A general ruthenium-catalyzed synthesis of aromatic amines

Article abstract of DOI:10.1002/anie.200703119

(Chemical Equation Presented) Simple as that: The synthesis of aromatic amines from aliphatic amines proceeds under transfer hydrogenation conditions (see scheme). By applying the Shvo catalyst, general applicability is shown in the conversion of a variety of functionalized anilines and aliphatic amines. This base- and salt-free method can be an excellent alternative to the known synthesis of anilines.

Full text of DOI:10.1002/anie.200703119

Angewandte
Chemie
DOI: 10.1002/anie.200703119
Aminations
A General Ruthenium-Catalyzed Synthesis of Aromatic Amines**
Dirk Hollmann, Sebastian Bähn, Annegret Tillack, and Matthias Beller*
Aromatic amines play a prominent role as biologically active
compounds and as industrial chemicals.[1] Hence, the develop-
ment of new efficient syntheses is of enormous interest.
Atom-economical methods such as Lewis acid catalyzed
amination,[2] intermolecular hydroaminations,[3] and hydro-
aminomethylations[4] represent attractive approaches for the
synthesis of substituted anilines. Among the various methods,
the widely used palladium- and copper-catalyzed aminations
of aryl halides, tosylates, and triflates are probably most
important.[5,6] In comparison to these substrates, anilines are
readily available and inexpensive. In principle, aryl amines
could be aminated, leaving ammonia as the only by-product
(Scheme 1).
Scheme 2. Catalytic hydrogen transfer in N alkylation of anilines with
aliphatic amines.
the transfer hydrogenation is the primary amine. Hence, no
additional hydrogen or hydrogen transfer reagent is required.
An advantage of this method compared to most reductive
aminations is that there is no need for high-pressure equip-
ment. Interestingly, the same type of dehydrogenation–
reaction–hydrogenation sequence has recently been used in
Scheme 1. Synthesis of aromatic amines.
Recently, we developed a procedure for the synthesis of
secondary amines starting from the corresponding alcohols
using ruthenium carbonyl ([Ru3(CO)12]) and N-phenyl-2-
(dicyclohexylphosphino)pyrrole.[7] Using this method, we
were able to convert only aliphatic amines but no aryl
amines. Hamid and Williams described an alternative ruthe-
nium–dppf complex that is able to catalyze the amination of
primary alcohols with primary aliphatic and aryl amines.[8]
Herein, we present a new methodology for the synthesis
of substituted aniline derivatives, which combines the advan-
tages of our and of Williamsꢀs catalyst systems. In analogy to
the amination of alcohols, the reaction occurs through a
hydrogen-borrowing mechanism (Scheme 2).[9] In the first
step, dehydrogenation of the alkyl amine to an imine occurs.
After nucleophilic attack of the aniline to form an unstable
aminoaminal and subsequent elimination of ammonia, the
corresponding secondary imine is hydrogenated to the
alkylated aniline.[10] In this reaction, the hydrogen donor for
alkane metathesis,[11] b-alkylation of alcohols,[12] and C C
À
bond formation by means of a Wittig or Knoevenagel
reaction.[13–15]
To start our investigations, we examined the amination of
aniline with n-hexylamine. Different ruthenium complexes
were tested using 1 mol% catalyst and two equivalents of
aniline at 1508C without solvent in a sealed tube (Table 1).
Several precatalysts and catalyst systems were investigated,
including the ruthenium–dppf system of Hamid and Wil-
liams[8] (Table 1, entry 12), the TsDPEN system reported by
Noyori and co-workers[16] (Table 1, entry 11), and our ruthe-
nium carbonyl–phosphine system[7] (Table 1, entry 14). Of all
ruthenium catalysts tested, the Shvo complex 1[17,18] and the
analogous ShvoÀH2 complex 2 showed the highest reactivity
(Table 1, entries 15 and 16). These catalysts are known to be
highly active in transfer hydrogenations. Studies of the
mechanism with 1 were performed by Bäckvall and co-
workers[19] and Casey et al.[20] It was demonstrated that 1
dissociates into two species. The 18-electron complex 1a is
active in the hydrogenation, and the 16-electron complex 1b
is active in the dehydrogenation reaction (Scheme 3). All
other tested catalysts showed low or no reactivity.
[*] D. Hollmann, S. Bähn, Dr. A. Tillack, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse an der Universität Rostocke.V.
Albert-Einstein-Strasse 29a, 18059 Rostock(Germany)
Fax: (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
Next, we investigated the influence of the temperature
and the solvent in more detail (Table 2). Below 1408C the
reaction rate and yield dropped dramatically (Table 2,
entries 1–4), and diamines were observed as by-products.
Surprisingly, variation of the solvent had no significant effect
on the amination reaction. In nonpolar solvents (heptane,
[**] This workhas been supported by the BMBF (Bundesministerium für
Bildung und Forschung) and the Deutsche Forschungsgemein-
schaft (DFG BE 1931/16-1, Leibniz prize) as well as the Fonds der
Chemischen Industrie (FCI).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Arylation of n-hexylamine with aniline in the presence of
different ruthenium catalysts.[a]
Table 2: Arylation of n-hexylamine with aniline under different condi-
tions.[a]
Entry
Catalyst
Yield [%][b]
Entry
T
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
–
–
–
–
2
5
–
–
–
–
14
–
9
–
–
94
70
1
2
3
4
5
6
7
8
9
150
140
130
120
140
140
140
140
140
140
140
–
–
–
–
95
95
60
[{Ru[(+)-binap](Cl)}2]
[Ru(Cl)2(bipy2]·2H2O
[RuCO(H)2(PPh3)3]
[Ru(Cl)2(PPh3)3]
[{Ru(Cl)(cod)}2]
[RuCp2]
12
heptane
cyclohexane
toluene
acetonitrile
DMF
>99
>99
>99
96
[{RuCp*Cl2}x]
[RuCp*(cod)Cl]
9
90[c]
>99
>99
10
11
12
13
14
15
16
[{Ru(p-cymene)(Cl)2}2][c]
[{Ru(p-cymene)(Cl)2}2]/TsDPEN[d]
[{Ru(p-cymene)(Cl)2}2]/dppf[d]
[Ru3(CO)12]
10
11
DMSO
2-methylbutan-2-ol
[a] Reaction conditions: 1 mol% Shvo catalyst 1 relative to n-hexylamine,
2 mmol n-hexylamine, 4 mmol aniline, 24 h. [b] Conversion and yield
were determined by GC with hexadecane as internal standard. Con-
versions and yields are based on the conversion of n-hexylamine and N-
hexylaniline. [c] Formylaniline was formed as by-product.
[Ru3(CO)12]/cataCXium PCy
Shvo (1)
ShvoÀH2 (2)
[a] Reaction conditions: 1 mol% catalyst relative to n-hexylamine,
2 mmol n-hexylamine, 4 mmol aniline, 1508C, 24 h. [b] Conversion and
yield were determined by GC with hexadecane as internal standard.
Conversions and yields are based on the conversion of n-hexylamine and
N-hexylaniline. [c] 4 mol% K2CO3. [d] 2 mol% ligand, 4 mol% K2CO3, 4-ꢀ
M.S. Binap=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, bipy=bipyr-
idine, cod=cycloocta-1,5-diene, Cp=cyclopentadienyl, Cp*=pentame-
thylcyclopentadienyl, TsDPEN=N-(4-toluenesulfonyl)-1,2-diphenylethy-
catalytic experiments were performed with 1 mol% of 1 in the
presence of two equivalents of aryl amine in 2-methylbutan-2-
ol at 1508C.[21] Various aryl amines react with n-hexylamine to
give the desired products in excellent yields. High yields over
93% were observed with activated and electron-rich anilines
such as o/p-toluidine and o/p-anisidine (Table 3, entries 1, 2, 4
and 5). The amination of sterically hindered 2,6-dimethyl-
substituted aniline was more problematic and gave only a low
yield of 34% (Table 3, entry 3). However, reactions with
pharmaceutically important aniline derivatives such as 3,4,5-
trimethoxyaniline and 3,4-(methylenedioxy)-aniline occurred
in high yields of 97 and 86% (Table 3, entries 6 and 7).
Furthermore, halogenated anilines can be employed as
selective arylation reagents. 4-Fluoro-, 4-chloro-, and 4-
bromoaniline gave excellent yields of the corresponding
alkylated aniline (Table 3, entries 8–10). In general, such
products cannot be easily prepared by the palladium-cata-
lyzed Buchwald–Hartwig reaction. The catalyst also tolerates
nitro, nitrile, and amide groups (Table 3, entries 11–14).
However, the reaction of 4-nitroaniline with n-hexylamine
gave a poor yield of 20%, as a number of decomposition
products formed (Table 3, entry 11). In addition to aniline
derivatives, heterocyclic aminopyridines such as 2-amino-
pyridine and 3-aminopyridine also react smoothly with n-
hexylamine (Table 3, entries 15 and 16).
lenediamine,
dppf=1,1’-bis(diphenylphosphanyl)ferrocene,
cata-
CXium PCy=N-phenyl-2-(dicyclohexylphosphino)pyrrole.
Scheme 3. Shvo complex (1), dissociated species 1a, 1b, and the
analogous ShvoÀH2 complex 2.
cyclohexane, and toluene, Table 2, entries 5–7) as well as
polar solvents (acetonitril and DMSO, Table 2entries 8 and
10) and polar protic solvents (2-methylbutan-2-ol, Table 2
entry 11), complete conversion and excellent yield (over
99%) is observed. Considering the different solubilities and
melting points of the aryl or aliphatic amine substrates, this
finding seems important.
To demonstrate the general applicability of the Shvo
catalyst for this reaction and the scope of the process, various
aryl and alkyl amines were investigated (Table 3). In general,
In general, we did not observe a strong dependence of the
product yield on donor or acceptor substitution of the aryl
amine. Merely the amination of very sterically hindered 2,6-
dimethyl-substituted aniline and the decomposition of nitro-
anilines seem to be challenges for the future (Table 3,
entries 3 and 11).
Finally, our protocol was applied to different alkyl amines
(Table 4). n-Octyl-, phenethyl- and benzylamine are con-
verted in excellent yields to the corresponding aniline
derivatives (Table 4, entries 1–3). Branched amines such as
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Table 3: Amination of aryl and heteroaryl amines.[a]
Table 4: Arylation of alkyl amines.[a]
Yield [%][b]
98
Entry Amine
1
Product
Yield [%][b]
99
Entry
1
Aniline
Product
2
3
99
94
2
3
93
34
4
5
6
99
99
99
4
5
98
97
6
7
97
86
7
8
89
97
8
9
99
97
94
20
76
95
9
93
[a] Reaction conditions: 1 mol% 1 relative to alkyl amine, 2 mmol alkyl
amine, 4 mmol aniline, 24 h, 2-methylbutan-2-ol, 1508C. [b] Yields of
isolated product are based on alkyl amine.
10
11
12
13
2-octylamine, cyclohexylamine, and cyclooctylamine gave
yields of isolated product of 99% (Table 4, entries 4–6).
Moreover, furane-, thiophene-, and indole-substituted amines
gave yields up to 97% (Table 4, entries 7–9).
In summary, we described the first arylation of aliphatic
amines with anilines that proceeds under transfer hydro-
genation conditions. In the presence of the Shvo catalyst 1, a
variety of functionalized anilines and aliphatic amines react
smoothly to give the corresponding aryl amines in excellent
yields. It is important to emphasize that halogenated anilines
and heterocyclic aminopyridine derivates can be easily
synthesized. This base- and salt-free method can be a useful
alternative to the known methods for the synthesis of aniline
derivatives.
14
83
15
16
96
77
Experimental Section
[a] Reaction conditions: 1 mol% Shvo catalyst 1 relative to n-hexylamine,
2 mmol n-hexylamine, 4 mmol aryl amine, 2-methylbutan-2-ol, 24 h,
1508C. [b] Yields of isolated product are based on n-hexylamine.
General amination procedure: In an ACE-pressure tube under an
argon atmosphere, Shvo catalyst (1; 0.02mmol) and 2-(thiophen-2-
yl)ethanamine (2 mmol) were dissolved in 2-methylbutan-2-ol
(0.5 mL) and aniline (4 mmol). The pressure tube was fitted with a
teflon cap and heated at 1508C for 24 h in an oil bath. The solvent was
removed in vacuo, and the crude product was easily purified by
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column chromatography with pentane/ethyl acetate (20:1) to afford
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Received: July 12, 2007
Published online: September 24, 2007
Keywords: aminations · aniline · homogeneous catalysis ·
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out at 1508C.
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