Ruthenium hydride/nitrogen tridentate ligand-catalyzed α-alkylation of acetamides with primary alcohols

Article abstract of DOI:10.1039/c3ra42834f

The α-alkylation reaction of acetamides with primary alcohols to afford the corresponding amides was accomplished effectively using RuHCl(CO)(PPh₃)₃ as a catalyst, nitrogen tridentate ligand L1 as an additive, and KO^tBu as a base. While the addition of bpy was effective only for benzylic alcohols, L1 affected the alkylation reaction when both benzylic and non-benzylic type alcohols were used.

Full text of DOI:10.1039/c3ra42834f

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Ruthenium hydride/nitrogen tridentate ligand-
catalyzed a-alkylation of acetamides with primary
alcohols3
Cite this: RSC Advances, 2013, 3, 13702
Received 7th June 2013,
Accepted 21st June 2013
Takashi Kuwahara, Takahide Fukuyama and Ilhyong Ryu*
DOI: 10.1039/c3ra42834f
www.rsc.org/advances
The a-alkylation reaction of acetamides with primary alcohols to
tion of simple amides, in which they used an iridium pincer
13
afford the corresponding amides was accomplished effectively
complex as a catalyst.
Using RuHCl(CO)(PPh ) as a catalyst, we initially investigated
using RuHCl(CO)(PPh
3
)
3
as a catalyst, nitrogen tridentate ligand
3
3
t
L1 as an additive, and KO Bu as a base. While the addition of bpy
was effective only for benzylic alcohols, L1 affected the alkylation
reaction when both benzylic and non-benzylic type alcohols were
used.
the reaction conditions using N,N-dimethylacetamide (1a) and
benzyl alcohol (2a) as test substrates (Table 1). When 1.1 equiv. of
1a was reacted with 2a in the presence of 3 mol% of
RuHCl(CO)(PPh ) and 1.3 equiv. of potassium tert-butoxide at
3
3
140 uC (bath temp) for 18 h in toluene (2 mL), the desired amide
In recent years, transition-metal-catalyzed a-alkylation reactions of
carbonyl compounds using primary alcohols have attracted much
attention in view of the atom-economy in which water is the only
3a was obtained in 39% yield (entry 1). We examined some other
bases, such as NaO Bu (entry 2), Cs CO (entry 3) and KOH (entry
2 3
t
4), but these bases were less effective or totally ineffective, unlike
1
3
byproduct. These transformations employ classical aldol reac-
the case of ketone alkylation. To encourage further the reaction
t
tions for the C–C bond-forming step, in which aldehydes are
provided via the transfer dehydrogenation of primary alcohols by a
metal catalyst and dehydrated aldol products act as dihydrogen
acceptors from primary alcohols (Scheme 1). While the alkylation
using KO Bu, we then tested several additives. The addition of
1,10-phenanthroline (Phen), which worked well for the accelera-
tion of ketone a-alkylation, did not work in the present amide
alkylation (entry 5). However, the addition of 10 mol% of
2,29-bipyridine (bpy) resulted in a significant improvement in
the yield of 3a to 49% (entry 6). When 1a was used in large excess
without solvent, we obtained 3a in 68% yield (entry 7). Inspired by
the recent work of Yu and coworkers who found that Ru(II)
complexes having a pyrazolyl-pyridyl-pyrazole ligand, L1, exhibited
2
,3
4
5
of methyl ketones, acetic acid esters, cyanoacetates, mal-
6
7
8,9
onates, ketonitriles and acetonitrile has been attained, the
alkylation of amides is only restricted to the specific amides, such
1
0
11
as oxindoles and 1,3-dimethyl barbituric acid.
During the course of our study to explore the atom-economical
reactions of alcohols based on the multitask ability of
14
high catalytic activity in the transfer hydrogenation of ketones,
12
RuHCl(CO)(PPh
3
)
3
as a catalyst, we recently reported the
we examined the N,N,N-tridentate ligand, L1 for the present
RuHCl(CO)(PPh ) -catalyzed a-alkylation reaction of ketones by
3
3
3
primary alcohols, in which we found that addition of a catalytic
amount of 1,10-phenanthroline (Phen) dramatically accelerated
the alkylation of ketones by nonbenzylic primary alcohols. In this
work, we focused on the a-alkylation of acetamides using the same
RuH complex as a catalyst, but with a combination of
N,N-bidentate or N,N,N-tridentate ligands, such as 2,29-bipyridine
(bpy) or tridentate ligand L1 (Fig. 1). Especially the tridentate
ligand L1 accelerated alkylation using both benzylic and non-
benzylic alcohols. It should be noted that almost concurrently with
this work, Huang and co-workers have reported similar a-alkyla-
Department of Chemistry, Graduate School of Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, Japan. E-mail: ryu@c.s.osakafu-u.ac.jp; Tel: +81 72 254
9
695
Scheme 1 General concept of metal-catalyzed a-alkylation of carbonyl com-
3
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra42834f
pounds with alcohols.
1
3702 | RSC Adv., 2013, 3, 13702–13704
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a
Table 2 Ru-catalyzed a-alkylation of acetamides by primary alcohols
Fig. 1 Structure of L1.
Yield
(%)
b
Entry Amide 1
Alcohol 2 Method Product 3
a-alkylation of 1a. Gratifyingly, the yield of 3a was further
improved to 76% (entry 8).
Using the reaction conditions of entry 7 (method A, bpy) and/or
entry 8 (method B, L1), we then examined the generality of the
a-alkylation of acetamides (Table 2). Using substituted benzyl
alcohols 2a–g, N,N-dimethyl-3-arylpropionamides 3a–g were
obtained in moderate to good yields (entries 1–7). The reaction
of 1a with 1-naphthalenemethanol (2h) gave the corresponding
amides 3h in 65% yield (entry 8). The alkylation of 1a by furfuryl
alcohol (2i) gave 3i in modest yield (entry 9). The reaction of
N-acetyl morpholine (1b) with 2a in toluene gave the correspond-
ing amide 3j in 78% yield (entry 10). Compared to benzyl alcohols,
non-benzylic type alcohols resulted in poorer yields when we used
method A. However, when using method B, alkylation using
hexanol (2j), cyclohexanemethanol (2k), and isoamyl alcohol (2l)
gave the desired products 3k, 3l, and 3m in good yields (entries
1
2
3
4
5
6
7
R = H 2a
p- Bu 2b
p-Ph 2c
o-OMe 2d (B)
m-OMe 2e (B)
p-OMe 2f (A)
(B)
(A)
(A)
3a
3b
3c
3d
3e
3f
76
61
89
73
76
70
85
65
t
c
m-CF
3
2g (B)
3g
8
1a
1a
(B)
9
(B)
(A)
45
78
11–13).
Although the detailed mechanism has to wait further study,
possible reaction mechanism is summarized in Scheme 2. An
d
10
2a
alkoxyruthenium complex A would be formed in situ from
3 3
RuHCl(CO)(PPh ) , L1, and an alcohol 2a, which would then
undergo b-hydride elimination to give a ruthenium hydride B and
1
5
an aldehyde. Base promoted aldol condensation of the resultant
aldehyde with 1a would give an a,b-unsaturated amide. Addition
of the ruthenium hydride complex B to the a,b-unsaturated amide
would afford a ruthenium enolate C, which would be protonated
by an alcohol to give the a-alkylated amide 3 and the
alkoxyruthenium A.
11
1a
(B)
76
1
1
2
3
1a
1a
(B)
(B)
74
61
a
Table 1 Optimization of the reaction conditions
a
3 3
Method A: alcohol 2 (0.5 mmol), RuHCl(CO)(PPh ) (3 mol%), bpy
t
(
10 mol%), KO Bu (1.3 equiv.), 1a (2 mL), 140 uC (bath temp), 18 h.
b
Method B: L1 (6 mol%) was used instead of bpy. Isolated yield by
c
d
silica gel chromatography. 13 h. Toluene solution (2 mL) of 1b (1
mmol) was used.
b
Entry
Base
Additive (mol %)
Yield (%)
t
1
2
3
4
5
6
KO Bu
—
—
—
—
39
10
0
0
31
49
t
In summary, we have found that the a-alkylation reaction of
NaO Bu
acetamides with primary alcohols can be successfully catalyzed by
Cs
2
CO
3
t
KOH
readily available RuHCl(CO)(PPh
3
)
3
as a catalyst, KO Bu as a base,
t
KO Bu
Phen (10)
bpy (10)
bpy (10)
L1 (6)
t
and tridentate amine L1 as an ligand. A detailed mechanistic
study and the applications using the ruthenium complexes having
L1 are currently underway in our laboratory.
This work was supported by a Grant-in-Aid for Scientific
Research from MEXT and JSPS.
KO Bu
c
t
d
7
KO Bu
68
76
c
t
d
8
KO Bu
a
Reaction conditions: 1a (0.55 mmol), benzyl alcohol 2a (0.50
(3 mol%), base (1.3 equiv.), additive,
toluene (2 mL), 140 uC for 18 h. NMR yield. 1a was used as a
3 3
mmol), RuHCl(CO)(PPh )
b
c
d
solvent (2 mL). Isolated yield.
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3
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3704 | RSC Adv., 2013, 3, 13702–13704
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