetate to afford corresponding product.
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1,3-diphenylpropan-1-one (4aa).5e White solid; 90% yield (188 mg); mp 69-70 oC; 1H NMR
(500 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 6.9 Hz, 1H), 7.46 (t, J = 6.9 Hz, 2H),
7.32-7.26 (m, 4H), 7.21 (t, J = 7.2 Hz, 1H), 3.31 (t, J = 7.3 Hz, 2H), 3.07 (t, J = 7.3 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 199.2, 141.2, 136.8, 133.0, 128.6, 128.5, 128.4, 128.0,
126.1, 40.4, 30.1.
1-phenyl-3-o-tolylpropan-1-one (4ab).8d White solid; 86% yield (193 mg); mp 48-49 oC; 1H
NMR (500 MHz, CDCl3) δ 7.98-7.96 (m, 2H), 7.56 (t, J = 6.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H),
7.20-7.14 (m, 4H), 3.26 (t, J = 7.9 Hz, 2H), 3.06 (t, J = 7.9 Hz, 2H), 2.35 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 199.4, 139.4, 136.8, 136.0, 133.1, 130.3, 128.7, 128.6, 128.0, 126.3, 126.2,
39.1, 27.5, 19.3.
3-(3,4-dimethylphenyl)-1-phenylpropan-1-one (4ac).19j White solid; 85% yield (203 mg);
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mp 59-60 C; H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H),
7.45 (t, J = 7.6 Hz, 2H), 7.08-6.99 (m, 3H), 3.28 (t, J = 7.8 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H),
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2.25 (s, 3H), 2.23 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.4, 138.7, 136.9, 136.6, 134.3,
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3-(4-isopropylphenyl)-1-phenylpropan-1-one (4ad).27 Pale-yellow oil; 87% yield (220 mg);
1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.6 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6
Hz, 2H), 7.20-7.16 (m, 4H), 3.30 (t, J = 7.8 Hz, 2H), 3.04 (t, J = 7.8 Hz, 2H), 2.91-2.86 (m, 1H),
1.25 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.4, 146.7, 138.5, 136.9, 133.0,
128.6, 128.3, 128.0, 126.5, 40.5, 33.7, 29.7, 24.0.
3-(4-methoxyphenyl)-1-phenylpropan-1-one (4ae).5e White solid; 89% yield (213 mg); mp
64-65 oC; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.5 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.45
(t, J = 7.6 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 2H), 3.79 (s, 3H), 3.27 (t, J =
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7.4 Hz, 2H), 3.01 (t, J = 7.4 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 199.3, 158.0, 136.9,
133.3, 133.0, 129.3, 128.6, 128.0, 113.9, 55.2, 40.7, 29.3.
3-(4-fluorophenyl)-1-phenylpropan-1-one (4af).28 White solid; 85% yield (193 mg); mp 65-
66 oC; 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
= 7.5 Hz, 2H), 7.22-7.19 (m, 2H), 6.98 (t, J = 8.7 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 3.05 (t, J =
7.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 199.0, 162.3, 160.4, 136.9, 133.1, 129.8 (d, JC-
F = 6.4 Hz), 128.6, 128.0, 115.3 (d, JC-F = 19.9 Hz), 40.4, 29.2.
3-(4-chlorophenyl)-1-phenylpropan-1-one (4ag).29 White solid; 88% yield (215 mg); mp 53-
54 oC; 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
= 7.7 Hz, 2H), 7.26 (d, J = 4.2 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 3.04 (t,
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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, 127.8, 40.1, 29.3.
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3-(2,4-dichlorophenyl)-1-phenylpropan-1-one (4ah).28 White solid; 90% yield (252 mg); mp
64-65 oC; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45
(t, J = 7.7 Hz, 2H), 7.37 (d, J = 2.1 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 8.2 and 2.1
Hz, 1H), 3.31 (t, J = 7.6 Hz, 2H), 3.15 (t, J = 7.5 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ
198.6, 137.4, 136.6, 134.5, 133.2, 132.6, 131.6, 129.3, 128.6, 128.0, 127.2, 38.1, 27.6.
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3-(4-bromophenyl)-1-phenylpropan-1-one (4ai).30 White solid; 89% yield (258 mg); mp 63-
64 oC; 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
= 7.7 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 3.28 (t, J = 7.5 Hz, 2H), 3.03 (t,
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J = 7.5 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 198.8, 140.2, 136.7, 133.2, 131.2, 130.2,
128.6, 128.0, 119.9, 40.0, 29.4.
1-phenyl-3-(4-(trifluoromethyl)phenyl)propan-1-one (4aj).28 White solid; 83% yield (231
mg); mp 47-48 oC; 1H NMR (500 MHz, CDCl3) δ 7.96-7.94 (m, 2H), 7.58-7.54 (m, 3H), 7.46 (t,
J = 7.7 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 3.32 (t, J = 7.5 Hz, 2H), 3.13 (t, J = 7.5 Hz, 2H);
13C{1H} NMR (125 MHz, CDCl3) δ 198.5, 145.5, 136.7, 133.2, 128.8, 128.7, 128.2 (q, JC-F
=31.6 Hz), 128.0, 125.4 (q, JC-F =2.7 Hz), 123.2 (q, JC-F = 270.9 Hz), 39.8, 29.8.
1-phenyl-3-(4-(trifluoromethoxy)phenyl)propan-1-one (4ak).31 Pale-yellow oil; 80% yield
(234 mg); 1H NMR (500 MHz, CDCl3) δ 7.96-7.94 (m, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.45 (t, J =
7.8 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 3.29 (t, J = 7.5 Hz, 2H), 3.07 (t, J
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= 7.5 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 198.7, 147.6, 140.1, 136.7, 133.2, 130.0,
128.6, 128.0, 121.1, 119.5 (q, JC-F =255.3 Hz ), 40.1, 29.3.
3-(naphthalen-1-yl)-1-phenylpropan-1-one (4al).5e White solid; 84% yield (219 mg); mp
51-52 oC; 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.89
(d, J = 7.7 Hz, 1H), 7.75 (t, J = 4.4 Hz, 1H), 7.57-7.48 (m, 3H), 7.46-7.41 (m, 4H), 3.55 (t, J =
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7.4 Hz, 2H), 3.43 (t, J = 7.4 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 199.3, 137.4, 136.8,
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2-furfuryl alcohol (4am).32 Brown oil; 83% yield (166 mg); H NMR (500 MHz, CDCl3) δ
7.98 (d, J = 7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.31 (s, 1H), 6.28-6.27
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(m, 1H), 6.05-6.04 (m, 1H), 3.33 (t, J = 7.2 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H); C{1H} NMR
(125 MHz, CDCl3) δ 198.6, 154.7, 141.1, 136.7, 133.1, 128.6, 128.0, 110.2, 105.3, 36.9, 22.5.
1-phenyloctan-1-one (4an).33 Pale-yellow oil; 79% yield (162 mg); H NMR (500 MHz,
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CDCl3) δ 7.97 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 2.96 (t, J =
7.4 Hz, 2H), 1.77-1.71 (m, 2H), 1.36-1.25 (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, 24.4, 22.6, 14.0.
1-phenyldecan-1-one (4ao).34 Pale-yellow oil; 85% yield (197 mg); H NMR (500 MHz,
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CDCl3) δ 7.96 (d, J = 7.4 Hz, 2H), 7.55-7.52 (m, 1H), 7.46-7.43 (m, 2H), 2.95 (t, J = 7.4 Hz, 2H),
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1.76-1.70 (m, 2H), 1.36-1.27 (m, 12H), 0.88 (t, J = 6.9 Hz, 3H); C{1H} NMR (125 MHz,
CDCl3) δ 200.5, 137.1, 132.8, 128.5, 128.0; 38.6, 31.9, 29.5, 29.5, 29.4, 29.3, 24.4, 22.7.
4-methyl-1-phenylhexan-1-one (4ap).5e Pale-yellow oil; 83% yield (158 mg); 1H NMR (500
MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.6 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 3.03-
2.98 (m, 2H), 1.84-1.80 (m, 1H), 1.62-1.59 (m, 2H), 1.49-1.43 (m, 2H), 1.29-1.21 (m, 1H), 0.98-
0.93 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 200.8, 137.1, 132.8, 128.5, 128.0, 36.4, 34.2,
31.0, 29.3, 19.0, 11.3.
3-cyclohexyl-1-phenylpropan-1-one (4aq).5e White solid; 86% yield (186 mg); mp 39-40 oC;
1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.6
Hz, 2H), 2.98 (t, J = 7.7 Hz, 2H), 1.78-1.69 (m, 4H), 1.65-1.61 (m, 3H), 1.32-1.27 (m, 1H), 1.25-
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1.14 (m, 3H), 0,98-0.91 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 200.9, 137.1, 132.8, 128.5,
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3-phenyl-1-m-tolylpropan-1-one (4ba).35 Pale-yellow oil; 88% yield (196 mg); H NMR
(500 MHz, CDCl3) δ 7.77-7.74 (m, 2H), 7.36-7.33 (m, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.26-7.24
(m, 2H), 7.20 (t, J = 7.1 Hz, 1H), 3.28 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.39 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 199.4, 141.3, 138.4, 136.9, 133.8, 128.6, 128.5, 128.4,
128.4, 126.1, 125.2, 40.5, 30.2, 21.3.
3-phenyl-1-p-tolylpropan-1-one (4ca).35 White solid; 82% yield (184 mg); mp 68-69 oC; H
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NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.26-7.24 (m, 4H),
7.20 (t, J = 7.1 Hz, 1H), 3.28 (t, J = 7.8 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H), 2.40 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 198.9, 143.8, 141.4, 134.4, 129.3, 128.5, 128.4, 128.1, 126.1, 40.3,
30.2, 21.6.
1-(4-ethylphenyl)-3-phenylpropan-1-one (4da).31 White solid; 87% yield (208 mg); mp 64-
65 oC; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H), 7.32-7.25 (m, 6H), 7.21 (t, J = 7.1
Hz, 1H), 3.28 (t, J = 7.7 Hz, 2H), 3.06 (t, J = 7.7 Hz, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.25 (t, J =
7.6 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 198.9, 150.0, 141.4, 134.6, 128.5, 128.4, 128.2,
128.1, 126.1, 40.3, 30.2, 28.9, 15.2.
1-(4-methoxyphenyl)-3-phenylpropan-1-one (4ea).36 White solid; 88% yield (212 mg); mp
95-96 oC; 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 8.9 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.26
(d, J = 6.8 Hz, 2H), 7.21 (t, J = 7.1 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 3.25 (t, J =
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7.8 Hz, 2H), 3.06 (t, J = 7.8 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 197.8, 163.4, 141.4,
130.2, 129.9, 128.5, 128.4, 126.1, 113.7, 55.4, 40.1, 30.3.
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1-(3-fluorophenyl)-3-phenylpropan-1-one (4fa).37 Pale-yellow oil; 79% yield (179 mg); H
NMR (500 MHz, CDCl3) δ 7.73 (d, J = 7.8 Hz, 1H), 7.64-7.61 (m, 1H), 7.43-7.39 (m, 1H), 7.31
(t, J = 7.5 Hz, 2H), 7.26-7.19 (m, 4H), 3.28 (t, J = 7.6 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 197.9 (d, JC-F = 1.6 Hz), 163.8 (d, JC-F = 246.6 Hz), 141.0, 139.0 (d,
JC-F = 5.9 Hz), 130.0 (d, JC-F = 6.9 Hz), 128.6, 128.4, 126.2, 123.8 (d, JC-F = 2.0 Hz), 120.1(d, JC-
F = 21.1 Hz), 114.8 (d, JC-F = 21.8 Hz), 40.6, 30.0.
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1-(3-chlorophenyl)-3-phenylpropan-1-one (4ga).38 Pale-yellow oil; 83% yield (203 mg); 1H
NMR (500 MHz, CDCl3) δ 7.91-7.90 (m, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.51-7.49 (m, 1H), 7.37
(t, J = 7.9 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H), 7.24-7.19 (m, 3H), 3.26 (t, J = 7.7 Hz, 2H), 3.05 (t, J
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= 7.7 Hz, 2H); C{1H} NMR (125 MHz, CDCl3) δ 197.8, 141.0, 138.4, 134.9, 133.0, 129.9,
128.6, 128.4, 128.2, 126.2, 126.1, 40.5, 29.9.
1-(4-chlorophenyl)-3-phenylpropan-1-one (4ha).29 White solid; 82% yield (201 mg); mp 73-
74 oC; 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.30 (t, J
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= 7.4 Hz, 2H), 7.26 -7.20 (m, 3H), 3.27 (t, J = 7.7 Hz, 2H), 3.06 (t, J = 7.7 Hz, 2H); C{1H}
NMR (125 MHz, CDCl3) δ 197.9, 141.0, 139.5, 135.1, 129.4, 128.9, 128.5, 128.4, 126.2, 40.4,
30.0.
1-(4-bromophenyl)-3-phenylpropan-1-one (4ia).39 White solid; 89% yield (257 mg); mp 98-
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99 C; H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.31-
7.19 (m, 5H), 3.26 (t, J = 7.7 Hz, 2H), 3.06 (t, J = 7.7 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3)
δ 192.8, 141.0, 135.6, 131.9, 129.6, 128.6, 128.4, 128.2, 126.2, 40.4, 30.0.
3-phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-one (4ja).37 White solid; 81% yield (226
mg); mp 46 oC; 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H),
7.31 (t, J = 7.4 Hz, 2H), 7.24 (m, 3H), 3.33 (t, J = 7.6 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H);13C{1H}
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NMR (125 MHz, CDCl3) δ 198.2, 140.8, 139.5, 134.7 (q, JC-F = 32.5 Hz), 128.6, 128.4, 128.3,
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126.3, 125.7, 125.6, 40.7, 29.9.
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1-(naphthalen-2-yl)-3-phenylpropan-1-one (4ka).40 White solid; 84% yield (219 mg); mp
93-94 oC; 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 8.05 (dd, J = 8.6 and 1.7 Hz, 1H), 7.94 (d,
J = 8.1 Hz, 1H), 7.88 (t, J = 8.9 Hz, 2H), 7.60 (t, J = 6.8 Hz, 1H), 7.55 (t, J = 6.9 Hz, 1H), 7.34-
7.29 (m, 4H), 7.22 (t, J = 5.8 Hz, 1H), 3.45 (t, J = 7.8 Hz, 2H), 3.13 (t, J = 7.8 Hz, 2H); 13C{1H}
NMR (125 MHz, CDCl3) δ 199.1, 141.4, 135.6, 134.2, 132.5, 129.7, 129.5, 128.6, 128.5, 127.8,
126.8, 126.2, 123.8, 40.6, 30.3.
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2-methyl-1,3-diphenylpropan-1-one (4la).41 Pale-yellow oil; 80% yield (179 mg); H NMR
(500 MHz, CDCl3) δ 7.91 (d, J = 7.3 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H),
7.25 (t, J = 7.5 Hz, 2H), 7.20-7.15 (m, 3H), 3.75 (sextet, J = 7.0 Hz, 1H), 3.17 (dd, J = 13.7 and
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6.3 Hz, 1H), 2.69 (dd, J = 13.7 and 7.9 Hz, 1H), 1.2 (d, J = 7.0 Hz, 3H). C{1H} NMR (125
MHz, CDCl3) δ 203.7, 140.0, 136.5, 132.9, 129.1, 128.6, 128.4, 128.3, 126.2, 42.8, 39.4, 17.4.
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2-benzyl-2,3-dihydroinden-1-one (4ma).42 Yellow oil; 82% yield (183 mg); H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 6.1 Hz, 1H), 7.36
(d, J = 7.4 Hz, 1H), 7.29 (t, J = 7.4 Hz, 2H), 7.24-7.19 (m, 3H), 3.40 (dd, J = 14.0 Hz and 4.3 Hz,
1H), 3.16 (dd, J = 17.2 Hz and 7.8 Hz, 1H), 3.01-2.97 (m, 1H), 2.86 (dd, J = 17.2 Hz and 4.0 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,
126.6, 126.3, 124.0, 48.9, 37.0, 32.2.
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2-benzyl-3,4-dihydronaphthalen-1-one (4na).43 Pale-yellow oil; 80% yield (189 mg); H
NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 1H), 7.48-7.45 (m, 1H), 7.33-7.29 (m, 3H), 7.24-
7.21 (m, 4H), 3.50 (dd, J = 4.0 and 4.0 Hz, 1H), 2.95-2.91 (m, 2H), 2.77-2.72 (m, 1H), 2.67-2.62
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(m, 1H), 2.13-2.09 (m, 1H), 1.83-1.76 (m, 1H); C{1H} NMR (125 MHz, CDCl3) δ 199.4,
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144.0, 140.0, 133.2, 132.5, 129.2, 128.7, 128.4, 127.5, 126.6, 126.1, 49.4, 35.6, 28.6, 27.6.
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1-cyclopropyl-3-phenylpropan-1-one (4oa).44 Pale-yellow oil; 84% yield (147 mg); 1H NMR
(500 MHz, CDCl3) δ 7.29-7.24 (m, 2H), 7.20-7.17 (m, 3H), 2.92-2.87 (m, 4H), 1.91-1.88 (m,
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1H), 1.02-1.00 (m, 2H), 0.86-0.83 (m, 2H); C{1H} NMR (125 MHz, CDCl3) δ 209.9, 141.2,
128.4, 128.3, 126.0, 44.9, 29.9, 20.5, 10.7.
4-methyl-1-phenylpentan-3-one (4pa).34 Pale-yellow oil; 82% yield (145 mg); 1H NMR (500
MHz, CDCl3) δ 7.29-7.25 (m, 2H), 7.19-7.17 (m, 3H), 2.89 (t, J = 7.6 Hz, 2H), 2.76 (t, J = 7.6
Hz, 2H), 2.57-2.55 (m, 1H), 1.07 (d, J = 7.0 Hz, 6H); 13C{1H} NMR (125 MHz, CDCl3) δ 213.7,
141.3, 128.4, 128.3, 126.0, 41.9, 41.0, 29.8, 18.1.
The procedure for the direct coupling of a secondary alcohol with a primary alcohol
catalyzed by [Cp*Ir(2,2’-bpyO)(H2O)] (Scheme 5). In a round-bottomed flask with a
condenser tube, 1a (1 mmol), 2a (1.1 mmol, 1.1 equiv), Cat. 4 (5.3 mg, 0.01 mmol, 1 mol %),
Cs2CO3 (33 mg, 0.1 mmol, 0.1 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 and was then
cooled to ambient temperature. Yields of 4aa and 5aa were determined by 1H NMR spectrum of
the crude reaction mixture.
1,3-diphenylpropan-1-ol (5aa).13b Pale-yellow oil; H NMR (500 MHz, CDCl3) δ 7.34-7.33
1
(d, J = 4.1 Hz, 4H), 7.28-7.25 (m, 3H), 7.19-7.16 (m, 3H), 4.67-4.65 (m, 1H), 2.75-2.62 (m, 2H),
2.14-1.98 (m, 2H), 1.96 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 144.6, 141.8, 128.5, 128.5,
128.4, 127.6, 125.9, 125.9, 73.9, 40.5, 32.1.
Notes
The authors declare no competing financial interest.
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Acknowledgments
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The financial support of the National Natural Science Foundation of China (21272115) and State
Key Laboratory of Fine Chemicals (KF1401) is greatly appreciated.
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Supporting Information.
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1H NMR and C NMR spectra of the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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