Solvent-Free N-Alkylation of Amides with Alcohols Catalyzed by Nickel on Silica–Alumina

Article abstract of DOI:10.1002/ejoc.201901291

The N-alkylation of phenylacetamide with benzyl alcohol has been studied using Ni/SiO₂–Al₂O₃. In the optimized conditions, the desired product was isolated in an excellent 98 % yield. The reaction could advantageously be performed in neat conditions, with a slight excess of amide and a catalytic amount of base. These conditions were tested on a large range of amides and alcohols, affording 24 compounds in 13 to 99 % isolated yields.

Full text of DOI:10.1002/ejoc.201901291

DOI: 10.1002/ejoc.201901291
Communication
Heterogeneous Catalysis
Solvent-Free N-Alkylation of Amides with Alcohols Catalyzed by
Nickel on Silica–Alumina
Aubin Charvieux,[a] Louis Le Moigne,[a] Lorenzo G. Borrego,[a] Nicolas Duguet,*[a] and
Estelle Métay*[a]
Abstract: The N-alkylation of phenylacetamide with benzyl al- neat conditions, with a slight excess of amide and a catalytic
cohol has been studied using Ni/SiO2–Al2O3. In the optimized amount of base. These conditions were tested on a large range
conditions, the desired product was isolated in an excellent of amides and alcohols, affording 24 compounds in 13 to 99 %
98 % yield. The reaction could advantageously be performed in isolated yields.
Pd–Sn catalyst,[26] and Rh, with the Wilkinson catalyst.[27,28] Only
The formation of an amide C–N bond is one of the key proc-
two examples of homogeneous non-noble metal complexes
esses for the synthesis of peptides, pharmaceuticals, polymers
and natural products.[1–4] Amides are generally synthesized by
condensation of carboxylic acids (or their esters, anhydrides or
acyl chloride analogs) with amines, or by the reaction between
an amide and an aryl or aliphatic halide.[5–9] However, those
methods exhibit a poor atom economy, as they inevitably lead
to the formation of stoichiometric amounts of waste. Though
less explored than the previously cited methods, reductive alk-
ylation of amides with aldehydes has been reported by our
group as a greener alternative,[10] along with other nitrogen
nucleophiles.[11,12] A high hydrogen pressure is however re-
quired, and aldehydes generally need to be purified before use
as they easily oxidize. The borrowing hydrogen methodology
solves these issues, as it uses alcohols both as alkylating agents
and hydrogen sources.[13–15] The N-alkylation of amides with
alcohols has been firstly reported in the pioneer work of
Watanabe et al. with RuCl2(PPh3)3.[16] Shortly after, Jenner im-
proved the yields and the scope of this reaction by including
secondary alcohols with RuCl2(PBu3)3 as a catalyst.[17] More re-
cently, [Ru(p-cymene)Cl2]2 with DPEphos has been reported un-
der microwave activation.[18] The N-alkylation of amides with
alcohols has been mainly explored with homogeneous Ir cata-
lysts, such as [Cp*IrCl2]2 (1 to 5 mol-%, at 130–160 °C).[19–21] The
loading of the catalyst and the reaction temperature could be
reduced by using a N–Heterocyclic Carbene–phosphine li-
gand[22] or a benzoxazolyl ligand,[23] thus improving the activity
[29]
were reported, with Cu(OAc)2
and a NiBr2/phenanthroline
catalytic system.[30] Whereas some of these catalytic system re-
quire toxic solvents such as toluene or o-xylene, a significant
part of the previously cited examples does not require an addi-
tional solvent. However, in these cases, a large excess of alcohol
(from 3 to 6 equivalents) is used. Few heterogeneous catalysts
were used for the N-alkylation of amide with alcohols. An
Ag/Mo oxide (Ag6Mo10O33) was used by Shi et al.[31] However,
the authors did not report any recyclability test for their cata-
lyst. Kobayashi et al. reported an example of recyclable catalyst
for this reaction, with polymer-incarcerated Au/Pd nanoparticles
with carbon black as a secondary support, and Ba(OTf)2 as an
additive.[32] To this date, no non-noble metal based heterogene-
ous catalyst has been reported for this reaction. Our group has
been investigating the efficiency of Ni/SiO2–Al2O3 for the α-
alkylation of ketones with alcohols, including methanol.[33,34]
Furthermore, this catalyst has been fully characterized (see ESI).
Herein, we report our new findings on the catalytic activity of
Ni/SiO2–Al2O3 for the solvent-free N-alkylation of amides with
alcohols.
The N-alkylation of phenylacetamide 1a with benzyl alcohol
2a has been chosen as the model reaction for the initial investi-
gation, leading to the formation of the desired product: N-
benzyl-2-phenylacetamide 3a. During this optimization, benzyl
2-phenyl acetate 4 was identified as the major by-product. The
formation of the ester 4 is probably consequent to the nucleo-
philic addition of 2a on 1a, thus releasing ammonia. A range
of bases was first tested, with a 2 to 1 ratio of amide 1a to
alcohol 2a, 20 mol-% of 65 wt.-% Ni/SiO2–Al2O3 and 10 mol-%
of base. The reaction mixture was heated at 175 °C for 15 h,
without added solvent (Table 1). AcOK, a weak base, allowed to
obtain 3a in 60 % GC ratio, with moderate selectivity as the
ester 4 was formed in 17 % GC ratio (Table 1, Entry 1). Reaction
with stronger bases such as tBuOK and KOH lead to good re-
sults, with 90 % ratio and high conversion (Table 1, Entries 2
and 3). K3PO4, used in our previous work, allowed the formation
of the Ir catalyst. This reaction has also been reported with
[24,25]
homogeneous Pd, using Pd(OAc)2
or a heterobimetallic
[a] Univ. Lyon, Université Claude Bernard Lyon1, CNRS, INSA-Lyon, CPE-Lyon,
Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, ICBMS,
UMR 5246, Equipe CAtalyse, SYnthèse et ENvironnement (CASYEN),
Campus LyonTech La Doua, Bâtiment Lederer,
1 rue Victor Grignard, 69100 Villeurbanne, France
E-mail: nicolas.duguet@univ-lyon1.fr
estelle.metay@univ-lyon1.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901291.
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Communication
of 3a in a 93 % ratio (Table 1, Entry 4). Some carbonates were
then tested. Cs2CO3 afforded the product in 82 % ratio while it
was obtained in 95 % ratio with Na2CO3 and K2CO3 (Table 1,
Entries 5–7). The selectivity with Na2CO3 being slightly lower,
K2CO3 was selected as the most suitable base for this reaction.
Other parameters, such as nickel loading, 1a/2a ratio and reac-
tion conditions were then studied (Table 2). In an effort of in-
creasing the greenness of this reaction, the quantity of the
nickel catalyst was decreased to 10 mol-% Ni. Advantageously,
it did not highly impact the formation of the desired product
3a, as it was observed in an 81 % ratio (Table 2, Entry 1). Further
reduction of the quantity of nickel was not found suitable for
the reaction. Ratio of 1a/2a was then decreased to 1.5 to 1,
allowing to observe 3a in 92 % ratio, with a 93 % conversion of
2a (Table 2, Entry 2). Further decrease of this ratio to 1.2 to 1
impacted negatively the ratio of 3a (82 %, Table 2, Entry 3). The
conversion could be increased to 99 % by increasing the time
to 20 h, thus affording the desired N-benzylated amide 3a in
an excellent 98 % isolated yield (Table 2, Entry 4). Decreasing
the temperature to 160 °C highly impacted the kinetics of the
reaction, as conversion of 2a was only 47 % (Table 2, Entry 5).
Blank experiments were then performed. As expected, the de-
sired product was not formed when the reaction was run with-
out nickel catalyst (Table 2, Entry 6). Small amounts of product
were formed in the absence of base (Table 2, Entry 7). Interest-
ingly, ester 4 was the major product in this case. The formation
of the benzaldehyde intermediate by dehydrogenation of 2a is
most probably reversible. In the absence of base, the kinetics
of the condensation of 1a on 2a is likely to be decreased, as
the base is thought to catalyze this step and could also play a
role in the dehydrogenation of 2a. Consequently, from a macro-
scopic point of view, more benzyl alcohol 2a is probably avail-
able, thus increasing the rate of the nucleophilic addition of 2a
on 1a, leading to the formation of the corresponding ester. This
ester could also be formed by the insertion of nickel in the
C–N bond of 1a, as reported by Garg et al.[35,36] New investiga-
tions would be required in order to confirm the capacity of
Ni/SiO2–Al2O3 to perform this insertion.
Table 2. Conditions screening for the N-alkylation of phenylacetamide 1a with
benzyl alcohol 2a catalyzed by Ni/SiO2–Al2O3.[a]
Entry[a]
1a/2a ratio GC conv.[b]
3a[c]
4[c]
1
2
3
2:1
86
93
87
99
47
2
81
92
82
< 1
< 1
1
< 1
5
1.5:1
1.2:1
1.5:1
1.5:1
2:1
4[d]
5[f]
6[g]
7[h]
99 (98)[e]
42
0
19
1
31
2:1
59
[a] Reaction conditions: 1a (19.32 mmol, 2 equiv.), 2a (9.67 mmol, 1 equiv.),
65wt.-%Ni/SiO2–Al2O3 (10 mol-%), K2CO3 (10 mol-%), neat, 175 °C, 15 h.
[b] GC conversion of 2a. [c] GC ratio. [d] 20 h. [e] Isolated yield. [f] 160 °C.
[g] Ni: 0 mol-%. [h] K2CO3: 0 mol-%.
6, tribenzylamine 7 and N,N-dibenzyl-2-phenylacetamide 8. The
formation pathways of these products were studied. As previ-
ously mentioned, the formation of the ester 4 could produce
ammonia as a coproduct. This reactive compound could be
benzylated by benzyl alcohol through a borrowing hydrogen
mechanism, as reported in the literature, thus leading to the
formation of benzylamine.[37–40] This primary amine was suc-
cessfully alkylated by benzyl alcohol in the optimized condi-
tions, affording dibenzylamine (54 % GC ratio) and N-benzyl-
idene-1-phenylmethanamine (46 % GC ratio) (Scheme 1, A). Di-
benzylamine could be converted into tribenzylamine (2 % GC
ratio) with benzyl alcohol in the same conditions (Scheme 1, B).
These three amines could therefore be formed by consecutive
borrowing hydrogen processes. N,N-dibenzyl-2-phenylacet-
amide 8 could a priori be produced by direct benzylation of the
desired product 3a. However, 8 was not observed when 3a
and benzyl alcohol were submitted to the optimized conditions.
Interestingly, this product could be observed in a 25 % GC ratio
by reaction between dibenzylamine and the ester 4 in alkaline
conditions (K2CO3, 10 mol-%) at 175 °C during 20 h (Scheme 1,
C). After some optimization, this product was isolated in 24 %
yield. (Scheme 1, D) In the same manner, the desired product
3a could be formed by reaction between benzylamine and the
ester 4 in 79 % NMR ratio (Scheme 1, E). We have therefore
demonstrated that di-N-alkylation of phenylacetamide could be
performed indirectly through a borrowing hydrogen process.
This reaction will be further investigated in next works.
Table 1. Base screening for the N-alkylation of phenylacetamide 1a with
benzyl alcohol 2a catalyzed by Ni/SiO2–Al2O3.[a]
Entry
Base [mol-%]
GC conv.[b]
3a[c]
4[c]
A range of alcohols and amides was then tested to evaluate
the versatility of the optimized conditions. Phenylacetamide 1a
was first N-alkylated by several alcohols (Figure 1). Some benzyl
alcohols with electron-donating groups were first tested. Excel-
lent yields were obtained with p-methoxy and p-methylbenzyl
alcohols (3b and 3c resp., 99 and 96 % yield). As expected, a
slight decrease of yield was noticed with m- and o-methyl-
benzyl alcohols (3d and 3e resp., 80 and 71 % yield), which
could easily be explained by the increase of the steric hindrance
induced by the methyl group. Benzyl alcohols bearing an elec-
1
2
3
4
5
6
7
AcOK
tBuOK
KOH
K3PO4
Cs2CO3
Na2CO3
K2CO3
81
97
97
96
87
> 99
96
60
90
90
93
82
95
95
17
2
3
1
4
< 1
< 1
[a] Reaction conditions: 1a (19.32 mmol, 2 equiv.), 2a (9.67 mmol, 1 equiv.),
65wt.-%Ni/SiO2–Al2O3 (20 mol-%), base (10 mol-%), neat, 175 °C, 15 h. [b] GC
conversion of 2a. [c] GC ratio.
Other products were also observed in low amount during tron-withdrawing group seemed less reactive, as a moderate
this optimization study, such as benzylamine 5, dibenzylamine 55 % yield was obtained with p-trifluoromethylbenzyl alcohol
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Scheme 1. Study of the formation of the by-products. Starting materials were introduced in equimolar quantities, unless otherwise specified. [a] GC ratio.
[b] 5 equiv. [c] Isolated yield. See ESI for full procedure. [d] 1H NMR ratio.
(3f). p-Fluoro and p-chlorobenzyl alcohols afforded the desired
product in good yields (3g and 3h resp., 75 and 61 % yield).
For p-chlorobenzyl alcohol, the dechlorinated product 3a was
observed in low amounts. Surprisingly, the desired reaction did
not occur with p-bromobenzyl alcohol and p-bromobenzyl
phenyl acetate was obtained as the main product, in low
amounts. The N-alkylation of 1a with a range of aliphatic alco-
hols was also investigated. Linear alcohols, such as ethanol, 1-
propanol, 1-pentanol and 1-octanol gave good to low yields
(3i, 3j, 3k, 3l resp., 69, 46, 31, 13 % yield). It was observed that
the yield of the desired products decreased and that the
amount of ester increased when the chain length increased.
This could partially be explained by the increase of nucleophil-
icity of linear alcohols with the increase of the chain length.
The reaction 3-phenylpropan-1-ol afforded the desired product
3m in a low 31 % yield while the ester was observed in high
quantity. 2-Propanol and cyclohexanol gave the desired prod-
ucts in low and moderate yield (3n and 3o resp., 26 and 58 %
yield).
A range of amides was also N-alkylated with benzyl alcohol
in the optimized conditions (Figure 2). Phenylacetamides bear-
Figure 1. N-alkylation of phenylacetamide with alcohols catalyzed by Ni/SiO2–
Al2O3. Reaction conditions: 1a (19.32 mmol), 2b–o (12.88 mmol), 65wt.-%Ni/
SiO2–Al2O3 (10 mol-%), K2CO3 (10 mol-%), neat, 175 °C, 20 h unless otherwise
specified. [a] 60 h.
ing electron-withdrawing substituents on the aromatic ring desired product in very good yields (89 %, 84 % and 88 % for
gave high to excellent yields. The reaction using 4-methoxy- 3q, 3r and 3s resp.). A good 61 % yield was obtained with para-
phenylacetamide gave the desired product 3p in an excellent chlorophenylacetamide. Interestingly, dechlorination of the
94 % yield. Para-, meta-, and ortho-phenylacetamides gave the starting material or the desired product was negligible. A good
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yield was obtained with benzamide (3u, 76 %), while N-benzyl-
nicotinamide was formed in moderate yield (3v, 39 %).
1-naphthylacetamide gave the desired product 3w in a moder-
ate 60 % yield. A good result was obtained with acetamide,
affording the desired product 3x in 79 % yield. A sulfonamide,
para-tolylsulfonamide was engaged in reaction with benzyl
alcohol in the optimized conditions to afford the desired
N-benzylated product in a good yield (3y, 63 %).
Figure 3. Recycling study of the nickel catalyst for the N-alkylation of phenyl-
acetamide with benzyl alcohol.
The desired product was isolated in an excellent 98 % yield,
with a slight excess of phenylacetamide (1.5 equiv.), 10 mol-%
of Ni/SiO2–Al2O3 and K2CO3 in 20 h at 175 °C without any sol-
vent. The study of the reaction pathways leading to the reaction
by-products was performed. The scope of the reaction was in-
vestigated with a range of amides and alcohols, affording 24 N-
alkylated amides in 13 to 99 % isolated yield.
Acknowledgments
The authors thank the Ministère de l′Enseignement Supérieur,
de la Recherche et de l′Innovation (MESRI) for a Ph.D. grant to
A. C.
Figure 2. N-alkylation of various amides with benzyl alcohol catalyzed by
Ni/SiO2–Al2O3. Reaction conditions: 1p–y (19.32 mmol), 2a (12.88 mmol),
65 wt.-%Ni/SiO2–Al2O3 (10 mol-%), K2CO3 (10 mol-%), neat, 175 °C, 60 h un-
less otherwise specified. [a] 20 h.
Keywords: N-alkylation · Amides · Alcohols · Nickel ·
Heterogeneous catalysis
The recyclability of the Ni catalyst was studied with the
model reaction over 5 runs (Figure 3). The reactions were per-
formed in 6 h, at incomplete conversion, in order to detect
efficiently a potential loss of catalytic activity. After each run,
the crude mixture was filtered through Millipore paper (1 μm)
and the catalyst was washed with acetone and water, dried and
reengaged into reaction. The mass of the recycled catalyst was
measured each time and the quantities of the other compo-
nents of the reaction were recalculated accordingly. During this
study, the desired product was virtually obtained as the sole
product, as its GC selectivity was always greater than 98 %.
After 6 hours of reaction, GC ratio of 3a was 54 % after the first
run. Surprisingly, this ratio increased until run #3, reaching
82 %. The ratio then decreases rapidly (run# 5: 41 %). The cata-
lyst seems first to undergo an activation, then a deactivation. It
is noteworthy that the mass of the catalyst after each run de-
creases quickly, from 115 mg (run# 1) to 66 mg (run# 5). Inter-
estingly, 11 mg of nickel were detected in the solution obtained
by hot filtration after 6 h of reaction. This value corresponds to
a loss of 14.7 % of the initial mass, highlighting a leaching of
the catalyst into solution. The actual nickel loading on the cata-
lyst support probably decreases in the course of the different
runs due to this leaching. Further studies will be undertaken in
order to establish the cause of these observations.
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Received: August 30, 2019
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Heterogeneous Catalysis
A. Charvieux, L. Le Moigne,
L. G. Borrego, N. Duguet,*
E. Métay* .............................................. 1–6
Solvent-Free N-Alkylation of Amides
with Alcohols Catalyzed by Nickel
on Silica–Alumina
To date, the N-alkylation of amides amide was efficiently N-alkylated with
with alcohols has not been studied various alcohols using cheap and easy
with non-noble metal base hetero- to handle Ni/SiO2-Al2O3.
geneous catalyst. Herein, a range of
DOI: 10.1002/ejoc.201901291
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