Iridium-Catalyzed Alkylation of Secondary Alcohols with Primary Alcohols: A Route to Access Branched Ketones and Alcohols

Article abstract of DOI:10.1021/acs.joc.0c01099

Under borrowing hydrogen conditions, NHC-iridium(I) catalyzed the direct or one-pot sequential synthesis of α,α-disubstituted ketones via the alkylation of secondary alcohols with primary alcohols is reported. Notably, the present approach provides a new method for the facile synthesis of α,α-disubstituted ketones and featured with several characteristics, including a broad substrate scope, using easy-to-handle alcohols as starting materials, and performing the reactions under aerobic conditions. Moreover, the selective one-pot formation of β,β-disubstituted alcohols was achieved by the addition of an external hydrogen source to the reaction mixture.

Full text of DOI:10.1021/acs.joc.0c01099

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Article
Iridium-Catalyzed Alkylation of Secondary Alcohols with Primary
Alcohols: A Route to Access Branched Ketones and Alcohols
Sertaç Genç, Süleyman Gülcemal, Salih Günnaz, Bekir Cetinkaya, and Derya Gülcemal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01099 • Publication Date (Web): 25 Jun 2020
Downloaded from pubs.acs.org on June 25, 2020
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Iridium-Catalyzed Alkylation of Secondary Alcohols
with Primary Alcohols: A Route to Access Branched
Ketones and Alcohols
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Sertaç Genç, Süleyman Gülcemal*, Salih Günnaz, Bekir Çetinkaya, Derya Gülcemal*
Ege University, Chemistry Department, 35100 Bornova, Izmir,
KEYWORDS: N-heterocyclic carbene, iridium, borrowing hydrogen, alkylation, branched
ketones and alcohols.
O
OH
Ir(I) cat. (0.2 mol%)
2
R2
OH
+
F3C
R1
R2
R1
50 mol% KOH
PhMe, 140°C, 20 h
Cl
Cl
R2
branched ketones
N
N
Hydrogen
source
Ir
new method to branched products
low cost of alcohols as starting materials
low catalyst loading
Cl
OH
no stoichiometric base
air atmosphere
R1
R2
F3C
Ir(I) cat.
H2 and H2O are the only by-products
broad scope
R2
branched alcohols
ABSTRACT
Under borrowing hydrogen conditions, NHC‒iridium(I) catalyzed the direct or one-pot
sequential synthesis of α,α-disubstituted ketones via the alkylation of secondary alcohols with
primary alcohols is reported. Notably, the present approach provides a new method for the facile
synthesis of α,α-disubstituted ketones, and featured with several characteristics, including a
broad substrate scope, using easy-to-handle alcohols as starting materials and performing the
reactions under aerobic conditions. Moreover, the selective one-pot formation of β,β-
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disubstituted alcohols was achieved by the addition of an external hydrogen source to the
reaction mixture.
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INTRODUCTION
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The transition-metal (TM) catalyzed borrowing hydrogen (BH) strategy has become a
valuable alternative for the construction of C‒C bonds in organic chemistry to synthesize
functionalized complex molecules.1 The main advantage of this methodology is the utilization of
readily available and easy-to-handle alcohols as greener alkylating agents over mutagenic alkyl
halides.1 α,α-Di-substituted ketones are important intermediates that have been widely used in
organic synthesis and the pharmaceutical industry.2 Therefore, the development of green and
efficient catalytic systems for the synthesis of these products would be highly desirable. Over the
past five years, application of Ru,3 Rh,4 Ir,5 Pd,6 Mn,7 Fe8 and Ni9 catalysts for the
monoalkylation of linear methylene ketones with primary alcohols providing α,α-di-substituted
ketones is well established (Scheme 1a). There are also two reports on monoalkylation of
secondary alcohols providing α,α-disubstituted ketones.7d,8b The main disadvantage of this
monoalkylation approach is the preparation of linear methylene ketones or secondary alcohols as
starting materials in advance. Direct access to α,α-disubstituted ketones via the alkylation of
methyl ketones or secondary alcohols is also known but almost exclusively relies on the use of
methanol as the alkylating agent (Scheme 1b).3b,4,5a,7b,c,8a,9b,10
A three-component direct or one-pot sequential double alkylation of methyl ketones with
benzyl alcohol and methanol was also described by employing Ru,3b Rh,4 Ir,5a,b Pd,11 and Fe12
catalysts for the formation of α,α-disubstituted ketones (Scheme 1c). After the early reports by
the Donohoe and co-workers, a few groups extended this strategy by the sequential addition of
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two different primary alcohols other than methanol (Scheme 1c).3a,c,7a,8b,9a The main
disadvantages of these systems are the requirement of additional catalyst in the second step or
their limited substrate scopes (2-8 examples). Very recently, Leitner,13a Maji,13b and co-workers
have described the synthesis of α,α-disubstituted ketones from methyl ketones and diols by using
manganese-based catalysts. Although considerable progress has been achieved in α-alkylation of
carbonyl compounds to give α,α-disubstituted ketones, catalytic cross-coupling of secondary
alcohols with primary alcohols remain unexplored. Thus, it is desirable to develop a new strategy
for the synthesis of α,α-disubstituted ketones directly from secondary alcohols and primary
alcohols.
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Recently, we established a highly active catalytic system for the alkylation of secondary
alcohols with primary alcohols to give α-alkylated ketones14a and β-alkylated alcohols14b using
an iridium(I)‒N-heterocyclic carbene (NHC) catalyst (1a) (Scheme 1d). On the bases of these
reports, we further envisaged the cross-coupling of secondary alcohols with primary alcohols for
the synthesis of α,α-disubstituted ketones. Herein, we describe the synthesis of three new
NHC‒IrI complexes (1b-d) (Scheme 2) with different backbones on the 4,5-position of
imidazole. We then investigated the catalytic activities of NHC‒IrI complexes (1a-d) in the
direct double alkylation and one-pot sequential alkylation of secondary alcohols with primary
alcohols to obtain a variety of α,α-di-substituted ketones under aerobic conditions (Scheme 1e).
To the best of our knowledge, this study represents the first example of TM-catalyzed double
alkylation of secondary alcohols with primary alcohols in the selective synthesis of α,α-di-
substituted branched ketones. In addition, this catalytic system has also allowed the one-pot
selective formation of β,β-disubstituted alcohols by the subsequent addition of an external
hydrogen source to the reaction mixture.
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Scheme 1. Strategies for the TM-Catalyzed Formation of Branched Products
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Previous work
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a) Monoalkylation of methylene ketones with alcohols to give branched ketones
O
O
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[Ru, Rh, Ir, Pd, Mn, Ni, Fe]
R2
OH
+
R
R1
R
R1
R2
b) Double methylation of ketones or secondary alcohols with methanol to give branched products
O
OH
O
[Ru, Rh, Ir, Pd, Pt, Mn, Ni, Fe]
or
+
MeOH
R
R
R
c) Direct or one-pot sequential alkylation of ketones with alcohols to give branched ketones
O
O
O
[Ru, Ir, Fe, Pd]
R1 OH
[Ru, Rh, Ir, Mn, Ni, Fe]
R1
OH
......
R
R1
R
R
R1
R2
OH
+
R2
MeOH
Our previous work
d) Alkylation of secondary alcohols with primary alcohols to give linear ketones or alcohols
OH
OH
O
1a
1a
(0.0001 mol%)
NaOH (20 mol%)
(0.5 mol%)
KOH (10 mol%)
R
+
R
R1
R
R1
R1
OH
This work
e) Direct or sequential alkylation of secondary alcohols with primary alcohols to give branched products
[NHC-Ir] (0.2 mol%)
KOH (50 mol%)
O
OH
OH
H-source
R
R1
R
R1
+
R1
OH
R
PhMe
140°C, 20 h
(1 equiv.)
(2.2 equiv.)
R1
(19 examples)
R1
(10 examples)
R2
OH
[NHC-Ir] (0.2 mol%)
KOH (10 mol%)
(1.1 equiv.)
KOH (40 mol%)
O
OH
......
+
R1
OH
R
R1
(7 examples)
R
PhMe
140°C, 4 h
140°C, 16 h
(1 equiv.)
(1 equiv.)
R2
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RESULTS and DISCUSSION
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The electronic nature of the NHC ligand plays an important role for the catalytic activity
of the related complexes.15 For the classical NHCs, backbone modifications primarily change the
electronic properties.15a Based on our experience on NHC‒IrI catalyzed BH reactions,14 we
commenced to prepare a set of [IrCl(COD)(NHC)] complexes (1a-d) with potentially electron-
withdrawing backbones on the 4,5-position of imidazole and 4-trifluorobenzyl substituents as the
wingtip on the nitrogen atom of imidazole (Scheme 2). The synthesis of the ligand precursors
and NHC‒IrI complexes (1a-d) are summarized in Supporting Information (Scheme S1, S2). All
the new ligands and complexes were prepared in high yields as air- and moisture-stable solids
and were characterized by NMR spectroscopy and HRMS analysis.
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Scheme 2. NHC–IrI Complexes (1a-d) Used in This Study
Cl
Ar
Ar
Ar
Ar
Ar
Cl
Cl
Cl
Cl
N
N
N
N
N
N
N
N
Ir
Ir
Ir
Ir
Cl
Cl
Cl
Cl
Ar
Ar
Ar
Cl
1aref. 13a
1b
1c
1d
Ar = 4-CF3-C6H4
Reaction of 1-phenylethanol (2a) (0.5 mmol) with 2.0 equiv. benzyl alcohol (3a) (1.0
mmol), catalyst 1a-d (0.5 mol%), and KOH (50 mol%) in toluene solution was heated to 140 °C
(oil bath temperature) under air for an initial investigation (Table 1). Then, the reaction mixture
1
was analyzed by gas chromatography (GC) and H NMR spectroscopy. Conversions are based
on 1H NMR analysis of reaction mixtures by using 1,3,5-trimethoxybenzene as internal standard
(Table 1). The GC analysis of reaction mixtures confirmed that conversion of 1-phenylethanol
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(2a) in the presence of NHC‒IrI catalysts (1) was complete. However, the product distribution
showed that, along with the desired product 4a, the double alkylation process was interrupted
and unreacted monoalkylation intermediate 4a' left over in appreciable amounts within 16 h
(entries 1-4). Among all catalysts tested, the highest selectivity to 4a was obtained with
backbone substituted NHC‒IrI complex 1d (entry 4). Clearly, the electronic character of the
NHC ligand is important for the reactivity14 and it was observed that the catalytic activity of
iridium complexes was enhanced by introducing electron-withdrawing 4-chlorophenyl group on
the 4,5-position of imidazole. Increasing the reaction time to 20 h did not increase the formation
of 4a and similar product distribution was observed (entry 5). This is due to the formation of the
side product potassium benzoate via dehydrogenation of benzyl alcohol under these conditions.16
As a result, there was no benzyl alcohol left to react with 4a' to form the final product 4a. In
order to suppress this side reaction, we first decreased the amount of catalyst to 0.2 mol%: here,
amount of unreacted 4a' decreased to 12% and along with desired product 4a (72%) and reduced
double alkylated byproduct 5a (13%) (entry 6). Increasing the amount of benzyl alcohol to 2.2
equivalents resulted in a better outcome and formed the desired product 4a in 81% along with the
double alkylated alcohol 5a in 18% conversion (entry 7). Here, double alkylated products 4a and
5a were isolated in 78 and 13% yields, respectively. Notably, unreacted intermediate 4a' was not
observed. Further increasing the amount of benzyl alcohol to 3.0 equivalents, led to lower
selectivity to 4a (entry 8). Replacing KOH with NaOH, KOtBu or NaOtBu did not improve the
conversions (entries 9-11) where K-containing bases were found to be much more selective to
double alkylated ketone product (4a) than their Na counterparts. It is worth noting that, an inert
atmosphere seemed unnecessary (entry 12). When the reaction was carried out in a closed system
74% conversion of 4a was achieved (entry 13) and the evolution of H2 gas during the reaction
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was detected by GC analysis (Figure S1). In the control experiments performed without catalyst
or base, no double alkylated product was observed, indicating that catalyst and base are essential
for the occurrence of the reaction (entries 14 and 15).
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Table 1. Optimization of Reaction Conditionsa
O
OH
+
+
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a-d
Base (50 mol%)
OH
Ph
Ph
4a
5a
+
Ph
OH
Ph
PhMe (1 mL)
140°C
O
OH
2a
3a
4a'
5a'
Conversion (%) b
Cat.
(mol%)
Base
(mol%)
Entry
Time (h)
4a
4a'
21
22
31
27
26
12
-
5a
13
21
-
5a'
5
4
-
1
2
1a (0.5)
1b (0.5)
1c (0.5)
1d (0.5)
1d (0.5)
1d (0.2)
1d (0.2)
1d (0.2)
1d (0.2)
1d (0.2)
1d (0.2)
1d (0.2)
1d (0.2)
-
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
NaOH
KOtBu
16
16
16
16
20
20
20
20
20
20
61
53
67
71
73
72
81
45
48
76
31
79
74
-
3
4
-
-
5
-
-
6
13
18
30
43
15
36
17
18
-
-
7 c
8 d
9 c
-
10
7
8
-
10 c
11 c
12 c,e
13 c,f
14 c
15 c
5
-
NaOtBu
KOH
KOH
KOH
-
20
20
20
20
20
14
3
17
-
8
-
-
19
-
1d (0.2)
-
-
-
aReaction Conditions: 2a (0.5 mmol), 3a (1.0 mmol), 1a-d (0.2-0.5 mol%), base (0.25 mmol;
50 mol%), toluene (1 mL), 140 ºC, 16-20 h, under air. Conversions were determined by H
b
1
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NMR analyses using 1,3,5-trimethoxybenzene as an internal standard. c3a (1.1 mmol). d3a (1.5
mmol). Reaction was performed under an argon atmosphere. Reaction was performed in a
closed tube.
e
f
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To examine the scope of the reaction, various secondary alcohols (2) were reacted with
primary alcohols (3) under the optimized conditions (Table 1, entry 7) and the results are
summarized in Scheme 3. Primarily, a range of para-substituted 1-phenylethanols decorated with
‒OMe, ‒Me, ‒Cl, or ‒Br substituents were benzylated to give α,α-disubstituted ketones (4b-e) in
good yields (65-90%). When 1-phenylethanol (2a) was reacted with benzyl alcohol on 5.0 mmol
scale, the corresponding product 4a was isolated in 74% yield (1.10 g), highlighting the
practicability of this reaction. Furthermore, 1-(2-naphthyl)ethanol (2f) and 1-(ferrocenyl)ethanol
(2g) gave the corresponding products 4f and 4g in 73 and 61% yields, respectively. Nevertheless,
application of electron deficient 1-(4-(trifluoromethyl)phenyl)ethanol did not result any desired
product under standard catalytic conditions. Again, aliphatic secondary alcohol (2-heptanol)
failed to give the desired product, and the number of undesired side products was observed,
probably due to more than one reactive α-carbon exist in the molecule.
Next, we examined the scope of double alkylation reaction with respect to primary
alcohols (3) (Scheme 3). The reaction of 1-phenylethanol (2a) with benzyl alcohols bearing
4‒OMe, 4‒Me, 4‒i-Pr, 4‒Cl, 4‒Br, 4‒NMe2, 2‒OMe, or 2‒Cl substitution on the aryl ring and
2-naphthalenemethanol all resulted with high yields (75-96%) to give a series of disubstituted
ketones (4h-p). In the case of 1-octanol as a primary alcohol, the corresponding ketone (4q) was
isolated in 34% yield. This is due to conversion of 1-octanol to the Guerbet self-condensation
product 2-octyl-1-octanol (observed by the NMR analysis of the crude reaction mixture) under
the basic reaction conditions.16b,17 Finally, the reaction of 2a with ferrocenemethanol and 2-
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furanmethanol afforded the desired products 4r and 4s in 93 and 51% isolated yields. However,
applications of primary alcohols such as 4-(trifluoromethyl)benzyl alcohol, 2,4,6-trimethylbenzyl
alcohol, 4-pyridinemethanol, 2-thiophenemethanol, 2-methoxyethanol, 2-phenoxyethanol, and
cinnamyl alcohol were not successful and we observed only trace or no product conversion to the
desired α,α-disubstituted ketones.
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Scheme 3. Scope of Direct Synthesis of α,α-Disubstituted Ketonesa
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9
1d
(0.2 mol%)
O
OH
KOH (50 mol%)
+
R2
OH
R1
R2
R1
PhMe (1 mL)
140°C, 20 h
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R2
2
3
4
O
O
O
Ph
Ph
Ph
Fe
R
Ph
: R = H, 78% (74%)
: R = OMe, 90%
: R = Me, 85%
: R = Cl, 71%
: R = Br, 65%
Ph
Ph
[b]
4a
4b
4c
4d
4f
4g
: 61%
: 73%
4e
R
O
R
O
O
Ph
Ph
Ph
R
R
4h
4i
4j
4k
4l
: R = OMe, 77%
: R = Me, 79%
: R = i-Pr, 88%
: R = Cl, 75%
: R = Br, 80%
4n
4o
: R = OMe, 96%
: R = Cl, 85%
4p
: 91%
4m
: R = NMe2, 96%
Fe
O
O
O
O
Ph
Ph
Ph
O
Fe
: 93%
4q
: 34%
4r
4s
: 51%
aReaction Conditions: 2 (0.5 mmol), 3 (1.1 mmol), 1d (0.2 mol%), KOH (0.25 mmol; 50
mol%), toluene (1 mL), 140 ºC, 20 h, under air. Reported yields correspond to isolated pure
compounds. b2a (5 mmol), 3a (11 mmol), 1d (0.2 mol%), KOH (1.25 mmol; 50 mol%), toluene
(5 mL), 140 ºC, 20 h, under air.
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Thereafter, we focused our studies on the one-pot sequential double alkylation of 1-
phenylethanol using two different primary alcohols to obtain unsymmetrical dialkylated ketones
(Scheme S3). When benzyl alcohol (1.0 equiv.) and 4-methoxybenzyl alcohol (3b) (1.1 equiv.)
were introduced to 1-phenylethanol in sequence, unsymmetrical dialkylated product 4t was
obtained in 56% yield. Crucial to the success of this reaction is the selective monoalkylation in
the first step and avoid the formation of dibenzylated ketone 4a. In order to suppress this side
reaction, we decreased the amount of KOH to 10 mol% in the first step and here, we were
pleased to detect only the monoalkylated product 4a' by means of NMR analysis after 4 h. A
second addition of KOH (40 mol%), together with 4-methoxybenzyl alcohol, resulted with the
formation 4t in 56% isolated yield. Interestingly, when the other fractions of the column
chromatography were analyzed by NMR, we also observed the formation of monoalkylated 3-(4-
methoxyphenyl)-1-phenylpropan-1-one (4b') (11%), symmetrical dialkylated 4a (9%) and 4b
(6%) accompanied by 4a' retrieved in 12% yield (Scheme S3). Similar product distributions
were also observed when dihydrochalcone 4a' (0.5 mmol) was reacted with 4-methoxybenzyl
alcohol (3b, 0.55 mmol) in the presence of 0.2 mol% 1d and 50 mol% KOH at 140 °C for 16 h
(Scheme 4a). These interesting results can be explained by reversibility of the second aldol
condensation of dihydrochalcone and 4-methoxybenzaldehyde in the presence of water generated
in the reaction (Scheme 4a). Similar reversibility of the second aldol condensation product in the
presence of water was previously reported by Renaud and co-workers in the case of benzyledene
adduct.12 To prove this observation, 1,2-diphenylethanone (6') was reacted with 3b under the
same reaction conditions and the desired product 3-(4-methoxyphenyl)-1,2-diphenylpropan-1-
one (6) was obtained in 98% yield as the sole product (Scheme 4b) where the isomerization of
the aldol adduct is not possible.
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Scheme 4. Proposed Pathway for the Reversibility of the Second Aldol Condensation Step.
5
6
7
8
9
a )
1d
(0.2 mol%)
O
KOH (50 mol%)
OH
+
Products
Ph
Ph
: 0.5 mmol
PhMe (1 mL)
140°C, 16 h
MeO
3b
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4a'
: 0.55 mmol
Ar
OH
- H2
O
O
O
O
+ H2
+
Ar
Ph
Ph
O
Ph
Ph
Ph
Ph
Ph
Ph
- H2O
Ar
Ar
Ar
: 59%
4t
( Not detected)
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ar
Ph
Ar
4a'
4b'
: 8%
:10%
Ph
Ar
+
+
( Not detected)
( Not detected)
Ar
Ph
O
O
+ H2
+ H2
O
O
Ph
Ph
Ph
Ar
Ar = 4-Methoxyphenyl
Ph
:9%
Ar
:7%
4a
4b
b )
1d
(0.2 mol%)
KOH (50 mol%)
O
O
OH
Ph
Ph
+
Ph
Ph
PhMe (1 mL)
140°C, 16 h
MeO
6'
: 0.5 mmol
3b
: 0.55 mmol
6
: 98%
OMe
aReaction Conditions: a) 4a' (0.5 mmol), 3b (0.55 mmol), 1d (0.2 mol%), KOH (0.25 mmol;
50 mol%), toluene (1 mL), 140 ºC, 16 h, under air. b) 6' (0.5 mmol), 3b (0.55 mmol), 1d (0.2
mol%), KOH (0.25 mmol; 50 mol%), toluene (1 mL), 140 ºC, 16 h, under air. Reported yields
correspond to isolated pure compounds.
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Other benzyl alcohols decorated with 4‒Me, 4‒i-Pr, 4‒Cl, or 4‒Br substitution on the aryl
ring resulted in 58-72% yield to give corresponding unsymmetrical disubstituted ketones 4u-x
(Scheme 5). In the case of aliphatic alcohols, 1-octanol was subjected in the first step of the
reaction, and then a sequential addition of benzyl alcohol resulted in the formation of 4y in 68%
isolated yield.18 Finally, one-pot sequential addition of benzyl alcohol and 2-aminobenzyl
alcohol to 1-phenylethanol afforded the quinoline derivative 4z in 66% yield (Scheme 5).
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Scheme 5. Scope of One-Pot Sequential Synthesis of α,α-Disubstituted Ketonesa
OH
R2
OH
1d
(0.2 mol%)
Ph
R1
O
O
2a
+
KOH (40 mol%)
KOH (10 mol%)
Ph
R1
Ph
R1
PhMe (1 mL)
140°C, 4 h
140°C, 16 h
OH
Ph
R2
4'
4
3
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
OMe
Cl
4t
: 56%
4u
: 58%
4v
4w
: 63%
: 61%
O
O
Ph
Ph
Ph
Ph
N
Ph
Ph
Br
4y
4z
: 66%
: 68%
4x
: 72%
aReaction Conditions: 2a (0.5 mmol), 3 (0.5 mmol), 1d (0.2 mol%), KOH (0.05 mmol; 10
mol%), toluene (1 mL), 140 ºC, 4 h, under air, then 3 (0.55 mmol), KOH (0.2 mmol; 40 mol%),
140 ºC, 16 h, under air. Reported yields correspond to isolated pure compounds.
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Encouraged by our results, we envisioned that we could also improve the selectivity of
the double alkylation reaction to the β,β-disubstituted alcohols (5) by adding an external
hydrogen source at some point of the reaction. As an initial test reaction, 1-phenylethanol was
reacted with benzyl alcohol under the optimized conditions (Table 1, entry 7) for 16 h and
resulted with the formation of 4a and 5a with a ratio of 78:22. After addition of 2-propanol (6.0
equiv) into the reaction mixture, reduction of the keto group occurred due to hydrogen transfer
from 2-propanol and the reaction resulted in the selective formation of 5a19 and the desired
alcohol product could be isolated in 92% yield (Scheme 6). Ethanol and n-propanol as an
external hydrogen sources led to lover selectivity to 5a (ratio of 4a:5a, ethanol, 60:40; n-
propanol, 58:42).
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Scheme 6. Synthesis of β,β-Disubstituted Alcohols (1H NMR conversions)
OH
Ph
0.5 mmol
1d
(0.2 mol%)
2-propanol
(6.0 equiv.)
KOH (50 mol%)
4a
5a
4a
5a
+
+
+
PhMe (1 mL)
OH
140°C, 16 h
140°C
Ph
80% 20%
1 h: 53% 47%
2 h: 22% 78%
1.1 mmol
4 h: 5%
95%
The one pot alkylation for the synthesis of β,β-disubstituted alcohols worked well when
electronically different secondary alcohols (2) were employed with benzyl alcohol and resulted
in 5a-e in 55-92% isolated yields (Scheme 7). Next, applications of different benzyl alcohols (3)
with 1-phenylethanol (2a) proceeded equally well, giving 5f-j in 56-87% yields. Nevertheless,
the addition of 2-propanol to the reaction mixture shown in Scheme S3, to obtain non-
symmetrical β,β-disubstituted alcohol, resulted in an inseparable complex mixture where 14%
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conversion to the desired product 2-benzyl-3-(4-methoxyphenyl)-1-phenylpropan-1-ol was
detected via 1H-NMR.
7
8
9
Scheme 7. Scope of β,β-Disubstituted Alcoholsa
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OH
1d
(0.2 mol%)
2-propanol
(6.0 equiv.)
R1
R2
OH
2
+
KOH (50 mol%)
4
5
]
[
+
R1
R2
PhMe (1 mL)
140°C, 16 h
140°C, 4 h
OH
R2
5
3
OH
OH
5a
: R = H, 92%
5b
: R = OMe, 55%
Ph
Ph
[b]
5c
: R = Me, 89%
R
Ph
Ph
5d
: R = Cl, 78%
[b]
5e
: 94%
R
5f
: R = Me, 84%
OH
OH
5g
5h
5i
: R = i-Pr, 67%
: R = Cl, 87%
: R = Br, 61%
Ph
Ph
R
[b]
5j
: 56%
aReaction Conditions: 2 (0.5 mmol), 3 (0.55 mmol), 1d (0.2 mol%), KOH (0.25 mmol; 50
mol%), toluene (1 mL), 140 ºC, 16 h, under air, then 2-propanol (3.0 mmol, 230 µL), 140 ºC, 4
h, under air. Reported yields correspond to isolated pure compounds b2-propanol was added after
12 h and the reaction was heated for additional 8 h.
Further, to investigate the reaction mechanism, initially we investigated the time profile
of the model reaction between 1-phenyl ethanol (2a) with benzyl alcohol (3a) under the
optimized conditions (Table 1, entry 7) (Figure 1). The results revealed that the reaction is very
fast and resulted with the full consumption of 1-phenylethanol mainly into monoalkylated
intermediates 4a' (34%) and 5a' (51%) along with a small amount of double alkylated 4a (12%)
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and 5a (3%) within 30 min. These monoalkylated intermediates were consumed over time and
led to the production of double alkylated products 4a (68%) and 5a (29%) within 6 h. After 6 h,
the double alkylated alcohol 5a slowly undergoes dehydrogenation to form 4a. This final
dehydrogenation step was also confirmed by independent experiments where the alcohol product
5a gradually dehydrogenated to 4a during the progress of the reaction and 94% conversion to 4a
was achieved within 8 h (Scheme 8). These observations are consistent with previous results.8b,14
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O
OH
+
+
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1d
(0.2 mol%)
OH
KOH (50 mol%)
Ph
Ph
4a
5a
+
Ph
OH
Ph
PhMe (1 mL)
140°C
O
OH
2a
3a
4a'
5a'
4a
4a'
5a
5a'
100
80
60
40
20
0
0
2
4
6
8
10
12
14
16
18
20
Time (h)
Figure 1. Time course of the reaction between 2a and 3a. Reaction Conditions: 2a (0.5 mmol),
3a (0.55 mmol), 1d (0.2 mol%), KOH (0.25 mmol; 50 mol%), toluene (1 mL), 140 ºC, under air.
1
Conversions were determined by H NMR analyses of the independent reaction mixtures using
1,3,5-trimethoxybenzene as internal standard.
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Scheme 8. Catalytic dehydrogenation of 5a to 4a (1H NMR conversions)
7
8
9
1d
(0.2 mol%)
OH
O
1 h: 14%
2 h: 37%
4 h: 64%
8 h: 94%
KOH (50 mol%)
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Ph
Ph
Ph
Ph
+
H2
PhMe (1 mL)
140°C
Ph
Ph
5a
4a
Next, we investigated the reaction of possible intermediates with benzyl alcohol or
benzaldehyde under the optimized reaction conditions for 8 h (Scheme 9). When the chalcone (7)
was reacted with benzyl alcohol, 30% conversion to 4a was achieved (Eq. 1). Here, reduction of
the 7 to 4a' (39%) and 5a' (14%) was also observed by using the hydrogen released from the
dehydrogenation of benzyl alcohol along with the formation of 17% benzyl benzoate as a self-
condensation product (Eq. 1). Reaction of 1,3-diphenylpropan-1-ol (5a') with benzyl alcohol
resulted with 68% 4a, 25% 5a and 11% 4a' (Eq. 2). Similar product distribution was observed
when 1,3-diphenylprop-2-en-1-ol (8) reacted with benzyl alcohol, possibly via the base promoted
isomerization of the allylic alcohol 8 into 4a',20 followed by the second alkylation of this
intermediate in the presence of catalyst 1d (Eq. 3). In addition, no accumulation of the second
aldol condensation product between dihydrochalcone and benzaldehyde was observed where
18% conversion to 4a was achieved and 67% dihydrochalcone was recovered (Eq. 4). Notably,
the reaction of 1,3-diphenylpropan-1-ol with benzaldehyde also resulted in the formation of 4a in
42%, also providing evidence for the participation of secondary alcohol as a hydrogen source
(Eq. 5).
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Scheme 9. Control Experiments
5
6
7
8
9
1d
(0.2 mol%)
O
KOH (50 mol%)
benzyl
benzoate
(Eq. 1)
(Eq. 2)
4a
4a'
5a'
+ +
+
+
Ph
OH
Ph
7
Ph
(0.5 mmol)
PhMe (1 mL)
140°C, 8h
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60
0.55 mmol
30% 39% 14%
17%
1d
(0.2 mol%)
OH
KOH (50 mol%)
4a
5a
4a'
+
+
+
Ph
OH
Ph
Ph
PhMe (1 mL)
140°C, 8h
5a'
(0.5 mmol) 0.55 mmol
68% 25% 7%
1d
(0.2 mol%)
OH
KOH (50 mol%)
4a
5a
4a'
+
+
(Eq. 3)
(Eq. 4)
(Eq. 5)
+
+
Ph
OH
Ph
8
Ph
(0.5 mmol)
PhMe (1 mL)
140°C, 8h
0.55 mmol
69% 20% 11%
1d
(0.2 mol%)
O
KOH (50 mol%)
benzyl
benzoate
4a
4a'
+
+
Ph
O
Ph
4a'
Ph
PhMe (1 mL)
140°C, 8h
(0.5 mmol) 0.55 mmol
18% 67%
15%
1d
(0.2 mol%)
OH
KOH (50 mol%)
4a
5a
4a'
5a'
+
+
+
+
Ph
O
Ph
5a'
Ph
PhMe (1 mL)
140°C, 8h
42% 15% 32% 11%
(0.5 mmol) 0.55 mmol
On the basis of these experimental evidences, a catalytic cycle for double alkylation of
secondary alcohols with primary alcohols catalyzed by 1 is proposed in Scheme 10. The first part
of the mechanism has been outlined in our reports14 which involves the formation of 4' via
acceptorless dehydrogenative cross-coupling of 2 and 3 catalyzed by in situ generated transient
iridium hydride.14a Then, a base mediated second cross-aldol condensation reaction between 4'
and 3' may produces enone-2. No accumulation of this second α,β-unsaturated ketone was
observed during the whole course of the reaction, which suggests that the hydrogenation of this
intermediate to the final products 4 and 5 by iridium hydride was very fast. Finally,
hydrogenation or dehydrogenation between 4 and 5 takes place in the presence of catalyst.
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Scheme 10. Proposed Mechanism for the Ir-Catalyzed Synthesis of Branched Ketones and
5
6
Alcohols
7
8
9
- H2
10
11
12
13
14
15
16
17
18
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60
+ H2
R2
O
base
OH
O
O
OH
R
OH
2
+
+
2
R1
R2
R1
R2
R1
enone-2
R2
R1
- H2O
2
3
5'
4'
R2
[Ir]
[Ir]-H
[Ir]-H
[Ir]
- 3H2
+ 2H2
+ H2
+ 2H2
+ H2
O
O
base
- H2O
R
2
2
+
O
R1
R2
R1
OH
O
+
2'
3'
enone-1
R1
R2
R1
R2
R2
R2
5
4
+ H2
- H2
CONCLUSIONS
In conclusion, we have developed an efficient catalytic cross-coupling of secondary
alcohols and primary alcohols under borrowing hydrogen conditions to give rise to a variety of
branched ketones and alcohols. To the best of our knowledge, the present approach is the first
example for the direct or one-pot sequential double alkylation of secondary alcohols with
primary alcohols. Furthermore, selectivity of the reaction to branched ketones or alcohols can be
controlled by a single catalyst with slightly modified reaction conditions. Use of easy-to-handle
alcohols as starting materials and performing the reactions under aerobic conditions will be
beneficial to broaden the scope of borrowing hydrogen catalysis.
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EXPERIMENTAL SECTION
5
6
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8
9
General Information. Experiments involving air or moisture sensitive reagents were performed
under an atmosphere of dry argon using standard Schlenk techniques. Unless otherwise
specified, all reagents were obtained commercially and used without further purification.
Imidazolium salt La and complexes 1a were synthesized according to published procedure and
the physical properties and spectroscopic data of the obtained compound are in accordance with
previous report.14a NMR spectra were recorded on Varian AS 400 Mercury NMR spectrometer at
25 ºC and reported in units of parts per million (ppm) relative to tetramethyl silane (δ = 0 ppm),
CDCl3 (δ = 7.26 ppm for 1H and δ = 77.0 ppm for 13C NMR) or DMSO-d6 (δ = 2.50 ppm for 1H
and δ = 39.5 ppm for 13C NMR). Melting points measured on Gallenkamp electrothermal
melting point apparatus without correction. HRMS were carried out on Agilent 6530 Accurate-
Mass Q-TOF mass spectrometer at Atatürk University East Anatolia High Technology
Application and Research Center. Gas chromatography (GC) analyses were performed on an
Agilent 6890N GC instrument with a HP-5 Agilent 19091J-413 column. GC analysis for H2
evolution experiment was performed on an Agilent 7890A GC instrument and gas products were
identified according to standard gas mixture (Agilent P/N 5190-0519).
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Synthesis of imiazolium salts Lb. A mixture of 5,6-dichloro-1H-benzimidazole (374 mg, 2
mmol) and K2CO3 (608 mg, 4.4 mmol) was suspended in CH3CN (5 mL) and stirred at ambient
temperature for 1 h. 4-(Trifluoromethyl)benzyl bromide (478 mg, 2 mmol) was then added to the
suspension and the reaction mixture was stirred under reflux conditions for 12 h. The solution
was filtered-off and the solvent was removed under reduced pressure. The resulting crude
product was dissolved in toluene (5 mL), and a second portion of 4-(Trifluoromethyl)benzyl
bromide (478 mg, 2 mmol) was added and stirred at reflux conditions for 12 h. The colorless
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solid that separated out after cooling to room temperature was filtered off and washed with Et2O
5
6
1
(2×10 mL) and dried under reduced pressure (841 mg, 72%). M.p. = 268 ºC. H NMR (400
7
8
9
MHz, DMSO-d6, TMS, 25ºC, ppm): δ = 10.29 (s, 1 H), 8.57 (s, 2 H), 7.78 (s, 8 H), 5.92 (s, 4 H).
13C{1H} NMR (100.6 MHz, DMSO-d6, TMS, 25ºC, ppm): δ = 145.9, 138.6, 131.1, 129.8, 129.6
(q, J(C,F) = 31.4 Hz), 126.2 (q, J(C,F) = 3.8 Hz), 124.4 (q, J(C,F) = 272.4 Hz), 116.3, 50.1. 19F
NMR (376 MHz, DMSO-d6, TMS, 25ºC, ppm): δ = ‒ 61.2. HRMS (APCI) m/z: [M–Br]+ calcd
for C23H15Cl2F6N2 503.0516; found: 503.0523, Δ = + 1.4 ppm.
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Synthesis of imiazolium salt Lc. A mixture of 4,5-diphenyl-1H-imidazole (441 mg, 2 mmol)
and K2CO3 (608 mg, 4.4 mmol) was suspended in CH3CN (5 mL) and stirred at ambient
temperature for 1 h. 4-(Trifluoromethyl)benzyl chloride (389 mg, 2 mmol) was then added to the
suspension and the reaction mixture was stirred under reflux conditions for 12 h. The solution
was filtered-off and the solvent was removed under reduced pressure. The resulting crude
product was dissolved in toluene (5 mL), and a second portion of 4-(Trifluoromethyl)benzyl
chloride (389 mg, 2 mmol) was added and stirred at reflux conditions for 12 h. The colorless
solid that separated out after cooling to room temperature was filtered off and washed with Et2O
(2×10 mL) and dried under reduced pressure (1.07 g, 93%). M.p. = 274 ºC. 1H NMR (400 MHz,
DMSO-d6, TMS, 25ºC, ppm): δ = 9.79 (s, 1 H), 7.67 (d, J = 8.4 Hz, 4 H), 7.41-7.26 (m, 14 H),
5.55 (s, 4 H). 13C{1H} NMR (100.6 MHz, DMSO-d6, TMS, 25ºC, ppm): δ = 139.1, 137.8, 132.2,
131.2, 130.6, 129.2 (q, J(C,F) = 31.8 Hz), 129.2, 129.1, 125.9 (q, J(C,F) = 4.0 Hz), 125.8, 124.4
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(q, J(C,F) = 272.6 Hz), 50.4. F NMR (376 MHz, DMSO-d6, TMS, 25ºC, ppm): δ = ‒ 61.2.
HRMS (APCI) m/z: [M–Cl]+ calcd for C31H23F6N2 537.1765; found: 537.1769, Δ = + 0.7 ppm.
Synthesis of imiazolium salt Ld. A mixture of 4,5-bis(4-chlorophenyl)-1H-imidazole (578 mg,
2 mmol) and K2CO3 (608 mg, 4.4 mmol) was suspended in CH3CN (5 mL) and stirred at
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ambient temperature for 1 h. 4-(Trifluoromethyl)benzyl bromide (478 mg, 2 mmol) was then
added to the suspension and the reaction mixture was stirred under reflux conditions for 12 h.
The solution was filtered-off and the solvent was removed under reduced pressure. The resulting
crude product was dissolved in toluene (5 mL), and a second portion of 4-
(Trifluoromethyl)benzyl bromide (478 mg, 2 mmol) was added and stirred at reflux conditions
for 12 h. The colorless solid that separated out after cooling to room temperature was filtered off
and washed with Et2O (2×10 mL) and dried under reduced pressure (1.21 g, 88%). M.p. = 271
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ºC. H NMR (400 MHz, DMSO-d6, TMS, 25ºC, ppm): δ = 9.70 (s, 1 H), 7.68 (d, J = 8.0 Hz, 4
H), 7.40 (t, J = 7.6 Hz, 8 H), 7.32 (d, J = 8.4 Hz, 4 H), 5.56 (s, 4 H). 13C{1H} NMR (100.6 MHz,
DMSO-d6, TMS): δ = 138.9, 137.9, 135.7, 133.1, 131.5, 129.4, 129.2 (q, J(C,F) = 32.2 Hz),
129.2, 125.9 (q, J(C,F) = 4.0 Hz), 124.4 (q, J(C,F) = 272.6 Hz), 123.9, 50.5. 19F NMR (376
MHz, DMSO-d6, TMS, 25ºC, ppm): δ = ‒ 61.2. HRMS (APCI) m/z: [M–Br]+ calcd for
C31H21Cl2F6N2 605.0986; found: 605.0988, Δ = + 0.3 ppm.
Synthesis of NHC–IrI complexes (1a-d). Under an argon atmosphere, a mixture of La-d (0.5
mmol) and Ag2O (58 mg, 0.25 mmol) was suspended in degassed CH2Cl2 (10 mL) and stirred at
ambient temperature for 1 h shielded from light. [IrCl(COD)]2 (168 mg, 0.25 mmol) was then
added to the suspension and the reaction mixture was stirred at ambient temperature for more 12
h. The resulting suspension was filtered over Celite®. The remaining solid was washed with
CH2Cl2 (2×5 mL) and the solvent of the filtrate was evaporated. The residue was purified by
column chromatography on silica gel using dichloromethane and hexane (6:4) mixture as eluent
to give pure complex as a yellow solid.
1b. Following the general procedure, the title product was obtained as a yellow solid using silica
gel column chromatography eluting with dichloromethane and hexane (6:4) mixture: yield 235
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mg, 56%. 1H NMR (400 MHz, CDCl3, TMS, 25ºC, ppm): δ = 7.66 (d, J = 8.4 Hz, 4 H), 7.55 (d,
J = 8.4 Hz, 4 H), 7.05 (s, 2 H), 6.38 (d, J = 15.6 Hz, 2 H), 5.89 (d, J = 16.0 Hz, 2 H), 4.85 (t, J =
2.8 Hz, 2 H), 2.86 (t, J = 2.8 Hz, 2 H), 2.25-2.16 (m, 2 H), 2.12-2.03 (m, 2 H), 1.86-1.79 (m, 2
H), 1.67-1.61 (m, 2 H). 13C{1H} NMR (100.6 MHz, CDCl3, TMS, 25ºC, ppm): δ = 196.5, 138.7,
133.9, 130.6 (q, J(C,F) = 32.4 Hz), 127.9, 127.5, 126.5 (q, J(C,F) = 270.0 Hz), 126.1 (q, J(C,F) =
2.8 Hz), 112.1, 89.9, 53.6, 52.2, 33.3, 29.1. 19F NMR (376 MHz, CDCl3, TMS, 25ºC, ppm): δ =
‒ 62.7. HRMS (APCI) m/z: [M–Cl]+ calcd for C31H26Cl2F6IrN2 803.1006; found 803.0983, Δ = ‒
2.9 ppm.
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1c. Following the general procedure, the title product was obtained as a yellow solid using silica
gel column chromatography eluting with dichloromethane and hexane (6:4) mixture: yield 336
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mg, 77%. H NMR (400 MHz, CDCl3, TMS, 25ºC, ppm): δ = 7.40 (d, J = 8.4 Hz, 4 H), 7.20-
7.16 (m, 6 H), 7.09 (t, J = 7.8 Hz, 4 H), 6.88 (d, J = 8.0 Hz, 4 H), 6.20 (d, J = 15.2 Hz, 2 H), 5.59
(d, J = 15.2 Hz, 2 H), 4.70 (t, J = 2.8 Hz, 2 H), 2.92 (t, J = 2.8 Hz, 2 H), 2.21-2.12 (m, 2 H),
2.09-2.00 (m, 2 H), 1.76-1.70 (m, 2 H), 1.61-1.51 (m, 2 H). 13C{1H} NMR (100.6 MHz, CDCl3,
TMS, 25ºC, ppm): δ = 181.7, 158.8, 140.6, 132.1, 130.4, 129.4 (q, J(C,F) = 32.4 Hz), 128.8,
128.3, 127.9, 127.9, 125.1 (q, J(C,F) = 2.8 Hz), 124.0 (d, J(C,F) = 270.0 Hz), 114.0, 85.9, 52.8,
52.3, 33.4, 29.3. 19F NMR (376 MHz, CDCl3, TMS, 25ºC, ppm): δ = ‒ 62.6. HRMS (APCI) m/z:
[M–Cl]+ calcd for C39H34F6IrN2 837.2255; found 837.2284, Δ = + 3.5 ppm.
1d. Following the general procedure, the title product was obtained as a yellow solid using silica
gel column chromatography eluting with dichloromethane and hexane (6:4) mixture: yield 362
mg, 71%. 1H NMR (400 MHz, CDCl3, TMS, 25ºC, ppm): δ = 7.44 (d, J = 8.4 Hz, 4 H), 7.22 (d,
J = 8.0 Hz, 4 H), 7.09 (d, J = 8.4 Hz, 4 H), 6.79 (d, J = 8.4 Hz, 4 H), 6.22 (d, J = 15.2 Hz, 2 H),
5.56 (d, J = 15.6 Hz, 2 H), 4.72 (t, J = 2.8 Hz, 2 H), 2.91 (t, J = 2.8 Hz, 2 H), 2.21-2.12 (m, 2 H),
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2.09-2.01 (m, 2 H), 1.78-1.70 (m, 2 H), 1.62-1.56 (m, 2 H). 13C{1H} NMR (100.6 MHz, CDCl3,
TMS, 25ºC, ppm): δ = 182.8, 140.3, 135.4, 131.5, 131.3, 129.8 (q, J(C,F) = 32.7 Hz), 128.8,
127.9, 126.0, 125.3 (q, J(C,F) = 3.8 Hz), 124.0 (d, J(C,F) = 280.0 Hz), 86.5, 52.9, 52.4, 33.4,
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29.3. F NMR (376 MHz, CDCl3, TMS, 25ºC, ppm): δ = ‒ 62.7. HRMS (APCI) m/z: [M–Cl]+
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calcd for C39H32Cl2F6IrN2 905.1476; found 905.1454, Δ = ‒ 2.4 ppm.
General optimization procedure for the direct synthesis of α,α-disubstituted ketones. In a
20 mL reaction tube (1 cm × 20 cm) with a condenser were added base (0.25 mmol, 0.5 equiv.),
1-phenylethanol (0.5 mmol), benzyl alcohol (1.1 mmol) and a solution of 1 (0.001-0.0025 mmol,
0.2-0.5 mol%) in toluene (1 mL). The reaction mixture was vigorously stirred (1200 rpm) under
reflux in a preheated oil bath at 140 ºC for 16-20 h. Then the reaction mixture was cooled to
ambient temperature, 2 M HCl (2 mL) and ethyl acetate (4 mL) were added to it, and then the
solution was extracted with ethyl acetate (2×5 mL), the combined organic phase was dried over
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MgSO4 and filtered. The solvent was evaporated and the crude product was submitted for H
NMR analysis to calculate the yield by using 1,3,5-trimethoxybenzene as internal standard.
Procedure for the hydrogen evolution experiment. In a 20 mL reaction tube (1 cm × 20 cm)
with a condenser were added KOH (0.25 mmol, 0.5 equiv.) 1-phenylethanol (0.5 mmol), benzyl
alcohol (1.1 mmol) and a solution of 1d (0.001 mmol, 0.2 mol%) in toluene (1 mL). The tube
was then sealed with a septum and vigorously stirred (1200 rpm) under reflux in a preheated oil
bath at 140 ºC for 20 h. It was then cooled to room temperature. Gas samples were taken with a
gas-tight syringe, and analyzed on a Agilent 7890A GC instrument. Hydrogen gas was detected
with a thermal conductivity detector referencing against standard gas with a known concentration
of hydrogen (Figure S13). Then to the resulting reaction mixture 2 M HCl (2 mL) and ethyl
acetate (4 mL) were added to it, and then the solution was extracted with ethyl acetate (2×5 mL),
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the combined organic phase was dried over MgSO4 and filtered. The solvent was evaporated and
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the crude product was submitted for H NMR analysis to calculate the yield by using 1,3,5-
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trimethoxybenzene as internal standard.
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General procedure for the direct synthesis of α,α-disubstituted ketones (4a-s). In a 20 mL
reaction tube (1 cm × 20 cm) with a condenser were added KOH (14 mg, 0.25 mmol, 0.5 equiv.),
secondary alcohol (0.5 mmol), primary alcohol (1.1 mmol) and a solution of 1d (0.001 mmol,
0.2 mol%) in toluene (1 mL) under air atmosphere. The reaction mixture was vigorously stirred
(1200 rpm) under reflux in a preheated oil bath at 140 ºC for 20 h. Then the reaction mixture
was cooled to ambient temperature and purified by silica gel column chromatography using
hexane and dichloromethane (6:4) mixture as eluent to afford the desired ketone.
2-Benzyl-1,3-diphenylpropan-1-one (4a).3a,9a Following the general procedure, the title product
was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 117 mg, 78%. Colorless solid (m.p.: 82 C). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.76 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.6
Hz, 2H), 7.24 (t, J = 7.2 Hz, 4H), 7.19-7.14 (m, 6H), 4.15-4.03 (m, 1H), 3.18 (dd, J1 = 13.8 Hz,
J2 = 7.6 Hz, 2H), 2.85 (dd, J1 = 13.6 Hz, J2 = 6.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz) δ
(ppm): 203.3, 139.5, 137.4, 132.7, 129.0, 128.4, 128.4, 128.1, 126.3, 50.5, 38.3.
2-Benzyl-1-(4-methoxyphenyl)-3-phenylpropan-1-one (4b).7a,9a Following the general
procedure, the title product was isolated by using silica gel column chromatography eluting with
hexane and dichloromethane (6:4) mixture: yield 149 mg, 90%. Colorless oil. 1H NMR (CDCl3,
400 MHz) δ (ppm): 7.76 (d, J = 9.2 Hz, 2H), 7.25-7.21 (m, 5H), 7.16 (d, J = 7.6 Hz, 5H), 6.82
(d, J = 8.8 Hz, 2H), 4.03-3.96 (m, 1H), 3.80 (s, 3H), 3.15 (dd, J1 = 13.6 Hz, J2 = 8.0 Hz, 2H),
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2.82 (dd, J1 = 13.6 Hz, J2 = 6.4 Hz, 2H). C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 201.6,
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2-Benzyl-3-phenyl-1-(p-tolyl)propan-1-one (4c).21 Following the general procedure, the title
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product was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 134 mg, 85%. Colorless solid (m.p.: 76 C). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.68 (d, J = 8.4 Hz, 2H), 7.26-7.22 (m, 5H), 7.18-7.14 (m, 7H),
4.07-4.00 (m, 1H), 3.16 (dd, J1 = 13.6 Hz, J2 = 7.6 Hz, 2H), 2.82 (dd, J1 = 13.8 Hz, J2 = 6.4 Hz,
2H), 2.36 (s, 3H). 13C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 202.8, 143.6, 139.6, 134.9,
129.2, 129.0, 128.4, 128.3, 126.2, 50.3, 38.2, 21.6.
2-Benzyl-1-(4-chlorophenyl)-3-phenylpropan-1-one (4d). Following the general procedure,
the title product was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 119 mg, 71%. Colorless solid (m.p.: 56 C). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.60 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.22 (t, J = 7.2
Hz, 4H), 7.17-7.13 (m, 5H), 4.00-3.93 (m, 1H), 3.13 (dd, J1 = 13.6 Hz, J2 = 8.0 Hz, 2H), 2.85
(dd, J1 = 13.6 Hz, J2 = 6.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 202.4, 139.3,
139.2, 135.9, 129.4, 128.9, 128.7, 128.5, 126.4, 50.7, 38.5. HRMS (ESI): m/z: [M+H]+ calcd for
C22H20ClO 335.1203; found: 335.1198, Δ = ‒ 1.5 ppm.
2-Benzyl-1-(4-bromophenyl)-3-phenylpropan-1-one (4e). Following the general procedure,
the title product was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 123 mg, 65%. Colorless solid (m.p.: 70 C). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.51 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 7.21 (t, J = 7.0
Hz, 4H), 7.16-7.11 (m, 6H), 3.98-3.91 (m, 1H), 3.11 (dd, J1 = 13.6 Hz, J2 = 8.4 Hz, 2H), 2.83
(dd, J1 = 13.6 Hz, J2 = 6.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 202.6, 139.2,
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136.3, 131.7, 129.5, 128.9, 128.5, 127.9, 126.4, 50.7, 38.5. HRMS (ESI): m/z: [M+H]+ calcd for
C22H20BrO 379.0698; found: 379.0699, Δ = + 0.3 ppm.
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2-Benzyl-1-(naphthalen-2-yl)-3-phenylpropan-1-one (4f). Following the general procedure,
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the title product was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 128 mg, 73%. Colorless solid (m.p.: 102 C). H NMR
(CDCl3, 400 MHz) δ (ppm): 8.17 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.82 (q, J = 6.1 Hz, 3H), 7.57
(t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.27-7.22 (m, 8H), 7.18-7.14 (m, 2H), 4.26-4.19 (m,
1H), 3.26 (dd, J1 = 13.6 Hz, J2 = 8.0 Hz, 2H), 2.95 (dd, J1 = 13.8 Hz, J2 = 6.4 Hz, 2H). 13C{1H}
NMR (CDCl3, 100.6 MHz) δ (ppm): 203.3, 139.6, 135.4, 134.8, 132.4, 129.8, 129.6, 129.1,
128.5, 128.4, 128.3, 127.7, 126.6, 126.3, 124.0, 50.7, 38.6. HRMS (ESI): m/z: [M+H]+ calcd for
C26H23O 351.1749; found: 351.1746, Δ = ‒ 0.9 ppm.
2-Benzyl-1-(ferrocenyl)-3-phenylpropan-1-one (4g). Following the general procedure, the title
product was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 125 mg, 61%. Yellow solid (m.p.: 154 C). H NMR
(CDCl3, 400 MHz) δ (ppm): 7.30-7.16 (m, 10H), 4.67 (t, J = 1.6 Hz, 2H), 4.41 (t, J = 1.6 Hz,
2H), 3.74 (s, 5H), 3.44-3.37 (m, 1H), 3.13 (dd, J1 = 13.6 Hz, J2 = 7.6 Hz, 2H), 2.66 (dd, J1 = 13.4
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Hz, J2 = 6.8 Hz, 2H). C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 205.4, 140.1, 129.3, 128.4,
126.4, 79.0, 72.1, 69.3, 69.2, 53.4, 37.7. HRMS (ESI): m/z: [M+H]+ calcd for C26H25FeO
409.1255; found: 409.1259, Δ = + 1.0 ppm.
2-(4-Methoxybenzyl)-3-(4-methoxyphenyl)-1-phenylpropan-1-one (4h). Following the
general procedure, the title product was isolated by using silica gel column chromatography
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eluting with hexane and dichloromethane (6:4) mixture: yield 139 mg, 77%. Yellow oil. H
NMR (CDCl3, 400 MHz) δ (ppm): 7.74 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.34 (t, J =
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7.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 4H), 6.76 (d, J = 8.8 Hz, 4H), 3.99-3.92 (m, 1H), 3.74 (s, 6H),
3.07 (dd, J1 = 13.8 Hz, J2 = 7.6 Hz, 2H), 2.76 (dd, J1 = 13.8 Hz, J2 = 6.0 Hz, 2H). 13C{1H} NMR
(CDCl3, 100.6 MHz) δ (ppm): 203.6, 158.0, 137.5, 132.7, 131.6, 129.9, 128.4, 128.1, 113.8,
55.2, 50.9, 37.3. HRMS (ESI): m/z: [M+H]+ calcd for C24H25O3 361.1804; found: 361.1800, Δ =
‒ 1.1 ppm.
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2-(4-Methylbenzyl)-1-phenyl-3-(p-tolyl)propan-1-one (4i). Following the general procedure,
the title product was isolated by using silica gel column chromatography eluting with hexane and
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dichloromethane (6:4) mixture: yield 130 mg, 79%. Yellow oil. H NMR (CDCl3, 400 MHz) δ
(ppm): 7.82 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 6.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.08 (q, J = 4.9
Hz, 8H), 4.09-4.02 (m, 1H), 3.16 (dd, J1 = 13.8 Hz, J2 = 7.6 Hz, 2H), 2.82 (dd, J1 = 13.8 Hz, J2 =
6.4 Hz, 2H), 2.31 (s, 6H). 13C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 203.4, 137.5, 136.5,
135.7, 132.7, 129.1, 128.9, 128.5, 128.2, 50.6, 37.7, 21.0. HRMS (ESI): m/z: [M+H]+ calcd for
C24H25O 329.1905; found: 329.1900, Δ = ‒ 1.5 ppm.
2-(4-Isopropylbenzyl)-3-(4-isopropylphenyl)-1-phenylpropan-1-one (4j). Following the
general procedure, the title product was isolated by using silica gel column chromatography
eluting with hexane and dichloromethane (6:4) mixture: yield 169 mg, 88%. Colorless solid
(m.p.: 77 oC). 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.74 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.4 Hz,
1H), 7.34 (t, J = 7.8 Hz, 2H), 7.09 (s, 8H), 4.06-3.99 (m, 1H), 3.13 (dd, J1 = 13.8 Hz, J2 = 8.0
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Hz, 2H), 2.90-2.80 (m, 4H), 1.21 (d, J = 7.2 Hz, 12H). C{1H} NMR (CDCl3, 100.6 MHz) δ
(ppm): 203.6, 146.7, 137.6, 136.9, 132.6, 128.9, 128.3, 128.2, 126.4, 50.5, 37.8, 33.7, 24.0.
HRMS (ESI): m/z: [M+H]+ calcd for C28H33O 385.2531; found: 385.2529, Δ = ‒ 0.5 ppm.
2-(4-Chlorobenzyl)-3-(4-chlorophenyl)-1-phenylpropan-1-one (4k). Following the general
procedure, the title product was isolated by using silica gel column chromatography eluting with
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hexane and dichloromethane (6:4) mixture: yield 139 mg, 75%. Yellow oil. H NMR (CDCl3,
400 MHz) δ (ppm): 7.72 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H),
7.18 (d, J = 8.4 Hz, 4H), 7.06 (d, J = 8.0 Hz, 4H), 3.98-3.91 (m, 1H), 3.09 (dd, J1 = 13.6 Hz, J2
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= 8.0 Hz, 2H), 2.75 (dd, J1 = 13.6 Hz, J2 = 6.4 Hz, 2H). C{1H} NMR (CDCl3, 100.6 MHz) δ
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(ppm): 202.6, 137.7, 137.1, 133.1, 132.2, 130.3, 128.6, 128.5, 128.0, 50.2, 37.5. HRMS (ESI):
m/z: [M+H]+ calcd for C22H19Cl2O 369.0813; found: 369.0818, Δ = + 1.4 ppm.
2-(4-Bromobenzyl)-3-(4-bromophenyl)-1-phenylpropan-1-one (4l). Following the general
procedure, the title product was isolated by using silica gel column chromatography eluting with
hexane and dichloromethane (6:4) mixture: yield 183 mg, 80%. Colorless solid (m.p.: 72 oC). 1H
NMR (CDCl3, 400 MHz) δ (ppm): 7.72 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H), 7.38-7.31
(m, 6H), 7.00 (d, J = 8.4 Hz, 4H), 3.97-3.90 (m, 1H), 3.07 (dd, J1 = 13.6 Hz, J2 = 8.0 Hz, 2H),
2.73 (dd, J1 = 13.8 Hz, J2 = 6.0 Hz, 2H). C{1H} NMR (CDCl3, 100.6 MHz) δ (ppm): 202.5,
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138.2, 137.0, 133.1, 131.5, 130.7, 128.6, 128.0, 120.2, 50.0, 37.5. HRMS (ESI): m/z: [M+H]+
calcd for C22H19Br2O 456.9803; found: 456.9803, Δ = 0 ppm.
2-(4-(Dimethylamino)benzyl)-3-(4-(dimethylamino)phenyl)-1-phenylpropan-1-one
(4m).
Following the general procedure, the title product was isolated by using silica gel column
chromatography eluting with hexane and dichloromethane (6:4) mixture: yield 186 mg, 96%.
Yellow solid (m.p.: 118 oC). 1H NMR (CDCl3, 400 MHz) δ (ppm): 7.77 (d, J = 8.0 Hz, 2H), 7.45
(t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.01 (d, J = 8.8 Hz, 4H), 6.61 (d, J = 8.8 Hz, 4H),
3.96-3.89 (m, 1H), 3.02 (dd, J1 = 14.0 Hz, J2 = 7.6 Hz, 2H), 2.87 (s, 12H), 2.71 (dd, J1 = 13.8
Hz, J2 = 6.4 Hz, 2H). 13C NMR (CDCl3, 100.6 MHz) δ (ppm): 204.0, 149.2, 137.6, 132.5, 129.6,
128.3, 128.2, 127.9, 112.9, 51.1, 40.8, 37.1. HRMS (ESI): m/z: [M+H]+ calcd for C26H31N2O
387.2436; found: 387.2437, Δ = + 0.3 ppm.
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