Direct amide synthesis from either alcohols or aldehydes with amines: Activity of Ru(II) hydride and Ru(0) complexes

Article abstract of DOI:10.1021/jo100254g

An in situ generated catalyst from readily available RuH ₂(PPh₃)₄, an N-heterocyclic carbene (NHC) precursor, NaH, and acetonitrile was developed. The catalyst showed high activity for the amide synthesis directly from either alcohols or aldehydes with amines. When a mixture of an alcohol and an aldehyde was reacted with an amine, both of the corresponding amides were obtained with good yields. Homogeneous Ru(0) complexes such as (⁴-1,5-cyclooctadiene)(⁶-1,3,5- cyclooctatriene)ruthenium [Ru(cod)(cot)] and Ru₃(CO)₁₂ were also active in the amidation of an alcohol or an aldehyde with the help of an in situ generated NHC ligand.

Full text of DOI:10.1021/jo100254g

pubs.acs.org/joc
Direct Amide Synthesis from Either Alcohols or Aldehydes with Amines:
Activity of Ru(II) Hydride and Ru(0) Complexes
Senthilkumar Muthaiah, Subhash Chandra Ghosh, Joo-Eun Jee, Cheng Chen, Jian Zhang,
and Soon Hyeok Hong*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
hongsh@ntu.edu.sg
Received February 12, 2010
An in situ generated catalyst from readily available RuH2(PPh3)4, an N-heterocyclic carbene (NHC)
precursor, NaH, and acetonitrile was developed. The catalyst showed high activity for the amide
synthesis directly from either alcohols or aldehydes with amines. When a mixture of an alcohol and an
aldehyde was reacted with an amine, both of the corresponding amides were obtained with good
yields. Homogeneous Ru(0) complexes such as (η4-1,5-cyclooctadiene)(η6-1,3,5-cyclooctatriene)-
ruthenium [Ru(cod)(cot)] and Ru3(CO)12 were also active in the amidation of an alcohol or an
aldehyde with the help of an in situ generated NHC ligand.
Introduction
oxidative amidation of aldehydes with primary amines has been
reported using Cu,5 Pd,6 Rh,7 Ru,8 and lanthanide9,10 complexes.
Recently, several groups have reported direct amide synthesis
even from alcohols with amines using Ru-,8,11-15 Rh-,16 and Ag-
based17 catalytic systems by liberating two molecules of hydro-
gen.18 The direct acylations of amines with alcohols or aldehydes
are highly desired atom economical transformations that evolve
The amide bond is a key functional group in organic and
biological chemistry.1 Beyond conventional methods toward
the synthesis of amides,2 many alternative strategies have
been reported.3 The importance of the alternative strategies
for the amide synthesis was adequately demonstrated by Tani
and Stoltz for the synthesis of 2-quinuclidonium tetrafluoro-
4
borate using an intramolecular Schmidt-Aube reaction.
Among the alternative strategies, transition-metal-catalyzed
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Synth. Catal. 2009, 351, 2643.
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3002 J. Org. Chem. 2010, 75, 3002–3006
Published on Web 04/06/2010
DOI: 10.1021/jo100254g
r
2010 American Chemical Society

Muthaiah et al.
JOCArticle
SCHEME 1. Proposed [Ru]H2-Mediated Mechanism
hydride complexes. Herein, we report an in situ generated
catalyst based on RuH2(PPh3)4 for the efficient direct amide
synthesis whether from alcohols or aldehydes with primary
and secondary amines. To the best of our knowledge, this is the
first example of a transition-metal-based catalytic system that
efficiently transforms either alcohols or aldehydes into amides
under the same reaction condition by a single step.
Results and Discussion
Optimization of Reaction Conditions. A reaction of 2-phenyl-
ethanol (7) with benzylamine (8) was chosen as a model to
investigate Ru hydride based catalytic systems for the amida-
tion of alcohols (Table 1). RuH2(PPh3)4 itself afforded a trace
amount of 9 (entry 1). With the help of an in situ generated
NHC ligand, the yield was dramatically improved (entry 2).
Various supporting ligands were screened along with other Ru
hydride complexes. It was interesting to see economical acet-
onitrile most effective rather than oxidation-susceptible phos-
phines, such as PCy3, as we observed the same trend in the
[Ru]Cl2-based catalytic systems.14 Readily available RuH2-
(PPh3)4 showed the highest activity of the Ru hydride sources
screened. Among the tested NHC precursors (Figure 1), diiso-
propylimidazolium bromide (1) exhibited the best yield, also
consistent with previous reports (entries 10-14).12,14 Next we
applied some of the Ru hydride based conditions to the reaction
of benzaldehyde (10) and benzylamine (Table 2). To our
hydrogen as a sole byproduct with less waste than traditional
amide synthesis that often produces toxic chemical waste with
tedious procedures.
Although it is logically proposed that the direct amidation
of alcohols catalyzed by Ru complexes occurs through alde-
hydes generated by oxidation of alcohols, the reported NHC-
promoted Ru catalytic systems showed limited or no activity
on the amidation of aldehydes.12,14,15 To address the problem,
our group proposed a [Ru]H2-mediated mechanism with
experimental evidence that the limited activity from the alde-
hydes was due to the not facile generation of the active [Ru]H2
catalytic intermediate without the help of primary alcohols
(Scheme1).15 From the mechanistic insight, we postulated that
an active catalyst that can transform either alcohols or alde-
hydes to amides with amines could be developed from Ru
TABLE 1. Catalyst Screening for the Amidation of 7 with 8a
FIGURE 1. NHC precursors.
entry
catalyst
NHC precursor base ligand yieldb (%)
<3
TABLE 2. Catalyst Screening for the Amidation of an Aldehyde 10a
1
2
3
4
5
6
7
8
9
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
RuH2(PPh3)4
1
1
1
1
1
1
1
1
2
3
4
5
6
2
3
4
5
6
1
1
1
1
1
1
1
1
1
1
NaH
47
92
79
55
74
55
61
6
54
32
67
17
31
23
9
NaH CH3CN
KOtBu CH3CN
NaH pyridine
NaH PPh3
NaH PCy3
NaH PCy2Ph
NaH DPPE
NaH CH3CN
NaH CH3CN
NaH CH3CN
NaH CH3CN
NaH CH3CN
NaH PPh3
NaH PPh3
NaH PPh3
NaH PPh3
NaH PPh3
NaH CH3CN
NaH pyridine
NaH PPh3
NaH PCy3
NaH PPh3
entry
catalyst
ligand
yieldb (%)
1
2
3
4
5
6
RuH2(PPh3)4
RuH2(PMe3)4
RuH2(CO)(PPh3)3
RuH2(CO)(PPh3)3
RuH2(CO)(PPh3)3
RuHCl(CO)(PPh3)3
CH3CN
CH3CN
CH3CN
pyridine
PPh3
96
21
87
74
57
49
10 RuH2(PPh3)4
11 RuH2(PPh3)4
12 RuH2(PPh3)4
13 RuH2(PPh3)4
14 RuH2(PPh3)4
15 RuH2(PPh3)4
16 RuH2(PPh3)4
17 RuH2(PPh3)4
CH3CN
aRu complex (5 mol % of [Ru]), NHC-precursor (5 mol %), base
(20 mol %), ligand (5 mol %), aldehyde (1 equiv), amine (1.1 equiv), toluene,
reflux, 24 h. bDetermined by GC using dodecane as an internal standard.
12
9
18 RuH2(PPh3)4
19 RuH2(PPh3)4
10
86
80
58
56
80
80
75
76
37
20
20 RuH2(CO)(PPh3)3
21 RuH2(CO)(PPh3)3
22 RuH2(CO)(PPh3)3
23 RuH2(CO)(PPh3)3
24 RuHCl(CO)(PPh3)3
25 RuHCl(CO)(PPh3)3
26 RuHCl(CO)(PPh3)3
27 RuHCl(CO)(PPh3)3
28 Shvo catalyst
SCHEME 2. RuH2(PPh3)4-Catalyzed Amidationa
NaH CH3CN
NaH pyridine
NaH PCy3
NaH CH3CN
NaH CH3CN
29 RuH2(PMe3)4
aRu complex (5 mol % of [Ru]), NHC-precursor (5 mol %), base
(20 mol %), ligand (5 mol %), alcohol (1 equiv), amine (1.1 equiv), toluene,
reflux, 24 h. bDetermined by GC using dodecane as an internal standard.
aIsolated yields, average of two runs
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Muthaiah et al.
JOCArticle
TABLE 3. Direct Amide Synthesis from Alcohols and Aminesa
TABLE 4. Direct Amide Synthesis from Aldehydes and Aminesa
aRuH2(PPh3)4 (5 mol %), 1 (5 mol %), NaH (20 mol %), CH3CN
(5 mol %), alcohol (1 equiv), amine (1.1 equiv), toluene, reflux, 24 h,
unless otherwise noted. bIsolated yields, average of at least two runs.
c48 h.
aRuH2(PPh3)4 (5 mol %), 1 (5 mol %), NaH (20 mol %), 5 mol %
CH3CN, aldehyde (1 equiv), amine (1.1 equiv), toluene, reflux, 24 h,
unless otherwise noted. bIsolated yields, average of at least two runs.
cDetermined by GC using dodecane as an internal standard, average of
at least two runs. dYield of the corresponding imine, determined by GC
using dodecane as an internal standard.
delight, the RuH2(PPh3)4-based catalytic system showed ex-
cellent activity on the amidation of 10 as well (entry 1, Table 2),
realizing the idea of a Ru hydride based catalytic system for the
amidation of both alcohols and aldehydes under the same
reaction conditions (Scheme 2).
hemiaminal Ru intermediates affects the fate of the hemi-
aminal intermediate as to whether to produce an imine by
elimination of water (or an alkylated amine by further
reduction of the generated imine) or to produce an amide
by further oxidation.12-15 Similar [(arene)RuCl2]2-based
catalytic systems produced the different product, either the
alkylated amine or the amide, depending on the nature of
supporting L-type ligands.13-15,19
Proposed Mechanism. The proposed Ru(0)/Ru(II) cycle
(Scheme 1) from the previous study was supported on the
basis of the observation of elimination of hydrogen from an
NMR reaction between RuH2(PPh3)4, 1, and NaH under the
reaction conditions. At 115 °C, the hydride peak of the
catalytic mixture observed at ambient temperature comple-
tely disappeared within 30 min, strongly indicating elimina-
tion of hydrogen at the reaction temperature. Similar
mechanisms involving [Ru]H2 have been proposed in Ru-
catalyzed N-alkylation of amines with alcohols19,20 and
Amidation of Alcohols. The scope of the RuH2(PPh3)4-
catalyzed amidation reaction of alcohols and amines is
presented in Table 3. Excellent yields were obtained when
sterically less hindered substrates were reacted (entries 1-5).
Cyclic secondary amines and sterically hindered substrates
showed diminished activity (entries 6 and 7). The use of
5-hexen-1-ol gave hexanamide with 100% reduction of the
double bond (entry 8) as reported.12,14 Intramolecular amida-
tion was also carried out by using 5-amino-1-pentanol with
excellent formation of a lactam, showing significant improve-
ment over the previous RuH2(PPh3)4 and hydrogen acceptor
system reported by Naota and Murahashi (92% vs 65%,
entry 9).8
Amidation of Aldehydes. The same reaction conditions
were applied to the amidation reactions of aldehydes, and
moderate to excellent yields were obtained (Table 4). The
reactions of aryl aldehydes proceeded smoothly with pri-
mary amines and cyclic secondary amines. We studied
electronic effect on aldehyde using benzyl alcohol and ben-
zaldehyde derivatives, but there is no explicit trend in the
yields (entries 3, 10, and 11, Table 3 and entries 1-7, Table 4).
In case of alkyl aldehydes, slightly reduced yields were
obtained with the observation of imine byproducts (entries
9-11). It has been proposed that electronic variation on the
(19) Hamid, M.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum,
H. C.; Watson, A. J. A.; Williams, J. M. J. J. Am. Chem. Soc. 2009, 131, 1766
and more therein.
(20) For early examples of the N-alkylation of amines with aliphatic
alcohols, see: (a) Murahashi, S.-I.; Kondo, K.; Hakata, T. Tetrahedron Lett.
1982, 23, 229. (b) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai,
N. J. Chem. Soc., Chem. Commun. 1981, 611. (c) Watanabe, Y.; Tsuji, Y.; Ige,
H.; Ohsugi, Y.; Ohta, T. J. Org. Chem. 1984, 49, 3359.
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Muthaiah et al.
JOCArticle
SCHEME 3. Reactions of a Mixture of an Aldehyde and an Alcohola
aDetermined by GC using dodecane as an internal standard; the yields are calculated on the basis of 10 or 12 individually.
TABLE 5. Activity of Ru(0) Complexes on the Amidation of 2-Pheny-
lethanol (7) or Benzaldehyde (10) with Benzylamine (8)a
entry
substrate
catalyst
base (mol %)
amideb (%)
1
2
3
4
5
6
7
7
7
7
10
10
Ru(cod)(cot)
Ru3(CO)12
Ru black
Ru on Al2O3
Ru(cod)(cot)
Ru3(CO)12
NaH (15)
NaH (30)
NaH (15)
NaH (15)
NaH (40)
NaH (40)
83
59
19
15
88
41
aCatalyst (5 mol % of [Ru]), 1 (5 mol %), NaH, 7 or 10 (1 equiv), 8 (1.1
equiv), toluene, reflux, 24 h. bDetermined by GC using dodecane as an
internal standard.
esterification of alcohols.21 On the basis of the proposed
mechanism, we believe that usage of [Ru]H2 is the key to the
improvement on aldehydes over the reported [Ru]Cl2, which
showed limited activity on amidation of aldehyde.22
In relation with Ru(0) involvement, Ru3(CO)12, (η4-1,5-
cyclooctadiene)(η6-1,3,5-cyclooctatriene)ruthenium [Ru(cod)-
(cot)], and other heterogeneous Ru(0) complexes were screened
for the amidation reaction of 7 and 10 in the presence of 1 and
NaH (Table 5). Ru3(CO)12 and Ru(cod)(cot) complexes
showed good activity whether starting from an alcohol 7 or
an aldehyde 10 (entries 1, 2, 5, and 6). The in situ generated
NHC ligand was essential to make Ru(0) species active. No
activity was observed without 1and a strong base. The screened
heterogeneous Ru sources were not as active as homogeneous
Ru(0) complexes (entries 3 and 4). Attempts to increase the
activity by adding other ligands, such as pyridine, acetonitrile,
and phosphines, were not successful. The requirement of
increased amounts of NaH, more than for generation of the
NHC ligand, was noticed (entries 2, 5, and 6). The reason is
not clear, and we think that the role of substoichiometric
base is to prevent elimination of water and facilitate the
dehydrogenation of the hemiaminal or activate precatalyst
from generated alkoxides. It has been reported that a strong
base was required to generate catalytically active species in
the case of well-defined (arene)Ru(NHC)Cl2 complexes.15
Ru3(CO)12 and Ru(cod)(cot) complexes were reported
FIGURE 2. Comparison of reaction progress monitored by GC.
active for the alkylation of amines with alcohols under
different conditions.23
Reactivity and Selectivity Difference between Aldehyde and
Alcohol. To see whether alcohol or aldehyde is more reactive
under our catalytic systems, at first, reaction progress was
individually monitored by GC (Figure 2). The reaction with
benzaldehyde was faster than that with benzyl alcohol,
especially at the initial stage, as expected because one
more dehydrogenation step is required for the amidation
of alcohol. Retarded reaction rates were observed in both
reactions as the reactions progressed, suggesting decomposi-
tion of the active catalyst.
Selectivity between an aldehyde and an alcohol was also
examined (Scheme 3). When a reaction mixture (10:12:8 =
1:1:2.2) was reacted, both of the corresponding amides were
obtained in good yields, demonstrating the advantage of the
methodology of direct amide synthesis whether from alco-
hols or aldehydes. However, when we used a decreased
amount of an amine (10:12:8 = 1:1:1.1), we obtained a
mixture of products with observation of benzyl alcohol
during the reaction, showing no selectivity between alcohol
and aldehyde with transfer hydrogenation from 12 to 10.
(21) (a) Murahashi, S.-I.; Ito, K. I.; Naota, T.; Maeda, Y. Tetrahedron
Lett. 1981, 22, 5327. (b) Murahashi, S.-I.; Naota, T.; Ito, K.; Maeda, Y.;
Taki, H. J. Org. Chem. 1987, 52, 4319. (c) Zhao, J.; Hartwig, J. F.
Organometallics 2005, 24, 2441.
(22) For some examples of NHC-based Ru hydride complexes on hydro-
gen tranfer reactions, see: (a) Ledger, A. E. W.; Mahon, M. F.; Whittlesey,
M. K.; Williams, J. M. J. Dalton Trans. 2009, 6941. (b) Burling, S.;
Whittlesey, M. K.; Williams, J. M. J. Adv. Synth. Catal. 2005, 347, 591.
(c) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.; Shermer, D. J.;
Whittlesey, M. K.; Williams, J. M. J.; Edney, D. D. Chem. Commun. 2004, 90.
(23) (a) Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T. J. Org.
Chem. 1996, 61, 4214. (b) Tillack, A.; Hollmann, D.; Michalik, D.; Beller, M.
Tetrahedron Lett. 2006, 47, 8881. (c) Hollmann, D.; Tillack, A.; Michalik, D.;
Jackstell, R.; Beller, M. Chem.-Asian J. 2007, 2, 403. (d) Tillack, A.;
Hollmann, D.; Mevius, K.; Michalik, D.; Bahn, S.; Beller, M. Eur. J. Org.
Chem. 2008, 4745.
Conclusions
In conclusion, we have demonstrated that an in situ
generated Ru catalyst can synthesize amides directly from
either alcohols or aldehydes with amines. The developed
catalyst is operatively simple and more active, especially
toward aldehyde substrates, than the previously reported
J. Org. Chem. Vol. 75, No. 9, 2010 3005

Muthaiah et al.
JOCArticle
well-defined (p-cymene)(NHC)RuCl2-type catalysts. When
the reaction rate was compared, benzaldehyde was trans-
formed to N-benzylbenzamide faster than benzyl alcohol
especially at the initial stage. If a mixture of benzaldehyde
and 1-hexanol was reacted with benzylamine, both of the
corresponding amides were formed with good yields. To
understand the nature of active catalytic intermediates, some
Ru(0) species were screened. Homogeneous Ru(0) com-
plexes such as Ru(cod)(cot) and Ru3(CO)12 were active in
the amidation of alcohol or aldehyde with the help of an in
situ generated NHC ligand suggesting that the proposed
Ru(0)/Ru(II) cycle is viable.
General Procedure for the Amide Synthesis. RuH2(PPh3)4 (28mg,
0.025 mmol), 1,3-diisopropylimidazolium bromide (5.8 mg, 0.025
mmol), NaH (2.4 mg, 0.1 mmol), and acetonitrile (1.2 μL, 0.025
mmol) were placed in an oven-dried Schlenk tube inside the glove-
box; toluene (0.6 mL) was added to the mixture. The Schlenk tube
was taken out and heated to reflux in an oil bath under an argon
atmosphere. The flask was removed from the oil bath after 20 min,
and the alcohol or aldehyde (0.50 mmol) and amine (0.55 mmol)
were added. The mixture was heated to reflux under a flow of argon
to facilitate removal of hydrogen for 24 h. The reaction mixture was
cooled to room temperature. The solvent was removed in vacuo,
and the residue was purified by silica gel flash column chro-
matography to afford the amide. All of the amides, N-benzyl-2-
phenylacetamide,14 N-hexyl-2-phenylacetamide,14 N-benzylbenza-
mide,14 N-benzylhexanamide,14 phenyl(piperidin-1-yl)methanone,14
N-benzylpivalamide,14 piperidin-2-one,14 N-benzyl-4-methoxyben-
zamide,15 N-benzyl-4-fluorobenzamide,31 N-benzyl-4-methylbenza-
mide,32 N-benzyl-4-chlorobenzamide,32 piperidin-1-yl(p-tolyl)-
methanone,10 (4-chlorophenyl)(piperidin-1-yl) methanone,10
N-hexylbenzamide,33 N-pentylhexanamide,14 and N-benzylnona-
namide,34 were identified by spectral comparison with literature
data.
Experimental Section
General Considerations. All reactions were carried out using
standard Schlenk techniques or in an argon-filled glovebox.
Toluene, hexane, and ether were dried over a solvent purifica-
tion system.24 Deuterated solvents were dried over molecular
sieves. 1H and 13C NMR spectra at 400 and 100 MHz, respec-
tively, were recorded in CDCl3 using tetramethylsilane as a
reference. GC analyses were carried out using dodecane as an
internal standard. Mass spectrometry was performed using
electrospray ionization (ESI) mode. Anhydrous acetonitrile,
1,3-(2,6-diisopropylphenyl)imidazolium chloride, and 1,3-bis-
(2,4,6-trimethylphenyl)imidazolium chloride were purchased
and used without further purification. Ru3(CO)12, Ru black,
and Ru on Al2O3 were purchased from Strem Chemicals and
used without further purification. 1,3-Dimethylimidazolium
iodide,25 1,3-diisopropylimidazoliumbromide,26 RuH2(PPh3)4,27
RuH2(PMe3)4,28 RuH2(CO)(PPh3)3,29 RuHCl(CO)(PPh3)3,29
and Ru(cod)(cot)30 were prepared according to the reported
procedures.
N-Pentyl-2-furancarboxamide35. Purified by silica gel column
chromatography using hexane/ethyl acetate (3:1) solvent mixture
as an eluent. Pale yellow liquid. Yield: 78%. 1H NMR (CDCl3) δ
7.4 (m, 1H), 7.0 (m, 1H), 6.5 (m, 1H), 6.4 (bs, 1H), 3.4 (m, 2H), 1.6
(m, 2H), 1.3 (m, 4H), 0.9 (t, 3H); 13C NMR (CDCl3) δ 158.5,
148.2, 143.6, 114.0, 112.1, 39.2, 29.5, 29.1, 22.5, 14.0. HRMS
(ESI) calcd for C10H15NO2: 182.1181. Found: 182.1182 [MHþ].
Acknowledgment. We thank the Singapore National Re-
search Foundation for generous support of this research (NRF-
RF2008-05). C.C. and J.Z. gratefully acknowledge Nanyang
Technological University for graduate student scholarships.
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