Ruthenium-Catalyzed Reductive Amidation without an External Hydrogen Source

Article abstract of DOI:10.1002/ejoc.201701527

A catalytic reaction between aldehydes and primary amides that leads to N-alkylated amides was investigated. The developed protocol employs carbon monoxide as a deoxygenative agent and, therefore, avoids the use of an external hydrogen source. Cyclopentad

Full text of DOI:10.1002/ejoc.201701527

A Journal of
Accepted Article
Title: Ruthenium-catalyzed reductive amidation without an external
hydrogen source
Authors: Niyaz Z Yagafarov, Karim Muratov, Klim Biriukov, Dmitry
Usanov, Olga Chusova, Dmitry S Perekalin, and Denis
Chusov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701527
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10.1002/ejoc.201701527
European Journal of Organic Chemistry
FULL PAPER
Ruthenium-catalyzed reductive amidation without an external
hydrogen source
Niyaz Z. Yagafarov,[a] Karim M. Muratov,[a] Klim Biriukov,[a] Dmitry L. Usanov,[b] Olga Chusova,[c] Dmitry
S. Perekalin,[a] and Denis Chusov*[a,c]
Abstract: The catalytic reaction of aldehydes with primary amides
leading to N-alkylated amides was investigated. The developed
protocol employs carbon monoxide as a deoxygenative agent and
therefore allows to avoid an external hydrogen source.
Cyclopentadienyl ruthenium complexes demonstrated excellent
catalytic efficiency and could be used at as low as 0.5-1 mol %
catalyst loading. A representative number of secondary amides were
successfully prepared in 70-84% yields.
Introduction
From the point of view of sustainable development, the use of
industrial side products in chemical synthesis represents an
interesting and promising approach. Even though the worldwide
demand for carbon monoxide requires its directed synthesis, this
side product of steelmaking can be produced in large excess at
a given factory, and large amount of CO are ubiquitously
disposed of by simple burning into carbon dioxide. In this context,
we have been interested developing new atom- and step-
economical reactions, which employ carbon monoxide as
deoxygenative agent.1
The central role of amide bond in both natural biopolymers
and human-made materials renders development of efficient
methods for amide synthesis undoubtedly important.2 On the
grounds of our methodological paradigm we have recently
developed the first protocol for reductive amidation3 with carbon
monoxide catalysed by rhodium acetate.4 However, high cost of
rhodium represents
applications both in academic and industrial settings. Herein, we
describe detailed investigation of reductive amidation
a substantial obstacle for scaled-up
a
chemistry, which resulted in the development of catalytic system
based on ruthenium complexes.5
Figure 1. Ruthenium complexes tested in reductive amidation.
Results and Discussion
Unfortunately, poor results were observed for various
heterogeneous catalysts (Table 1, entries 2-9); catalytic activity
was detected only for rhodium-based systems. We then tested a
representative list of homogeneous ruthenium precatalysts
(Table 1, entries 10-27). We noticed that ruthenium complexes
with bulky cyclopentadienyl ligands (11-15, entries 22-27)
demonstrated superior results. Among those Cp*Ru(cod)Cl
complex has lower activity, presumably because of the difficult
dissociation of the Ru−Cl bond. We assume that all these
complexes generate similar catalytic species with a general
formula [(C5R5)Ru(CO)x]+.7 The cyclopentadienyl ligand protects
such species against side reactions and precipitation (note that
unsubstituted Cp ligand in complexes 2 and 7 is less efficient).8
The cationic ruthenium center plays a dual role; on one hand, it
acts as a Lewis base, which facilitates condensation of an amide
and an aldehyde. On the other hand, it coordinates CO ligand
and activates it towards nucleophilic attack of OH group, which
eventually gives CO2 and a hydride required for reduction (vide
We studied a number of potential catalysts for the model
reductive amidation of p-methoxybenzaldehyde with benzamide
in the presence of carbon monoxide6 (Figure 1, Table 1).
[a]
Nesmeyanov Institute of Organoelement Compounds of Russian
Academy of Sciences
119991, Vavilova St. 28, Moscow, Russian Federation
E-mail: denis.chusov@gmail.com
[b]
[c]
Department of Chemistry and Chemical Biology, Harvard University
12 Oxford Street, Cambridge, MA 02138, USA
Faculty of Science, RUDN University
6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701527
European Journal of Organic Chemistry
FULL PAPER
infra). Interestingly, the best catalysts, namely naphthalene 14
and anthracene 15 complexes displayed very similar activity in
acetonitrile and diethyl ether, however only 15 remained active
in toluene. After a number of tests, we chose anthracene
complex 15 for further optimization, not only due to its high
catalytic activity, but also because it is air-stable and can be
easily obtained from RuCl3.9
Table 2 shows the results of solvent and temperature
screening. Tetrahydrofuran, ethyl acetate, acetonitrile and
dichloromethane gave similar results (entries 3-6), whereas
lower yields were observed for reactions in alcohols (entries 1-2).
Highest yields were achieved in toluene and diethyl ether.
Increasing the temperature of the reaction from 130 to 150 °C
was important (36 vs. 78% yield); further heating led to slight
erosion of the yield. The influence of the pressure was found to
be insignificant, the reaction proceeded well even under 10 bar
of CO. We found that as low as 0.5 mol% of the catalyst can be
successfully employed, however, 0.1 mol% loading led to a
substantial drop of the yield. We separately screened conditions
for acetamide as a substrate and observed different trends
compared to benzamide reactions (see Supporting Information
Table 1. Screening of catalysts.
Entry
1[b]
2[b]
3[b]
4[c]
5[c]
6[b]
7[b]
8[b]
9[b]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Catalyst
Yield[a], %
for details). In particular, we observed
dependence of the reaction yields from the reaction temperature
with best results achieved at 160 °C (82% yield).
a
bell-shaped
Rh2(OAc)4
10
0
Ni/C
Pd/C
0
Table 2. Screening of solvents and temperature.
Ru/C (activated charcoal)
Ru/Al2O3 (Degussa type)
Rh/Al2O3
0
0
3
Rh/Al2O3 (Degussa type)
Rh/Al2O3 (act)
3
5
Entry
1
Solvent
Temperature, oC
Yield[a], %
Rh/C (activated charcoal)
CpRu(PPh3)2Cl (2)
Ru(acac)3
5
ethanol
130
130
130
130
130
130
130
130
130
140
150
160
170
180
4
0
2
methanol
9
1
3
tetrahydrofuran
ethyl acetate
acetonitrile
dichloromethane
neat
14
17
18
21
26
30
33
36
78
73
72
72
Ru3(CO)12 (3)
1
4
[(cod)RuCl2]2 (5)
2
5
[(benzene)RuCl2]2 (6)
CpRu(antracene)PF6 (7)
[(cod)Ru(CO)Cl2]2 (8)
[(p-cymene)RuCl2]2 (9)
[(C6Me6)RuCl2]2 (10)
RuCl3
2
6
2
7
4
8
toluene
5
9
diethyl ether
diethyl ether
diethyl ether
diethyl ether
diethyl ether
diethyl ether
8
10
11
12
13
14
11
1
[Ru(CO)3Br2]2 (4)
[Ru(CO)3Br2]2 (4) + KPF6
Cp*Ru(cod)Cl (11)
Cp*Ru(cod)Cl (11) + KPF6
Cp*Ru(naphthalene)BF4 (12)
Cp*Ru(MeCN)3PF6 (13)
(C5Me4OMe)Ru(naphthalene)PF6 (14)
(C5Me4OMe)Ru(antracene)PF6 (15)
9
7
8
[a] 0.2 mmol scale. Yields were determined by NMR.
13
14
17
18
With the optimized conditions in hand, we tested the
substrate scope of Ru-mediated amidation (Figure 2). High
yields were observed for substrates with various substitution
patterns (1a-1o). Only aliphatic aldehydes (1q) and aromatic
aldehydes with electron-acceptor substituents (e.g. CF3), (1p)
showed lower yields, which might be due to formation of by-
products cause by high electrophilicity. The opposite situation
was previously observed in rhodium-catalyzed reductive
[a] 0.2 mmol scale. Yields were determined by NMR. [b] MeCN was used as a
solvent; THF was used as a solvent in all other cases.
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10.1002/ejoc.201701527
European Journal of Organic Chemistry
FULL PAPER
amidation with hydrogen gas, where aliphatic aldehydes gave
notably better results than aromatic ones.10 Benzyloxy group
was found to be stable under the reaction conditions; product
1m was isolated in 72% yield. No enhanced reactivity was
observed for electron-rich amides (e.g. 1a vs. 1o).
Aldehydes with electron-donating groups are more suitable with
ruthenium catalysis, whereas substrates with electron-
withdrawing groups are more suitable with rhodium catalysis.
We propose a possible mechanism based on the current
observations and previous DFT calculations1a (Figure 3). As
mentioned above, under atmosphere of carbon monoxide
complex 15 is expected to generate the active species
[(C5Me4OMe)Ru(CO)x]+ (A).7 The methoxy group of C5Me4OMe
ligand may help stabilize such species and prevent formation of
inactive clusters. Coordination of amide to A leads to complex B
and a protonated aldehyde, which activates it for the nucleophilic
addition to give C. Intramolecular attack of the hydroxyl moiety
on the carbonyl ligand (via D) can lead to species E. Its
decarboxylation (that is similar to Hieber base reaction11) gives
ruthenium hydride complex F, which intramolecularly reduces
the acyl-imine to give the amine product and the regenerated
catalyst. The amount of carbon dioxide in the gas phase after
the reaction in agreement with the amount of the product (see
SI).
Figure 3. Plausible mechanism of the catalytic reaction.
Figure
2. Substrate scope studies for the developed methodology. The
reactions were conducted at 150 °C for aromatic amides and at 160 °C for
aliphatic amides.
Conclusions
In summary, we developed a catalytic system for Ru-
catalyzed atom-economical reductive amidation of aldehydes.
The methodology takes advantage of the unique deoxygenative
potential of carbon monooxide and does not require an external
hydrogen source. A representative number of secondary amides
were prepared in 70-84% yields. The reaction works well for
various types of amides and aromatic aldehydes. The possible
mechanism for reduction via Hieber base-type reaction was
proposed.
Compare to our previous results with rhodium catalyzed
reaction4 we found a few differences. Generally, rhodium is
working better in different solvents but THF is the leading one.
For ruthenium catalyzed version toluene and diethyl ether is the
best choice. Generally, ruthenium catalysis is working better at 1
mol% of metal and rhodium at 2 mol% (1 mol% of dimer).
Rhodium acetate is less efficient in case of sterically hindered
substrates. Even ortho-methoxybenzaldehyde with acetamide
gave only 73% yield compare to 90% in case of catalyst 15.
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10.1002/ejoc.201701527
European Journal of Organic Chemistry
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Experimental Section
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.13)
to afford 51.0 mg (84%) of the product as a white crystals.
Unless otherwise stated, all reagents were purchased from commercial
suppliers and used without further purification (THF was distilled over
sodium/benzophenone, methanol was distilled over Mg). Carbon
monoxide of >98% purity was obtained from NII KM (Moscow, Russia).
Isolation of products on less than 200 mg scales was performed by
preparative TLC (Macherey-Nagel, Silica gel 60 GF254, fluorescence
quenching with UV light at 254 nm); hexane-ethyl acetate system was
used as eluent. 1H and 13C NMR spectra were recorded on Bruker AV-
300, AV-400 and AV-600 spectrometers at ambient temperature.
Chemical shifts δ are reported in ppm using the solvent resonance signal
as an internal standard. NMR yields were calculated with HMDS
(hexamethyldisiloxane) as an internal standard (unless otherwise noted).
The following abbreviations were used to designate chemical shift
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad; coupling constants are given in Hertz (Hz). HRMS (ESI-MS):
spectra were recorded on Bruker micrOTOF II and Maxis instruments
under electrospray ionization (ESI) conditions in a positive ion mode
(interface capillary voltage: 4500 V) with a mass range m/z 50–3000 Da;
external and internal calibrations were performed with Electrospray
Calibrant Solution. All samples for ESI-MS were prepared in MeCN;
syringe injections were used (flow rate: 3 μL/min). Nitrogen was applied
as a dry gas; interface temperature was set at 180 oС. The spectra were
processed with DataAnalysis software package.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.18 (d, J = 8.5 Hz, 2H), 6.83 (d, J =
8.5 Hz, 2H), 6.04 (br. s, 1H), 4.31 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H), 1.96
(s, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.9, 158.9, 130.3, 129.1, 114.0,
55.2, 43.1, 23.1;
N-(4-methylbenzyl)acetamide (1c): Cp*OMeRu(antracene)PF6 (2.0 mg,
1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and p-
methylbenzaldehyde (0.041 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 80% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.23)
to afford 40.0 mg (72%) of the product as a white crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.15 (q, J = 8.2 Hz, 4H), 5.88 (br. s,
1H), 4.36 (d, J = 5.6 Hz, 2H), 2.33 (s, 3H), 1.99 (s, 3H);
Procedure: A 10 mL stainless steel autoclave was charged with 1 mol%
of catalyst, the corresponding solvent, 1 eq. of the amine and 1 eq. of the
amide. The autoclave was sealed, flushed three times with 10 atm of CO,
and then charged with the indicated pressure of CO. The reactor was
placed into a preheated oil bath. After the indicated time, the reactor was
cooled to room temperature and depressurized. The reaction mixture
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.8, 137.2, 135.2, 129.3, 127.8,
43.5, 23.2, 21.0;
N-(4-(benzyloxy)benzyl)acetamide (1d): Cp*OMeRu(antracene)PF6
(2.0 mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol)
and p-benzyloxybenzaldehyde (72 mg, 1 eq, 0.34 mmol) were dissolved
in diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 80% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.13)
to afford 64.0 mg (74%) of the product as a white crystals.
was transferred into
a flask and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. The residue was purified by flash chromatography on silica
gel.
N-(4-methoxybenzyl)benzamide (1a): Cp*OMeRu(antracene)PF6 (1.9
mg, 1 mol%, 0.0033 mmol), benzamide (40 mg, 1 eq, 0.33 mmol) and p-
methoxybenzaldehyde (0.04 mL, 1 eq, 0.33 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 150 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 78% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (5:1); Rf=0.20)
to afford 56.0 mg (70%) of the product as a white crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.43-7.30 (m, 5H), 7.20 (d, J = 8.6
Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 5.77 (br. s, 1H), 5.05 (s, 2H), 4.35 (d, J
= 5.6 Hz, 2H), 1.99 (s, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.8, 158.2, 136.8, 130.6, 129.2,
128.6, 128.0, 127.4, 115.0, 70.0, 43.2, 23.3;
1H NMR (CDCl3, 300 MHz, 25 °C) δ 7.76 (d, J = 7.4 Hz, 2H), 7.46 (t, J
=7.4 Hz, 1H), 7.42 (t, J =7.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 6.85 (d, J
= 8.4 Hz, 2H), 6.61 (br. s, 1H), 4.53 (d, J = 5.5 Hz, 2H), 3.77 (s, 3H);
N-(naphthalen-2-ylmethyl)acetamide (1e): Cp*OMeRu(antracene)PF6
(2.0 mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol)
and 2-naphtaldehyde (53 mg, 1 eq, 0.34 mmol) were dissolved in diethyl
ether (0.2 mL). The autoclave was sealed, flushed three times with 10
atm of CO, and then charged with 30 atm CO. The reactor was placed
into an oil bath preheated to 160 °C. After 22 h the reactor was cooled to
room temperature and depressurized. The reaction mixture was
13C NMR (CDCl3, 100 MHz, 25 °C) δ 167.3, 159.0, 134.4, 131.4, 130.3,
129.2, 128.5, 126.9, 114.1, 55.2, 43.5;
transferred into
a flask, and the autoclave was washed with
N-(4-methoxybenzyl)acetamide (1b): Cp*OMeRu(antracene)PF6 (2.0
mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and p-
methoxybenzaldehyde (0.041 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 93% yield by NMR. The residue was purified by preparative
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 76% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.18)
to afford 64.0 mg (71%) of the product as a white crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.82-7.77 (m, 3H), 7.68 (s, 1H),
7.49-7.44 (m, 2H), 7.37 (d, J = 8.4 Hz, 1H), 6.07 (br. s, 1H), 4.55 (d, J =
5.6 Hz, 2H), 2.02 (s, 3H);
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10.1002/ejoc.201701527
European Journal of Organic Chemistry
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13C NMR (CDCl3, 100 MHz, 25 °C) δ 170.0, 135.6, 133.3, 132.7, 128.5,
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 75% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.21)
to afford 47.0 mg (71%) of the product as white crystals.
127.6, 126.3, 126.3, 125.9, 125.9, 43.8, 23.2;
N-(2-methoxybenzyl)acetamide (1f): Cp*OMeRu(antracene)PF6 (2.0
mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and o-
methoxybenzaldehyde (0.041 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 90% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.20)
to afford 51.0 mg (82%) of the product as a white crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.16 (d, J = 8.7 Hz, 2H), 6.82 (d, J =
8.7 Hz, 2H), 6.01 (br. s, 1H), 4.31 (d, J = 5.6 Hz, 2H), 3.99 (q, J = 7.0 Hz,
2H), 1.97 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.9, 158.3, 130.1, 129.1, 114.5,
63.4, 43.1, 23.2, 14.7;
N-(2,5-dimethylbenzyl)acetamide (1j): Cp*OMeRu(antracene)PF6 (2.0
mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and
2,5-dimethylbenzaldehyde (0.048 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 75% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.35)
to afford 43.0 mg (71%) of the product as white crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.27-7.24 (m, 2H), 6.92-6.86 (m, 2H),
6.07 (br. s, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.84 (s, 3H), 1.96 (s, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.8, 157.5, 129.8, 128.8, 126.2,
120.6, 110.2, 55.3, 39.4, 23.3;
N-(3-methoxybenzyl)acetamide (1g): Cp*OMeRu(antracene)PF6 (2.0
mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and m-
methoxybenzaldehyde (0.041 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 74% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.21)
to afford 43.0 mg (70%) of the product as a yellow oil.
1H NMR (CDCl3, 400 MHz, 25 °C) δ7.07-6.99 (m, 3H), 5.79 (br. s, 1H),
4.36 (d, J = 5.3 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H), 1.99 (s, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.8, 135.7, 135.5, 133.2, 130.4,
129.4, 128.4, 41.8, 23.1, 20.8, 18.4;
N-(4-methoxybenzyl)butyramide (1k): Cp*OMeRu(antracene)PF6 (2.0
mg, 1 mol%, 0.0034 mmol), butyramide (30 mg, 1 eq, 0.34 mmol) and p-
methoxybenzaldehyde (0.042 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 78% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.43)
to afford 51.0 mg (73%) of the product as a white crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.26-7.21 (m, 1H), 6.85-6.79 (m, 3H),
6.04 (br. s, 1H), 4.36 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 1.99 (s, 3H).
13C NMR (CDCl3, 100 MHz, 25 °C) δ 170.0, 159.8, 139.8, 129.7, 120.0,
113.4, 112.8, 55.2, 43.6, 23.1;
N-(2,3,4-trimethoxybenzyl)acetamide (1h): Cp*OMeRu(antracene)PF6
(2.0 mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol)
and 2,3,4-trimethoxybenzaldehyde (67 mg,
1 eq, 0.34 mmol) were
dissolved in diethyl ether (0.2 mL). The autoclave was sealed, flushed
three times with 10 atm of CO, and then charged with 30 atm CO. The
reactor was placed into an oil bath preheated to 160 °C. After 22 h the
reactor was cooled to room temperature and depressurized. The reaction
mixture was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 87% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.16)
to afford 64.0 mg (79%) of the product as yellow crystals.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.18 (d, J = 8.6 Hz, 2H), 6.84 (d, J =
8.6 Hz, 2H), 5.88 (br. s, 1H), 4.34 (d, J = 5.6 Hz, 2H), 3.77 (s, 3H), 2.15 (t,
J = 7.5 Hz, 2H), 1.73-1.59 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 172.8, 158.9, 130.5, 129.1, 114.0,
55.2, 42.9, 38.6, 19.1, 13.7;
N-(2-methoxybenzyl)butyramide (1l): Cp*OMeRu(antracene)PF6 (2.0
mg, 1 mol%, 0.0034 mmol), butyramide (30 mg, 1 eq, 0.34 mmol) and о-
methoxybenzaldehyde (0.041 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 79% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.51)
to afford 51.0 mg (73%) of the product as yellow oil.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 6.94 (d, J = 8.5 Hz, 1H), 6.59 (d, J =
8.5 Hz, 1H), 6.04 (br. s, 1H), 4.32 (d, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.84
(s, 3H), 3.82 (s, 3H), 1.95 (s, 3H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 169.7, 153.4, 151.8, 142.0, 124.0,
123.9, 107.1, 60.9, 60.7, 55.9, 39.0, 23.2;
N-(4-ethoxybenzyl)acetamide (1i): Cp*OMeRu(antracene)PF6 (2.0 mg,
1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and p-
ethoxybenzaldehyde (0.047 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
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10.1002/ejoc.201701527
European Journal of Organic Chemistry
FULL PAPER
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.27-7.23 (m, 2H), 7.01-6.77 (m, 2H),
6.02 (br. s, 1H), 4.42 (d, J = 5.8 Hz, 2H), 3.84 (s, 3H), 2.14 (t, J = 7.4 Hz,
2H), 1.69-1.60 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).
13C NMR (CDCl3, 100 MHz, 25 °C) δ 166.8, 162.1, 159.0, 130.5, 129.2,
128.7, 126.7, 114.0, 113.6, 55.3, 55.2, 43.4;
N-(4-(trifluoromethyl)benzyl)acetamide
(1p):
13C NMR (CDCl3, 100 MHz, 25 °C) δ 172.6, 157.4, 129.7, 128.7, 126.3,
120.6, 110.2, 55.2, 39.2, 38.7, 19.1, 13.7;
Cp*OMeRu(antracene)PF6 ((1.9 mg, 1 mol%, 0.0033 mmol), acetamide
(20 mg, 1 eq, 0.34 mmol) and p-(trifluoromethyl)benzaldehyde (0.046 mL,
1 eq, 0.34 mmol) were dissolved in diethyl ether (0.2 mL). The autoclave
was sealed, flushed three times with 10 atm of CO, and then charged
with 30 atm CO. The reactor was placed into an oil bath preheated to
160 °C. After 22 h the reactor was cooled to room temperature and
depressurized. The reaction mixture was transferred into a flask, and the
autoclave was washed with dichloromethane (2x1mL); combined
N-(4-(benzyloxy)benzyl)butyramide (1m): Cp*OMeRu(antracene)PF6
(2.0 mg, 1 mol%, 0.0034 mmol), butyramide (30 mg, 1 eq, 0.34 mmol)
and p-benzyloxybenzaldehyde (72 mg, 1 eq, 0.34 mmol) were dissolved
in diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 77% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.11)
to afford 69.0 mg (72%) of the product as a white crystals.
solvents were removed on a rotary evaporator. 26% yield by NMR
.
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz,
2H), 5.91 (s, 1H), 4.48 (d, J = 6.0 Hz, 2H), 2.05 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 170.2, 142.5, 130.42 – 129.44 (m), 128.1,
125.8 (q, J = 3.7 Hz), 124.2 (d, J = 271.9 Hz), 43.3, 23.4.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.43-7.31 (m, 5H), 7.20 (d, J = 8.6
Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 5.69 (br. s, 1H), 5.05 (s, 2H), 4.37 (d, J
= 5.5 Hz, 2H), 2.17 (t, J = 7.5 Hz, 2H), 1.73-1.63 (m, 2H), 0.95 (t, J = 7.5
Hz, 3H);
19F NMR (376 MHz, CDCl3) δ -62.53 (s).
N-(cyclopropylmethyl)acetamide (1q): Cp*OMeRu(antracene)PF6 (2
mg, 1 mol%, 0.0034 mmol), acetamide (20 mg, 1 eq, 0.34 mmol) and
cyclopropanecarboxaldehyde (0.025 mL,
1
eq, 0.34 mmol) were
13C NMR (CDCl3, 100 MHz, 25 °C) δ 172.7, 158.2, 136.9, 130.8, 129.2,
128.6, 128.0, 127.4, 115.0, 70.0, 43.0, 38.7, 19.1, 13.8;
dissolved in diethyl ether (0.2 mL). The autoclave was sealed, flushed
three times with 10 atm of CO, and then charged with 30 atm CO. The
reactor was placed into an oil bath preheated to 160 °C. After 22 h the
reactor was cooled to room temperature and depressurized. The reaction
mixture was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 25% yield by NMR.
N-(4-methoxybenzyl)-3-methylbutanamide
Cp*OMeRu(antracene)PF6 (2.0 mg,
methylbutanamide (34 mg, eq,
(1n):
1
mol%, 0.0034 mmol), 3-
1
0.34
mmol)
and
p-
methoxybenzaldehyde (0.042 mL, 1 eq, 0.34 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 160 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 92% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.58)
to afford 63.0 mg (84%) of the product as a white crystals.
1H NMR (400 MHz, CDCl3) δ 5.63 (s, 1H), 3.09 (dd, J = 7.0, 5.6 Hz, 2H),
1.98 (s, 3H), 1.03 – 0.88 (m, 1H), 0.55 – 0.46 (m, 2H), 0.22 – 0.15 (m,
2H).
13C NMR (75 MHz, CDCl3) δ 44.6, 23.5, 10.8, 3.5.
Acknowledgements
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.17 (d, J = 8.5 Hz, 2H), 6.83 (d, J =
8.5 Hz, 2H), 6.01 (br. s, 1H), 4.33 (d, J = 5.6 Hz, 2H), 3.76 (s, 3H), 2.14-
2.07 (m, 1H), 2.03 (d, J = 6.4 Hz, 2H), 0.92 (d, J = 6.4 Hz, 6H).
We thank the Russian Foundation for Basic Research (grant No.
15-03-02548 A) and the Council of the President of the Russian
Federation (Grant for Young Scientists No. МК-520.2017.3) for
the financial support. O.C. and D.C. thanks the Ministry of
Education and Science of the Russian Federation (Agreement
number 02.a03.21.0008). The contribution of the Center for
molecule composition studies of INEOS RAS is gratefully
acknowledged.
13C NMR (CDCl3, 100 MHz, 25 °C) δ 172.4, 158.8, 130.5, 129.0, 113.9,
55.2, 45.9, 42.8, 26.1, 22.4;
4-methoxy-N-(4-methoxybenzyl)benzamide
(1o):
Cp*OMeRu(antracene)PF6 (1.9 mg,
methoxybenzamide (50 mg,
1
eq,
mol%, 0.0033 mmol), p-
1
0.33
mmol)
and
p-
methoxybenzaldehyde (0.041 mL, 1 eq, 0.33 mmol) were dissolved in
diethyl ether (0.2 mL). The autoclave was sealed, flushed three times
with 10 atm of CO, and then charged with 30 atm CO. The reactor was
placed into an oil bath preheated to 150 °C. After 22 h the reactor was
cooled to room temperature and depressurized. The reaction mixture
was transferred into a flask, and the autoclave was washed with
dichloromethane (2x1mL); combined solvents were removed on a rotary
evaporator. 74% yield by NMR. The residue was purified by preparative
thin-layer chromatography (eluent: hexane/ethyl acetate (1:1); Rf=0.50)
to afford 63.0 mg (70%) of the product as a white crystals.
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FULL PAPER
Key Topic*
Niyaz Z. Yagafarov, Karim M. Muratov,
Klim O. Biriukov, Dmitry L. Usanov, Olga
Chusova, Dmitry S. Perekalin, Denis
Chusov*
Page No. – Page No.
Ruthenium-catalyzed reductive
amidation without an external
hydrogen source
An amide will share hydrogen atom with an aldehyde
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