Iridium-catalyzed selective α-methylation of ketones with methanol

Article abstract of DOI:10.1039/c3cc49626k

Iridium-catalyzed selective α-dimethylation and α-methylation of ketones or phenylacetonitriles, using methanol as the methylating agent, were achieved. In addition, three-component cross α-methyl-alkylation was successfully performed using methyl ketones with methanol and primary alcohols with long-chain alkyl groups. This method provides a very convenient direct route to α-methylated ketones, using methanol.

Full text of DOI:10.1039/c3cc49626k

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DOI: 10.1039/C3CC49626K
ARTICLE TYPE
Iridium-catalyzed selective α-methylation of ketones with methanol†
Shinji Ogawa and Yasushi Obora*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
1
5
5
Iridium-catalyzed selective α-dimethylation and α-
ketone methylation.
methylation of ketones or phenylacetonitriles, using methanol 50 In this communication, we report a simple and versatile method
as the methylating agent, were achieved. In addition, three-
component cross α-methyl-alkylation was successfully
performed using methyl ketones with methanol and primary
alcohols with long-chain alkyl groups. This method provides a
very convenient direct route to α-methylated ketones, using
methanol.
for selective α-methylation of ketones or phenylacetonitriles, with
methanol as the methylating agent, in the presence of an Ir
catalyst and a base. In addition, we report the three-component
one-step or one-pot α-methyl-alkylation of methyl ketones using
methanol and primary alcohols with long-chain alkyl groups.
Initially, acetophenone (1a) and methanol (2) were used as
model substrates for optimization of the α-methylation
conditions; the results are shown in Table 1.
1
0
5
5
The development of transition-metal-catalyzed C−C bond
formation using sustainable feedstocks is vital for bulk and fine
chemical manufacture. In particular, methylation is an essential 60 under Various Conditions
Table 1. Ir-Catalyzed Reactions of Acetophenone (1a) with Methanol (2)
1
a
1
2
2
3
3
4
4
5
0
5
0
5
0
5
function of biologically active molecules. The development of
methyl functionalization is therefore a topic of current interest.
[
Ir] (cat.)
Base
2
O
O
OH
Me
+
Me
+
MeOH
Ketone methylation using iodomethane or diazomethane as the
20 oC, 15 h
1
Me
Me
3
methylating agent is a typical example. However, such methods
use toxic or extremely sensitive explosive reagents. It is well
known that Ir and Ru complexes are efficient catalysts for
transfer hydrogenation (also known as hydrogen borrowing) from
1a
2
3a
4a
b
Yield (/%)
Entry
1
Ir catalyst
[Cp*IrCl
Base
3
a
4a
<1
9
12
4
12
<1
11
n.d.
<1
2
]
2
KOH
KOH
KOH
KOH
KOH
CO
t-BuOK
Na CO3
KOH
87 (83)
39
4
alcohols to aldehydes and ketones. This important strategy has
c
2
3
[IrCl(cod)] /PPh
[Ir(OH)(cod)] /PPh3
[Cp*RhCl
RuHCl(CO)(PPh
2
3
c
been applied to C−C bond formation in α- and β-alkylation
55
18
12
76
51
n.d.
79
2
5
reactions, using alcohols as alkylating agents. Our group has
4
5
6
7
8
2
]
2
6
a
6b
3
)
3
reported Ir-catalyzed α-alkylations of ketones, methyl esters,
[Cp*IrCl
[Cp*IrCl
2
]
]
2
Cs
2
3
6
c
6d
active
methylquinolines, and dimerizations of alcohols.
we achieved Ir-catalyzed reactions of alcohols with alkynes or
methylene
compounds,
acetonitrile,
and
In addition,
2
2
6
e
6f–g
d
[Cp*IrCl2]2
[Cp*IrCl
2
e
9
2
]
2
7
a
7b
enones led to homoallylic alcohols, β-enones, and 1,3-
diketones. These reactions were restricted to benzyl alcohols or
aliphatic alcohols with long-chain alkyl groups; only a few
reactions using methanol have been reported, although methanol
is an abundant and renewable resource. In our previous study,
a
Conditions: 1a (1 mmol), 2 (1.5 mL), Ir catalyst (0.05 mmol), and base
(0.50 mmol) at 120 °C for 15 h under Ar. GC yields based on 1a used.
7
c
b
c
The number in parentheses shows isolated yield. PPh
3
(0.20 mmol) was
d
e
8
used. Not detected by GC. [Cp*IrCl ] (0.005 mmol) was used.
2 2
9
For example, the reaction of 1a (1 mmol) with 2 (1.5 mL) was
performed in the presence of [Cp IrCl ] (0.05 mmol, 5 mol%)
and KOH (0.5 mmol, 50 mol%) at 120 °C for 15 h, giving the α-
dimethylated product 3a in 87% yield. This reaction was highly
*
we showed that methyl esterification was selectively achieved by
the Ir-catalyzed reactions of methanol and alcohols with long-
2
2
1
0
chain alkyl groups, because methanol oxidation is relatively
difficult; the reaction energy for methanol dehydrogenation (H 65 chemoselective (Table 1, entry 1). With regard to the Ir complex,
−
1
*
=
84 kJ mol ) is higher than those for the dehydrogenation of
2 2
[Cp IrCl ] gave 3a in high yield with high selectivity. The use of
[IrCl(cod)] /PPh and [Ir(OH)(cod)] /PPh gave 3a in moderate
2 3 2 3
yields, along with the formation of 4a (9–12%; entries 2 and 3).
When [Cp*RhCl2]2 and RuHCl(CO)(PPh3)3 were used as
−1 11
higher alcohols such as ethanol (H = 68 kJ mol ).
In pioneering work on transfer hydrogenation using methanol,
Krische reported Ir-catalyzed direct C–C coupling of methanol
1
2
and allenes. Li described Ir-catalyzed N-monomethylation of 70 catalysts, the yields of ketone methylation products were low
aromatic primary amines with methanol, and reported the
reaction of indoles with methanol to give 3,3'-
(entries 4 and 5). The methylation was influenced by the base
used. KOH and Cs CO were found to be suitable bases (entries 1
and 6). When t-BuOK, was used, 4a was also detected (entry 7).
2
3
13
bisindolylmethanes. Beller and Grützmacher reported Ru-
catalyzed dehydrogenation of methanol to hydrogen and carbon
However, weak bases such as Na CO resulted in total inactivity
2
3
1
4
dioxide. Recently, Donohoe reported Rh-catalyzed O -assisted 75 under these conditions (entry 8).
2
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a
Table 2. Ir-Catalyzed Reactions of Ketones 1 with Methanol (2)
After obtaining these optimized conditions, we investigated the
reactions of various ketones 1 with methanol (2) (Table 2).
cat.
[
Cp*IrCl2]
2
View Article Online
O
O
10 Various aryl methyl ketones (1b–1f) were allowed to react with 2
KOH
DOI: 10.1039/C3CC49626K
R2
+
MeOH
R2
Me
under the optimized conditions (entries 1–5). 4-
Methylacetophenone (1b), 4-methoxyacetophenone (1c), 4-
naphthylacetophenone (1d), 2-acetylfuran (1e), and 2-
methylacetophenone (1f) participated in the reaction and the
corresponding α-dimethylated products 3b–3f were obtained in
80–85% isolated yields, with high chemoselectivity. When
butyrophenone (1g) was used, the monomethylated product 3g
was obtained in 89% yield (entry 6). Aliphatic and benzyl
ketones (1h–1k) were also used in this reaction and the products
R1
120 oC, 15 h
R1
1
2
3
Entry
Ketone (1)
Product (3)
Yield (%)
82
1
5
O
O
Me
1
Me
1
b
3
b
O
O
Me
Me
20 were isolated in 78–91% yields (entries 7–10). If Na CO was
2 3
2
3
85
80
used instead of KOH in the reaction of benzyl ethyl ketone (1k),
monomethylation proceeded at the benzyl position with high
chemoselectivity (entry 11). Time-course monitoring of the
reaction of 1k with 2 showed initial formation of 3k', followed by
25 formation of 3k (See Fig. S1, ESI†); this is probably the result of
MeO
MeO
1
c
3c
O
O
Me
Me
1
6
a
the different pK values at the benzyl and ethyl positions.
1
d
3
O
d
We anticipated that this catalytic system would be compatible
with other compounds. A series of phenylacetonitriles bearing
electron-donating or electron-withdrawing groups gave the α-
methylated products 6a–6c in good to excellent yields; the results
are shown in Table 3.
O
O
Me
Me
4
5
6
O
80
84
89
1
e
3e
3f
3
0
O
O
Me
Me
Table 3. Ir-Catalyzed Reactions of Phenylacetonitriles 5 with Methanol
a
1
f
(2)
O
O
Me
1
g
3g
O
O
b
Me
Me
c
7
78
Me
CN
Me
CN
Me
CN
1
h
3h
3i
O
O
O
F
3
C
MeO
d,e
Me
c
8
85
b
b,c
7
76% (6a)
87% (6b)
75% (6c)
7
Me Me
O
1
i
a
Reaction conditions: 3 (1.0 mmol), 2 (1.5 mL), Ir catalyst (0.05 mmol),
and KOH (0.50 mmol) at 120 °C for 15 h under Ar. All yields are
isolated yields. Corresponding amide (<10%) was also obtained.
c
b
9
91
c
Me Me
Reaction temperature was 130 °C.
1
j
3j
O
3
5
With the results in hand for the selective -dimethylation of
methyl ketones using methanol, the catalytic system was
successfully extended to three-component one-step or one-pot
cross α-methyl-alkylations of methyl ketones using methanol and
primary alcohols; the results are shown in Table 4.
e
c
1
0
O
78
Me Me
O
1
1
k
k
3k
b,f,g
c
1
1
O
74
Me
40 For example, the reaction of 1a (2 mmol) with 2 (1.0 mL) and
benzyl alcohol (7a) (1 mmol) was performed in the presence of
3k'
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mL), Ir catalyst (0.05 mmol),
and KOH (0.50 mmol) at 120 °C for 15 h under Ar. All yields are
isolated yields. Reaction temperature was 130 °C. The stereochemistry
is not determined. Reaction temperature was 150 °C. KOH (1.0 mmol)
2 3
was used. 2 (0.75 mL) was used. Na CO (0.50 mmol) was used instead
[Cp*IrCl2]2 (0.05 mmol, 5 mol%) and KOH (0.5 mmol, 50
b
c
mol%) at 140 °C for 15 h, giving the α-methyl-alkylated product
8aa in 81% yield, with high chemoselectivity (Table 4, entry 1).
45 Ketones 1b and 1c participated in the reaction, and the
corresponding products 8ba and 8ca were obtained in 83–84%
yields (entries 2 and 3). Furthermore, acetone (1l), one of the
simplest ketones, was accommodated in this reaction and 8al was
isolated in good yield (entry 4). 4-Methylbenzyl alcohol (7b) and
d
e
f
g
of KOH.
Furthermore, a reduced catalyst loading was found to give 3a in
9% yield (entry 9). No reaction took place in the absence of an
7
5
Ir complex. The reaction proceeded with an excess of 2, and the 50 4-methoxybenzyl alcohol (7c) participated in the reaction and the
use of 1 equiv of 2 for 1a was found to be sluggish under these
corresponding products 8ab and 8ac were obtained in good yields
conditions.
(entries 5 and 6). We performed one-pot-type methyl-alkylations
2
|
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This journal is © The Royal Society of Chemistry [year]

Page 3 of 3
ChemComm
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Entry
1
1 (R )
7 (R )
7a
Product (8)
Yield (%)
81
1a
1b
1c
C
6
H
5
8aa
2
3
7a
7a
8ba
84
83
8ca
5
O
55
Me
6 5
C H
4
CH
3
1l
7a
61
Me Me
2
2
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al
5
6
1a
1a
1a
1a
p-CH
p-CH
n-C
n-C
3
C
6
H
4
7b
7c
8ab
8ac
8ad
8ae
79
72
88
90
6
6
0
5
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0.05 mmol), and KOH (0.50 mmol) at 140 °C for 15 h under Ar. All
6
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(
b
yields are isolated yields. Reaction conditions: 1 (1.2 mmol), 7 (1
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and, after adding 2 (1.5 mL), 140 °C for 15 h under Ar.
70
75
Ketone methylation is believed to proceed according to a
8
618. (g) T. Matsu-ura, S. Sakaguchi, Y. Obora and Y. Ishii, J. Org.
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1
2
2
0
5
0
5
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7
8
1
7
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8
9
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In conclusion, an efficient α-methylation of ketones or
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was successfully extended to three-component cross α-methyl-
alkylations of methyl ketones using methanol and primary
alcohols. This reaction provides a simple and atom-economical
direct route to various multisubstituted ketones in good yields.
This work was supported by Kansai University and the Strategic
Project to Support the Formation of Research Bases at Private
Universities (2010-2014), matching fund subsidy from the
Ministry of Education, Culture, Sports, Science and Technology.
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Notes and references
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L. K. M. Chan, D. L. Poole, D. Shen, M. P. Healy and T. J. Donohoe,
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Department of Chemistry and Materials Engineering, Faculty of
Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564-8680, Japan. Fax:+81-6-6339-4026; Tel:+81-6-6368-0876;
E-mail: obora@kansai-u.ac.jp.
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1
00
3
0
†
Electronic Supplementary Information (ESI) available: Fig. S1-2,
1
Experimental procedures and compound characterization data ( H NMR,
1
3
C NMR) of the compounds. See DOI:10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
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