Hydrogenation of amides catalyzed by a combined catalytic system of a Ru complex with a zinc salt

Article abstract of DOI:10.1039/c4cc04481a

Addition of catalytic amounts of zinc salts facilitated the hydrogenation of amides catalyzed by a ruthenium complex bearing 2-(diphenylphosphino) ethanamine (L1). The combined catalytic system of the ruthenium complex [RuCl₂(L1)₂] with a zinc salt such as Zn(OCOCF ₃)₂ mediated hydrogenation of various amides under mild conditions to afford the corresponding primary alcohols.

Full text of DOI:10.1039/c4cc04481a

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Hydrogenation of amides catalyzed by a combined
catalytic system of a Ru complex with a zinc salt†
Cite this: Chem. Commun., 2014,
50, 11211
Yusuke Kita, Takafumi Higuchi and Kazushi Mashima*
Received 12th June 2014,
Accepted 30th July 2014
DOI: 10.1039/c4cc04481a
www.rsc.org/chemcomm
Table 1 Optimization of reaction conditions for hydrogenation of 1a
catalyzed by the ruthenium complexa
Addition of catalytic amounts of zinc salts facilitated the hydro-
genation of amides catalyzed by a ruthenium complex bearing
2-(diphenylphosphino)ethanamine (L1). The combined catalytic
system of the ruthenium complex [RuCl2(L1)2] with a zinc salt
such as Zn(OCOCF3)2 mediated hydrogenation of various amides
under mild conditions to afford the corresponding primary
alcohols.
Entry
Additive
Yieldb (%)
Amide reduction is a widely utilized synthetic protocol to prepare
primary alcohols and amines. In general, amide reduction is
achieved using stoichiometric reduction reagents such as lithium
aluminum hydride1 or borane,2 although significant amounts of
waste are produced with the workup. The most straightforward
approach to address this issue is the use of molecular hydrogen as
the reducing reagent.3 Reduction of amides using hydrogen gas in
the presence of heterogeneous catalysts, such as copper chromite,4
ReO3,5 RANEYs Ni,6 PtO2,7 Rh–Re,8 Cu,9 Rh/Mo,10 Ru/Re,11 Pt–Re/
TiO2,12 Pt/Re/graphite,13 and Re/TiO2,14 has been successfully
applied to afford the corresponding amines instead of the primary
alcohols; however, these systems typically require high tempera-
1
2
3
4
5
6
7
8
9c
None
Zn(OTf)2
ZnCl2
ZnBr2
ZnI2
Zn(OAc)2
Zn(OCOCF3)2
Zn4(OCOCF3)6O
Zn(OCOCF3)2
Not detected
53
73
39
19
64
74
56
95
a
Reaction conditions: a mixture of the [RuCl2(L1)2] catalyst (0.010 mmol),
N-methylbenzamide (1.0 mmol), NaOMe (0.50 mmol), and additives
tures and high pressures. On the other hand, some homogeneous (0.050 mmol) in isopropyl alcohol (5.0 mL) was stirred under 3.0 MPa
b
c
hydrogen pressure at 120 1C, 18 h. GC yield. 1.0 mol% of the
catalyst, 2.0 mol% of additives, 20 mol% of KtOBu as a base and 1,4-
dioxane (3.0 mL) as a solvent were used and run at 100 1C.
catalysts based on ruthenium exhibit catalytic activities for hydro-
genation of amides to give the corresponding primary alcohols. In
some reports, however, a mixture of secondary amines, alcohols,
and alkylated amides was formed when using a ruthenium
complex with a tridentate phosphine ligand.15 Recently, pincer such as Zn(OCOCF3)2, dramatically increased the yield of the
ligands,16,17 a pyridyl amine ligand,18 and P,N ligands19,20 were hydrogenated product for Ru-catalyzed hydrogenation of amides
utilized to synthesize ruthenium catalysts active for amide hydro- under mild conditions.
genation, but rather severe reduction conditions were required.
We began with catalytic hydrogenation of N-methylbenzamide
We found that the addition of catalytic amounts of zinc salt, using a ruthenium complex bearing a P,N ligand (L1)21 with
NaOMe in isopropyl alcohol under hydrogen pressure (3.0 MPa)
at 120 1C for 18 h, and almost no reaction was observed (Table 1,
Department of Chemistry, Graduate School of Engineering Science,
Osaka University, and CREST, JST, Toyonaka, Osaka 560-8531, Japan.
E-mail: mashima@chem.es.osaka-u.ac.jp; Fax: +81-6-6850-6249;
Tel: +81-6-6850-6248
entry 1). The addition of catalytic amounts of zinc triflate for the
hydrogenation of N-methylbenzamide dramatically increased the
yield (53%) of benzyl alcohol (entry 2). Based on the positive effect
of the addition of a zinc salt, we screened a variety of zinc salts
(Table 1). Zinc chloride increased the yield of the product (entry 3),
whereas zinc bromide and zinc iodide did not (entries 4 and 5).
† Electronic supplementary information (ESI) available: Experimental details,
characterization data, and crystal data of 4. CCDC 1013588. For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/c4cc04481a
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Table 2 Hydrogenation of amides catalyzed by [RuCl2(L1)2]a
Zn(OAc)2 and Zn(OCOCF3)2 were also effective for the present
system (entries 6 and 7). We previously reported that tetra-
nuclear zinc clusters exhibit higher activity in transesterification
than mononuclear zinc salts.22 Thus, we used a tetranuclear zinc
cluster as an additive and observed moderate effects for the
present reaction (entry 8). We finally selected Zn(OCOCF3)2 as
the best additive for amide hydrogenation.23 The additive/
catalyst ratio was also important for determining the efficiency
of the present reaction. Changing the additive/catalyst ratio to
2 : 1 had little effect on the yield of the desired product, and large
amounts of additive were detrimental (see ESI†). To achieve a
more efficient catalytic system, we screened both the base and
solvent. The highest yield was produced using KOtBu as the base.
Among the solvents we examined (i.e., toluene, hexane, CH2Cl2,
MeCN, and THF), we selected 1,4-dioxane as the best solvent.
Further optimization provided a high yield (95%), even at a lower
temperature (100 1C) (entry 9). Consequently, we selected the
Yieldb (%)
99e
Amide
Entry
1c
Product
1b
2c
1c
80e
81
3d
1d
optimized conditions with KOtBu as the base and 1,4-dioxane as 4d
the solvent at 100 1C for 18 h.
1e
1f
28
We next explored the scope of amides under the optimized
conditions (Table 2). Initially, we examined N-methyl benzamide
derivatives. An electron-withdrawing group at the para-position
5d
13e
enhanced the reactivity of the substrates for hydrogenation (entries
1 and 2). On the other hand, substrates with an electron-donating
6d
7d
8c
9c
1g
1h
1i
68
group required a relatively longer reaction time (entries 3 and 4).
Sterically congested substrates such as ortho-substituted substrates
retarded the reaction (entries 5 and 6). In the hydrogenation of
3-carbamoyl indole (1h), both the amide bond and indole skeleton
were hydrogenated to give 2h selectively (entry 7). We then turned
our attention to the substituents on the nitrogen. A tertiary amide
was a good substrate for the present hydrogenation (entry 8). With
regard to the substituent on the secondary amides, an aryl group
accelerated the reaction, probably due to a decrease in amide
resonance (entry 9), whereas a bulky normal propyl and a cyclohexyl
group retarded the reaction (entries 10 and 11). Unfortunately, a
primary amide could not be applied to the present system
(entry 12).
55
499 f
499 f
1j
2a
We conducted a lactam reduction to evaluate the mechanism for
which there are two possible routes, C–N bond cleavage and CQO
bond cleavage, depending on the catalysis and ring size.20 In our
system, C–N bond cleavage was observed using a seven-membered
lactam. Hydrogenation of e-caprolactam proceeded to afford amino-
alcohol in 77% yield and no CQO bond cleavage product [eqn (1)].
In contrast, cyclic amine was obtained using a six-membered lactam
with the concomitant formation of aminoalcohol [eqn (2)]. The
selectivity between CQO cleavage and C–N cleavage was similar to
that in a previously reported Ru-catalyzed amide hydrogenation.20
This selectivity can be explained by the elimination step from the
hemiaminal intermediate. Based on the results observed in Table 2,
the major route is nitrogen elimination from the hemiaminal
intermediate to initially produce the corresponding aldehyde, which
is further hydrogenated to give the corresponding alcohol (C–N bond
cleavage). In the case of the six-membered lactam, oxygen elimina-
10c
1k
1l
2a
2a
2a
80 f
11c,d
61 f
12c
1m
Trace f
a
Reaction conditions: a mixture of [RuCl2(L1)2] (0.020 mmol), amide
(1.0 mmol), KOtBu (0.20 mmol), and Zn(OCOCF3)2 (0.040 mmol) in 1,4-
dioxane (3.0 mL) was stirred under 3.0 MPa hydrogen pressure at
b
c
100 1C, 18 h. Isolated yield. 0.010 mmol of the catalyst and
d
e
0.020 mmol of the zinc salt were used. Run for 45 h. NMR yield.
f
GC yield.
tion competed with nitrogen elimination, probably due to the for intramolecular attack. Oxygen elimination gave cyclic imine, and
re-formation of the hemiaminal intermediate by an intramolecular subsequent hydrogenation afforded cyclic amine (CQO bond
attack of the amine on the aldehyde oriented in a suitable position cleavage).
11212 | Chem. Commun., 2014, 50, 11211--11213
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synthetic protocol for hydrogenating amides. Further application
of the ruthenium complex–zinc salt combination is currently
under investigation in our laboratory.
This work was financially supported by The Core Research
for Evolutional Science and Technology (CREST) program of the
Japan Science and Technology Agency (JST) and a Grant-in-Aid
for Young Scientists (B) (No. 25810062) from MEXT, Japan. T.H.
expresses his special thanks for the financial support provided
by the JSPS Research Fellowship for Young Scientists.
(1)
(2)
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To gain additional insight into the effects of the best additive
Zn(OCOCF3)2, we performed controlled NMR experiments. When
the ruthenium complex [RuCl2(L1)2] was mixed with Zn(OCOCF3)2
in the presence of KOtBu in 1,4-dioxane-d8, a new singlet peak
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catalytic activity (Table 1, entry 1), the isolated complex 4 exhibited
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to afford 2a in 83% yield, suggesting that incorporation of a
trifluoroacetate ligand into the ruthenium center was essential
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23 Other metal salts also had additive effects on amide hydrogenation.
See Table S1 (ESI†).
In conclusion, we found that Zn(OCOCF3)2 had unique
additive effects on Ru-catalyzed hydrogenation of amides under
mild conditions. This catalytic system could be applied to the
hydrogenation of various amides, giving the corresponding
primary alcohols in good yield. Such a simple combination of
the ruthenium complex and the zinc salt provides a conventional
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Chem. Commun., 2014, 50, 11211--11213 | 11213