Catalytic N-Alkylation of Amines Using Carboxylic Acids and Molecular Hydrogen

Article abstract of DOI:10.1021/jacs.5b07994

A convenient, practical and green N-alkylation of amines has been accomplished by applying readily available carboxylic acids in the presence of molecular hydrogen. Applying an in situ formed ruthenium/triphos complex and an organic acid as cocatalyst, a broad range of alkylated secondary and tertiary amines are obtained in good to excellent yields. This novel method is also successfully applied for the synthesis of unsymmetrically substituted N-methyl/alkyl anilines through a direct three-component coupling reaction of the corresponding amines, carboxylic acids, and CO₂ as a C₁ source.

Full text of DOI:10.1021/jacs.5b07994

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Article
Catalytic N-Alkylation of Amines using
Carboxylic Acids and Molecular Hydrogen
Ivan Sorribes, Jose R. Cabrero-Antonino, Cristian Vicent, Kathrin Junge, and Matthias Beller
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07994 • Publication Date (Web): 30 Sep 2015
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Catalytic N-Alkylation of Amines using Carboxylic Acids and
Molecular Hydrogen
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Iván Sorribes,† Jose R. Cabrero-Antonino,† Cristian Vicent,‡ Kathrin Junge,† and Matthias Beller*,†
† Leibniz-Institut für Katalyse e.V. Albert Einstein Str. 29a, 18059 Rostock (Germany)
‡ Serveis Centrals d'Instrumentació Científica, Universitat Jaume I, Av. Sos Baynat s/n, 12071 Castelló de la Plana (Spain)
ABSTRACT: A convenient, practical and green N-alkylation of amines has been accomplished by applying readily available car-
boxylic acids in the presence of molecular hydrogen. Applying an in situ formed ruthenium/triphos complex and an organic acid as
co-catalyst, a broad range of alkylated secondary and tertiary amines are obtained in good to excellent yields. This novel method is
also successfully applied for the synthesis of unsymmetrically substituted N-methyl/alkyl anilines through a direct three-component
coupling reaction of the corresponding amines, carboxylic acids and CO2 as a C1 source.
alkylation of amines with different carboxylic acids under
mild conditions using silanes as reducing agents (Scheme
INTRODUCTION
1b).12 However, both protocols suffer from the low atom-
efficiency and the laborious workup procedures. In this re-
N-Alkylated amines constitute highly valuable organic
compounds in many research areas because of their use in the
spect, the use of molecular hydrogen – the least expensive and
preparation of natural products, pharmaceuticals, dyes, agro-
chemicals and other fine chemicals.1 Therefore, it is not sur-
most “green” reductant – would be advantageous. Therefore,
prising that in spite of the existing methods,2,3 the development
the development of a reductive alkylation using all kinds of
carboxylic acids in the presence of hydrogen is highly desired.
of new versatile and efficient protocols for their synthesis is of
To the best of our knowledge, there is only one known exam-
continuing interest.
ple. More specifically, Cole-Hamilton and co-workers report-
Well established methods to produce secondary and tertiary
ed the synthesis of a mixture of N-nonylamine and N,N-
amines involve reductive domino processes of carbonyl com-
dinonylamine in low yield (15% and 47%, respectively) and
pounds. Among them, the direct reductive alkylation using
selectivity by hydrogenation of nonanoic acid under an am-
aldehydes or ketones are the most popular.4,5 Compared to the
monia atmosphere.9a Herein, we disclose a general Ru-
catalyzed N-alkylation of amines with carboxylic acids using
conventional reduction of imines6,7 or amides,8,9 these tandem
processes constitute a more benign and practical strategy since
benign molecular hydrogen as reducing agent and trifluoro-
they avoid additional reaction steps for the synthesis and isola-
methanesulfonimide (HNTf2) as the co-catalyst (Scheme 1c).
tion of the corresponding substrates.10 However, in some cases
the necessary aldehydes or ketones are not easily available or
undergo unwanted side-reactions, e.g. aldol condensations. In
RESULTS AND DISCUSSION
addition to sensitive carbonyl compounds, readily available
and more stable carboxylic acids can also be employed for the
reductive alkylation of amines. Surprisingly, until now these
latter transformations have been scarcely investigated.
To identify critical reaction parameters, the alkylation of
aniline (1a) with acetic acid in the presence of molecular hy-
drogen was investigated as a benchmark system. Based on the
recent catalytic methylations using formic acid13 or CO2,14 as
well as the hydrogenation of carboxylic acid derivatives,8,9,15
initially several ruthenium complexes in the presence of the
so-called
triphos
ligand
(1,1,1-
tris(diphenylphosphinomethyl)ethane) were evaluated in the
model reaction (Table 1). The most active catalyst was gener-
ated by using ruthenium acetylacetonate [Ru(acac)3] (4 mol%;
metal/triphos ratio 1:1.5) as metal precursor in combination
with a catalytic amount of trifluoromethanesulfonimide
(HNTf2; 10 mol%) achieving full conversion of 1a with 16
and 78% yield of N-ethylaniline (2a) and N,N-diethylaniline
(3a), respectively (Table 1, entry 2). Among the other tested
ruthenium precursors, only [Ru(2-methylallyl)2(cod)] (cod =
cyclooctadiene) showed a similar reactivity (Table 1, entry 3).
The other tested ones did not afford any desired alkylated
products, and in all cases small amounts of N-phenylacetamide
were detected.
Scheme 1. N-alkylation of amines with carboxylic acids: a)
Borohydride reduction; b) Catalytic hydrosilylation; c)
Catalytic hydrogenation.
Known synthetic routes for the alkylation of amines with
alkyl and aryl carboxylic acids involve the use of stoichio-
metric amounts of metal borohydride reagents (Scheme 1a).11
More recently, we reported the first platinum-catalyzed N-
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Notably, in the absence of any ligand N- improvement of the degree of alkylation is observed (Table 1,
1
2
3
4
5
6
7
8
cyclohexylacetamide was formed as a main product, and the
use of other phosphane ligands with different structure re-
vealed almost no reactivity in the alkylation reaction (Table
SI1 in the Supporting Information). Temperature and pressure
proved to be also critical for the efficiency of the alkylation
reaction. Indeed, a decrease in conversion and yield of alkylat-
ed products was observed at 140 ºC or by dropping the pres-
sure to 15 bar (Table 1, entries 11 and 12, respectively).
entry 13; see also Supporting Information, Table SI3).
9
Table 1. Ruthenium-catalyzed N-Alkylation of Aniline (1a)
with Acetic Acid and H2
a
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entry
[Ru] precursor
Conv.
(%)b
yield (%)b
Figure 1. Influence of HNTf2 on the N-alkylation of 1a with
Acetic Acid.
2a
-
3a
-
4a
59
-
1
-
63
Table 2. N-Monoalkylation of Primary Amines with Acetic
Acid and H2
a
2
Ru(acac)3
>99
16
50
-
78
50
-
3
Ru(2-methylallyl)2(cod) >99
-
4
RuCl2(bipy)2·xH2O
RuCl3·xH2O
RuCl2[CH3S(O)CH3]4
RuCl2(PPh3)3
[RuCl2(C10H14)]2
Ru3(CO)12
59
57
55
49
59
-
entry
substrate
product
conv.
(%)b
yield
(%)b
5
67
-
-
6
67
-
-
7
65
-
-
8c
>99
56
-
-
1c,d
2c
X = 4-Me
X = 4-Cl
X = 4-Me
X = 4-Cl
95
96
90
94
93
98
91
85 (71)
83 (76)
80 (73)
85 (71)
86 (75)
77 (71)
86 (72)
9
-
-
49
-
10d
11d,e
12d,f,g
13d,g
14g,h
15i
Ru(acac)3
>99
77
31
59
43
19
2
61
2
3c
X = 3-Cl
X = 3-Cl
Ru(acac)3
-
4c,e
5c,d
6c
X = 4-F
X = 4-F
Ru(acac)3
>99
>99
>99
98
49
75
91
13
-
X = 4-OMe
X = 3-OMe
X = 4-OPh
X = 4-OMe
X = 3-OMe
X = 4-OPh
Ru(acac)3
-
Ru(acac)3
-
7c,d
Ru(acac)3
84
-
aReaction conditions: substrate (0.5 mmol), [Ru] precursor (4
mol%), Triphos (6 mol%), HNTf2 (10 mol%), CH3CO2H (2.5
8f,g,h
>99
91
b
equiv), Toluene (2 mL). Determined by GC using n-hexadecane
c
as an internal standard. N-cyclohexylacetamide was formed as
d
e
f
product. HNTf2 (5 mol%). 140 ºC. 15 bar H2. gnBu2O used as a
solvent. Ru catalyst (5 mol%), Triphos (7.5 mol%), HNTf2 (7.5
h
aReaction conditions: substrate (0.5 mmol), Ru(acac)3 (2 mol%),
Triphos (3 mol%), HNTf2 (2 mol%) CH3CO2H (1.7 equiv), THF
i
mol%), CH3CO2H (4 equiv). Ru catalyst (2 mol%), Triphos (3
mol%), HNTf2 (2 mol%), CH3CO2H (1.7 equiv), THF (2 mL).
b
(2 mL). Determined by GC using n-hexadecane as an internal
c
standard; Isolated yield in parentheses. Dialkylated product was
d
detected as a by-product. CH3CO2H (1.3 equiv). Ru(acac)3 (1.5
e
f
mol%), Triphos (2.25 mol%), HNTf2 (1.5 mol%). Ru(acac)3 (10
mol%), Triphos (15 mol%), HNTf2 (20 mol%), CH3CO2H (8
Next, the influence of different Lewis and BrØnsted acids on
equiv), nBu2O (2 mL). gN-(adamantan-1-yl)acetamide was detect-
ed as a by-product. yield < 10% upon isolation by column chro-
matography.
the model reaction in toluene was investigated (Table SI2 in
the Supporting Information). Without co-catalyst or in the
presence of methanesulfonic acid or LiCl significantly lower
reactivity was observed. Among the various triflate salts, the
best result for the dialkylated product are obtained using
HNTf2. Remarkably, using catalytic amounts of aluminum
triflate or lithium triflimide high selectivity towards the mono-
alkylated product are observed. Next, the influence of the
solvent was investigated. Gratefully, using nBu2O a slight
h
Finally, N,N-diethylaniline (3a) is afforded in 91% yield af-
ter increasing the amount of acetic acid (4 equiv) and adjusting
the co- and catalyst loading to 7.5 and 5 mol%, respectively
(Table 1, entry 14).
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product 2a, too. To our delight, by tuning the stoichiometry of
the reagents and using THF as solvent, N-ethylaniline (2a) is
obtained in 84% yield with a 10:1.5 mono/dialkylation ratio
(Table 1, entry 15).
Table 3. Preparation of Tertiary Amines Through to N-
Alkylation with Acetic Acid and H2
a
1
2
3
4
5
6
7
8
9
Encouraged by this result, the monoalkylation of a variety
of anilines bearing electron-withdrawing or electron-donating
substituents with acetic acid was examined in more detail
(Table 2). Under optimized conditions the desired substituted
monoalkylated products are obtained in high yields and selec-
tivity. It is noteworthy that both electronic and steric proper-
ties of the substituents affect the efficiency of the monoalkyla-
tion reaction. For example, para-substituted anilines with
electron-donating substituents, such as methyl or ether groups,
showed higher reactivity than electron-withdrawing groups in
the same ring position. Consequently, a lower amount of ace-
tic acid was required in order to avoid over alkylation. Moreo-
ver, monoalkylation of a sterically hindered aliphatic amine,
such as 1-adamantylamine, proceeded smoothly with high
selectivity affording N-ethyladamantan-1-amine in 91% yield
(Table 2, entry 8).
entry
substrate
product
conv. yield
(%)b
(%)b
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1c
X = 4-Me
X = 4-Cl
X = 4-Me
X = 4-Cl
X = 4-F
>99
>99
>99
>99
>99
>99
94
83 (76)
(72)
2c,d,e
3
X = 4-F
(80)
4d
X = 4-SMe
X = 3-OMe
X = 4-OPh
X = 2,6-Me
X = 2-Ph
X = 4-SMe
X = 3-OMe
X = 4-OPh
X = 2,6-Me
X = 2-Ph
(82)
5c
92 (83)
(77)
6c
Next, the potential of this catalytic protocol for the prepara-
tion of alkyl-substituted tertiary amines was further explored.
As shown in Table 3, a variety of primary and secondary
amines were reacted with acetic acid. Gratifyingly, both ani-
lines bearing electron-withdrawing and electron-donating
groups are efficiently alkylated affording the corresponding
tertiary anilines in good to excellent yields. Again, the alkyla-
tion activity is highly dependent on the electronic and steric
properties of the substituent. When the amino group is sterical-
ly hindered, an increased catalyst loading and amount of acetic
acid are required to afford the desired amines in moderated
yields (Table 3, entries 7-8). Notably, the selective N-
alkylation of amino alcohols can be achieved, thus avoiding
additional protection/deprotection steps for their preparation
(Table 3, entry 11). Moreover, our catalytic protocol also
allowed for the alkylation of benzylic and aliphatic amines.
Although less effective than the alkylation of aromatic amines,
good yields of the corresponding alkylated products are
achieved by increasing the stoichiometry of the reactants and
using THF as solvent (Table 3, entries 12-14).
7c,f
8c,g
(69)
>99
(65)
9
>99
(63)
10h
11h
>99
>99
>99 (94)
(70)
12g,i,j
13h,j,k
BnNH2
Bn2NH
BnNEt2
Bn2NEt
>99
>99
62 (50)
83 (68)
With good reactivity for acetic acid in hand, the generality
of this hydrogenative alkylation was explored by reaction of
aniline with different carboxylic acids (Table 4). Carboxylic
acids with both electron-donating and electron-withdrawing
substituents can be successfully used as alkylating reagents.
For example, carboxylic acids with longer alkyl chain length
including linear, branched as well as cyclic moieties gave the
corresponding secondary N-alkylated anilines in 76-94% yield
(Table 4, entries 1-9). Interestingly, fluoroalkyl-substituted
anilines with potential applications in the pharmaceutical
industry,16 are efficiently synthetized from easy available
fluorinated carboxylic acids (Table 4, entries 3 and 9). More-
over, heterocyclic and carboxylic acids containing aromatic
ethers were used as alkylating reagents (Table 4, entries 10-
11). Benzylation of aniline with benzoic acid in THF achieved
full conversion with 70% yield of N-benzylaniline and N-
phenylpyrrolidine as by-product, which is presumably formed
from the acid catalyzed reaction of aniline with THF (Table 4,
entry 12; X = OH).9c Unfortunately, the use of different sol-
vents in order to avoid the formation of this by-product led to
a much lower conversion and yield. However, when phenyl-
glyoxylic acid was used as an alkylating reagent, N-
14d,e,j,l,m
82
68
aReaction conditions: substrate (0.5 mmol), Ru(acac)3 (5 mol%),
Triphos (7.5 mol%), HNTf2 (7.5 mol%), CH3CO2H (4 equiv),
b
nBu2O (2 mL). Determined by GC using n-hexadecane as an
c
internal standard; Isolated yield in parentheses. Monoalkylated
product was detected as a by-product. dRu(acac)3 (6 mol%), Tri-
phos (9 mol%), HNTf2 (9 mol%). eCH3CO2H (5 equiv).
fRu(acac)3 (8 mol%), Triphos (12 mol%), HNTf2 (12 mol%),
CH3CO2H (7 equiv). Ru(acac)3 (10 mol%), Triphos (15 mol%),
g
h
HNTf2 (15 mol%), CH3CO2H (8 equiv). Ru(acac)3 (3 mol%),
Triphos (4.5 mol%), HNTf2 (4.5 mol%), CH3CO2H (2.5 equiv).
j
iAcetamide derivatives were detected as by-products. THF used
k
as a solvent. Tribenzylamine and N,N-dibenzylacetamide were
detected as by-products. lN-cyclohexyl-N-ethylacetamide was
detected as a by-product. yield < 10% upon isolation by column
chromatography.
m
Interestingly, as shown in Figure 1 the degree of alkylation
(di- versus monoalkylation) largely depends on the amount of
HNTf2 present in the reaction mixture. This prompted us to
investigate the possibility to get selectively the monoalkylated
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benzylaniline is afforded in 92% yield (Table 4, entry 12; X =
for the treatment of pain, inflammation and fever,18 afforded
1
2
3
4
5
6
7
8
CO2H). A plausible route for the formation of this product
involves a conventional reductive amination of the ketone
first, followed by a C-C bond cleavage.17 Interestingly, excel-
lent reactivity was observed with different arylacetic acids
furnishing the expected products in good to excellent yields
(Table 4, entries 13-18). Noteworthy, ibuprofen, which is an
important non-steroidal anti-inflammatory drug widely used
the corresponding derivative in 88% yield (Table 4, entry 18).
As expected, under the present reaction conditions the use of
the enantiomerically pure (S)-(+)-Ibuprofen led to a racemic
product. Finally, the reaction of 2-phenylsuccinic acid (5a)
with aniline gave a 2:1 mixture of the corresponding pyrrol-
idones (Scheme 2).
Table 4. N-Alkylation of Aniline (1a) with Various Carboxylic Acids and H2.a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
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entry RCO2H
product
conv. yield
entry
10
RCO2H
product
conv.
(%)b
yield
(%)b
(%)b
(%)b
1c,d
96
94 (84)
94
86
(79)
2c,d
97
93 (82)
11c
40 (32)
>99
99
70 (65)
92 (85)
3c,e
4c,f
5e,g
>99
96
(80)
12j
13c
14e
85 (76)
95
97
69 (61)
(77)
90
(81)
(76)
(93)
6h
89
15c
>99
>99
(82)
(78)
7i,g
>99
16c,k
8i,g
>99
>99
93 (87)
17e
98
(86)
(88)
9i,g
(91)
18e
>99
aReaction conditions: substrate (0.5 mmol), Ru(acac)3 (2 mol%), Triphos (3 mol%), HNTf2 (3 mol%), RCO2H (1.7 equiv), nBu2O (2 mL).
bDetermined by GC using n-hexadecane as an internal standard; Isolated yield in parentheses. Dialkylated product as a by-product.
c
e
f
dHNTf2 (2 mol%), THF (2 mL). Ru(acac)3 (4 mol%), Triphos (6 mol%), HNTf2 (6 mol%). Ru(acac)3 (2.5 mol%), Triphos (3.75 mol%),
HNTf2 (3.75 mol%). RCO2H (2 equiv). Ru(acac)3 (5 mol%), Triphos (7.5 mol%), HNTf2 (7.5 mol%), RCO2H (2.5 equiv). iRu(acac)3 (3
mol%), Triphos (4.5 mol%), HNTf2 (4.5 mol%). X = OH: Ru(acac)3 (6 mol%), Triphos (9 mol%), HNTf2 (10 mol%), RCO2H (3 equiv),
g
h
j
THF (2 mL). kRCO2H (1.1 equiv).
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mation of the carboxamide followed by reduction23 and 2)
1
2
3
4
5
6
7
8
9
Reduction of the carboxylic acid to the alcohol (via aldehyde)
and subsequent alkylation.14b,24 Indeed, the observation of
carboxamide intermediates and alcohols (vide supra) suggests
that both pathways might be feasible. To further understand
the reaction mechanism, the reduction of N,2-
diphenylacetamide (12a) was performed under standard reac-
tion conditions. Here, three major products are obtained: the
desired N-phenethylaniline (13a) in 20% yield, and the prod-
ucts generated from the reductive C-N bond cleavage, aniline
(1a) and phenethyl alcohol (14a) in 62% yield (Scheme 6b).
Furthermore, the alkylation of aniline (1a) with 14a was inves-
tigated under otherwise the same reaction conditions. As
shown in Scheme 6c, this reaction also affords the expected
alkylated product 13a in 25% yield.
Scheme 2. N-Alkylation of Aniline (1a) with 2-
Phenylsuccinic acid (5a).
Typically, under catalytic hydrogenation conditions carbox-
ylic esters are considered to be more reactive than carboxylic
acids and carboxamides.8b,19 Therefore, a selective carboxylic
acid-mediated reductive N-alkylation method in the presence
of carboxylic esters would be interesting.20 Surprisingly,
monoalkylation reactions of methyl 4-aminobenzoate with
acetic acid and aniline (1a) with monoethyl adipate gave in
both cases the desired products (Scheme 3).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
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33
34
35
36
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39
40
41
42
43
44
45
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Synthesis of Tertiary N-Methyl/Alkyl Anilines
from Carboxylic Acids, CO2 and H2
a
Scheme 3. N-Alkylations of Anilines in the Presence of
Esters.
entry RCO2H
product
conv.
(%)b
yield
(%)b
With respect to organic synthesis, the intramolecular cy-
clization of amino carboxylic acids, a structural motif largely
found in numerous bioactive compounds,21 would constitute a
useful tool for the preparation of cyclic amines. As shown in
Scheme 4, indoline (11a) is accessed in a straightforward
manner from 2-aminophenylacetic acid (10a) in 86% yield.
1c
>99
>99
(77)
(82)
2c
3c
>99
(59)
Scheme 4. Intramolecular N-Alkylation of Amino Carbox-
ylic Acids.
4c,d
5c,e,f
6c,d
>99
>99
>99
(62)
(58)
(65)
Next, we envisioned the possibility for a direct three-
component coupling reaction of primary amines, carboxylic
acids and CO2 as a renewable C1 building block to yield un-
symmetrical tertiary amines.22 As shown in Table 5, cyclic and
heterocyclic aliphatic as well as arylacetic carboxylic acids,
were successfully applied in this new one-pot domino trans-
formation affording the corresponding unsymmetrically sub-
stituted N-methyl/alkyl anilines in good yields.
It should be noted that in all cases the catalytic experiments
were performed on 0.5 mmol scale; however, it is no problem
to run similar experiments on g-scale (Scheme 5). In fact,
upscaling by a factor of 20 did not change the yield compared
to the standard 0.5 mmol-scale reaction.
aReaction conditions: substrate (0.5 mmol), Ru(acac)3 (6 mol%),
Triphos (9 mol%), HNTf2 (15 mol%), RCO2H (2 equiv), THF (2
mL). bYield of isolated products in parentheses. cN,N-
d
dimethylaniline was detected as a by-product 1.7 equiv RCO2H.
f
eDialkylated product was detected as a by-product. 1.3 equiv
RCO2H
Apparently, both reaction pathways involving either the direct
reduction of the amide or the alkylation from aldehydes or
alcohols, generated in situ by reduction of carboxylic ac-
ids15a,15b,25 or by reductive C-N cleavage of the initially formed
carboxamide,8c,26 are possible under our reaction conditions.
Scheme 5. Synthesis of N,N-diethylaniline (3a) on g-scale.
Regarding the mechanism of the hydrogenative alkylation
process, several reaction pathways exist (Scheme 6a): 1) For-
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Journal of the American Chemical Society
Page 6 of 10
O
a)
constitutes a non-catalytically relevant pathway. In fact, the
observed low catalytic activity can be explained by the pres-
-H2O
red.
R1NH2
+
RCO2
H
R1HN
R
H
R1HN
R
1
2
3
4
+H2O
ence of traces of the cationic complex 15+ in the reaction mix-
ture (Figure SI4 in the Supporting Information).
red.
red.
-
-
red.
R
H 2
N
2
O
red.
O
R1
-H2
O
+
R
R
H
R
1NH2
R1N
+H2
O
red.
-H2
O
5
+
OH
R1NH2
6
7
8
9
b)
Ru(acac)3 (2 mol%)
Triphos (3 mol%)
HNTf2 (3 mol%)
H
N
H
N
NH2
OH
+
+
160°C, 60 bar H2
18 h, nBu2
O
O
12a
13a
20% yield
14a
62% yield
1a
Full Conversion
62% yield
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c)
Ru(acac)3 (2 mol%)
Triphos (3 mol%)
HNTf2 (3 mol%)
H
N
NH2
OH
+
160°C, 60 bar H2
O
18 h, nBu2
14a
1a
13a
36% conversion
1.7 equiv
25% yield
Scheme 6. Control Experiments and Proposed Pathways
for the Ru-Catalyzed N-Alkylation of Amines with Car-
boxylic Acids and H2..
Figure 2. Recycling experiments of the N-alkylation of 1a
with Acetic Acid.
Inspired by the recyclability of a related formate complex
by Klankermayer and Leitner et al.,22n we decided to perform
recycling experiments of the catalyst. As shown in Figure 2
the catalyst was re-used up to five times in the model reaction.
Interestingly, the catalyst could be recovered after each run by
simple decantation of the colorless solution obtained by cool-
ing the reaction mixture to room temperature. After the first
recycling, a moderate decrease of reactivity of the catalyst is
observed, which is explained by the dimerization process to
give 16.
Finally, we addressed the identification and basic reactivity
of Ru-containing species involved in this hydrogenative alkyl-
ation
protocol.
When
a
mixture
of
Ru(acac)3/Triphos/CH3CO2H/HNTf2/aniline was submitted to
catalytic conditions, the ESI-MS and 31P NMR data of the
crude solid obtained by cooling the reaction mixture were
consistent with the formation of the previously reported cati-
onic [(Triphos)Ru(OAc)(solvent)]+ (15+) complex (Figure SI1
in the Supporting Information).22n,27 Minor amounts of dimeric
Ru-containing species, mainly the [Ru2(µ-H)2(Triphos)2] (16)
and [Ru2(µ-OH)2(Triphos)2] (17) compounds were also detect-
ed. It is noteworthy that no additional intermediates containing
aniline (1a) were observed on the basis of ESI-MS, and virtu-
ally identical spectroscopic data were obtained in the absence
of 1a (Figure SI2 in the Supporting Information).
In order to probe whether the cationic acetate complex 15+
is an active intermediate, the alkylation of 1a with acetic acid
was carried out by using the isolated [15(NTf2)]22n complex
(7.5 mol%) as pre-catalyst in the absence of any additional co-
catalyst. Notably, the dialkylated product 3a was achieved in
92% yield, thus revealing that the cationic acetate complex 15+
is the resting state, which is converted to the presumed ruthe-
nium-hydride intermediate species upon hydrogenative re-
moval of the acetate ligand.15a In addition, this result also
suggests that the major role of the required acid co-catalyst in
the combined in-situ Ru(acac)3/Triphos system is the genera-
tion of cationic ruthenium species as the catalytically active
complex (presumably [(Triphos)Ru(H)(H2)(solvent)]+). Such
species have also been proposed in the Ru/Triphos-catalyzed
hydrogenation of carbon dioxide to methanol.22n Noticeably,
by using the Ru(acac)3/Triphos system no obvious incubation
period is observed from a reaction profile of the alkylation of
1a with acetic acid under standard reaction conditions
(Scheme SI1 in the Supporting Information).
SUMMARY
In conclusion, we have developed the first general catalytic
N-alkylation of amines with a variety of carboxylic acids using
molecular hydrogen as reducing agent. The use of an in situ
formed ruthenium/Triphos-based catalyst in combination with
HNTf2 as co-catalyst allows for successful alkylation of aro-
matic and aliphatic amines with different kinds of carboxylic
acids affording selectively secondary or tertiary amines de-
pending on the reaction conditions. In addition, unsymmetri-
cally substituted N-methyl/alkyl anilines are accessible in a
most efficient manner through a new three-component cou-
pling reaction of the corresponding amines, carboxylic acids
and CO2. It should be noted that such compounds typically
have been prepared by using additional protec-
tion/deprotection steps.
Compared to the previously known reductive alkylations of
carboxylic acids (in the presence of stoichiometric amounts of
metal hydrides or hydrosilanes) the use of hydrogen makes
this protocol a cleaner and more atom-efficient methodology.
Moreover, the reaction is easily scaled up and the catalyst can
be recycled. We believe this method provides a convenient
alternative to traditional reductive aminations and will find
increasing applications including renewable feedstocks.
When a mixture of Ru(acac)3/Triphos/HNTf2 was heated
under catalytic conditions, the formation of dimer 16 is evi-
denced as a dominant product as shown by ESI-MS and
31P{1H} NMR (Figure SI3 in the Supporting Information).9c
Notably, with the reaction mixture containing dimer 16, a
marginal degree of alkylation of 1a with acetic acid (36%
yield of 2a; 3% yield of 3a) is achieved even using HNTf2 as
co-catalyst. This makes it likely that formation of dimer 16
EXPERIMENTAL SECTION
The general procedure for the dialkylation reaction of
aniline with acetic acid is as follows: An 8 mL glass vial
containing a stirring bar was sequentially charged with
[Ru(acac)3] (10 mg, 0.025 mmol), Triphos (23.3 mg, 0.038
mmol), 1a (46.6 mg, 0.5 mmol), n-hexadecane (50 µL) as an
internal standard, nBu2O (2 mL), CH3CO2H (115 µL, 2 mmol)
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Journal of the American Chemical Society
2014, 12, 7179-7193. (f) Hollmann, D. Chemsuschem 2014, 7, 2411-
2413.
(4) For reviews on the catalytic reductive amination of carbonyl
compounds, see: (a) Tararov, V. I.; Borner, A. Synlett 2005, 203-211;
(b) Lunde, S. A.; Sydnes, M. O. Synlett 2013, 24, 2340-2344. (c)
Gusak, K. N.; Ignatovich, Z. V.; Koroleva, E. V. Russ. Chem. Rev.
2015, 84, 288-309.
and a freshly prepared 0.2 M in nBu2O solution of co-catalyst
1
2
3
4
5
6
7
8
HNTf2 (188 µL, 0.038 mmol). Afterwards, the reaction vial
was capped with a septum equipped with a syringe and set in
the alloy plate, which was then placed into a 300 mL auto-
clave. Once sealed, the autoclave was purged 3 times with
hydrogen, then pressurized to 60 bar and placed into an alumi-
num block, which was preheated at 160 °C. After 18 h, the
autoclave was cooled in an ice bath, and the remaining gas
was carefully released. Finally, the reaction mixture was dilut-
ed with ethyl acetate and analysed by GC. To determine the
isolated yield of the alkylated amines, no internal standard was
added and the reaction mixture was purified by silica gel col-
umn chromatography (n-heptane/ethyl acetate mixtures) to
give the corresponding alkylated amines.
(5) For recent examples on the metal-catalyzed reductive amina-
tions of carbonyl compounds by using hydrogen, see: (a) Kadyrov, R.;
Riermeier, T. H.; Dingerdissen, U.; Tararov, V.; Borner, A. J. Org.
Chem. 2003, 68, 4067-4070. (b) Imao, D.; Fujihara, S.; Yamamoto,
T.; Ohta, T.; Ito, Y. Tetrahedron 2005, 61, 6988-6992. (c) Robichaud,
A.; Ajjou, A. N. Tetrahedron Lett. 2006, 47, 3633-3636. (d) Rubio-
Perez, L.; Perez-Flores, F. J.; Sharma, P.; Velasco, L.; Cabrera, A.
Org. Lett. 2009, 11, 265-268. (e) Sreedhar, B.; Reddy, P. S.; Devi, D.
K. J. Org. Chem. 2009, 74, 8806-8809. (f) Li, C.; Villa-Marcos, B.;
Xiao, J. J. Am. Chem. Soc. 2009, 131, 6967-6969. (g) Fleischer, S.;
Zhou, S.; Junge, K.; Beller, M. Chem. Asian J. 2011, 6, 2240-2245.
(h) Pagnoux-Ozherelyeva, A.; Pannetier, N.; Mbaye, M. D.; Gaillard,
S.; Renaud, J.-L. Angew. Chem. Int. Ed. 2012, 51, 4976-4980. (i)
Werkmeister, S.; Junge, K.; Beller, M. Green Chem. 2012, 14, 2371-
2374. (j) Moulin, S.; Dentel, H.; Pagnoux-Ozherelyeva, A.; Gaillard,
S.; Poater, A.; Cavallo, L.; Lohier, J.-F.; Renaud, J.-L. Chem. Eur. J.
2013, 19, 17881-17890. (k) Yang, H.; Cui, X.; Deng, Y.; Shi, F.
Synth. Commun. 2014, 44, 1314-1322. (l) Cabrera, A.; Sharma, P.;
Javier Perez-Flores, F.; Velasco, L.; Luis Arias, J.; Rubio-Perez, L.
Catal. Sci. Technol. 2014, 4, 2626-2630. (m) Zhou, S.; Fleischer, S.;
Jiao, H.; Junge, K.; Beller, M. Adv. Synth. Catal. 2014, 356, 3451-
3455. (n) Pisiewicz, S.; Stemmler, T.; Surkus, A.-E.; Junge, K.; Bel-
ler, M. Chemcatchem 2015, 7, 62-64. For selected examples on the
use of nitriles to functionalize amines, see: (o) Ikawa, T.; Fujita, Y.;
Mizusaki, T.; Betsuin, S.; Takamatsu, H.; Maegawa, T.; Monguchi,
Y.; Sajiki, H. Org. Biomol. Chem. 2012, 10, 293-304. (p) Srimani, D.;
Feller, M.; Ben-David, Y.; Milstein, D. Chem. Commun. 2012, 48,
11853-11855.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the one-pot synthesis of unsym-
metrically substituted N-methyl/alkyl anilines through the
direct three-component coupling reaction: The general
procedure described above for the alkylation of amines with
carboxylic acids was applied with a minor modification. After
the autoclave was sealed and purged 3 times with CO2, it was
pressurized with CO2 (20 bar) and H2 (60 bar).
ASSOCIATED CONTENT
Supporting Information. Extended data about optimization of
reaction conditions, scaled up and catalyst recycling experiments,
alkylation/time profile, ESI and NMR data of the chemical specia-
tion, and spectroscopic data of isolated products. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(6) For reviews on the catalytic reduction of imines, see: (a) Koba-
yashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094. (b) Nugent, T.
C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753-819. (c) Xie, J.-
H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713-1760. (d)
Wang, D.; Hou, C.; Chen, L.; Liu, X.; An, Q.; Hu, X. Chin. J. Org.
Chem. 2013, 33, 1355-1368.
matthias.beller@catalysis.de
Notes
The authors declare no competing financial interest.
(7) For selected examples on the catalytic hydrogenation of imines,
see: (a) Li, C.; Wang, C.; Villa-Marcos, B.; Xiao, J. J. Am. Chem.
Soc. 2008, 130, 14450-14451. (b) Hou, G.; Gosselin, F.; Li, W.;
McWilliams, C.; Sun, Y.; Weisel, M.; O'Shea, P. D.; Chen, C.-y.;
Davies, I. W.; Zhang, X. J. Am. Chem. Soc. 2009, 131, 9882-9883. (c)
Mrsic, N.; Minnaard, A. J.; Feringa, B. L.; de Vries, J. G. J. Am.
Chem. Soc. 2009, 131, 8358-8359. (d) Li, W.; Hou, G.; Chang, M.;
Zhang, X. Adv. Synth. Catal. 2009, 351, 3123-3127. (e) Baeza, A.;
Pfaltz, A. Chem. Eur. J. 2010, 16, 4003-4009. (f) Zhou, S.; Fleischer,
S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2011, 50, 5120-5124.
(g) Arai, N.; Utsumi, N.; Matsumoto, Y.; Murata, K.; Tsutsumi, K.;
Ohkuma, T. Adv. Synth. Catal. 2012, 354, 2089-2095. (h)
Werkmeister, S.; Fleischer, S.; Zhou, S.; Junge, K.; Beller, M.
Chemsuschem 2012, 5, 777-782. (i) Tang, W.; Johnston, S.; Li, C.;
Iggo, J. A.; Bacsa, J.; Xiao, J. Chem. Eur. J. 2013, 19, 14187-14193.
(j) Zhao, Q.; Wen, J.; Tan, R.; Huang, K.; Metola, P.; Wang, R.;
Anslyn, E. V.; Zhang, X. Angew. Chem. Int. Ed. 2014, 53, 8467-8470.
(k) Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.; Wan, K. Y.;
Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2014, 136, 1367-1380.
(8) For reviews on the catalytic hydrogenation of carboxylic acid
derivates, see: (a) Dub, P. A.; Ikariya, T. ACS Catal. 2012, 2, 1718-
1741. (b) Smith, A. M.; Whyman, R. Chem. Rev. 2014, 114, 5477-
5510. (c) Werkmeister, S.; Junge, K.; Beller, M. Org. Process Res.
Dev. 2014, 18, 289-302.
ACKNOWLEDGMENT
This work was supported by the state of Mecklenburg-
Vorpommern and the BMBF. J.R.C.-A. thanks Ramon Areces
Foundation for a postdoctoral fellowship. Special thank go to
Prof. Rosa Llusar from University Jaume I for providing us lab
facilities during the revision work. Authors also thank the Servei
Central d’Instrumentació Científica (SCIC) of the University
Jaume I for providing us ESI-MS facilities.
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Catalytic N-Alkylation of Amines using Carboxylic Acids and Molecular Hydrogen
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Iván Sorribes, Jose R. Cabrero-Antonino, Cristian Vicent, Kathrin Junge, and Matthias Beller*
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