Ruthenium-catalyzed synthesis of secondary alkylamines: Selective alkylation with aliphatic amines

Article abstract of DOI:10.1002/adsc.200800353

The chemoselective N-alkylation of tert-alkylamines applying aliphatic amines is described for the first time. In the presence of the Shvo catalyst 1, tert-octylamine 4 and 1-adamantylamine 5 are alkylated using primary, secondary, and even tertiary amine

Full text of DOI:10.1002/adsc.200800353

UPDATES
DOI: 10.1002/adsc.200800353
Ruthenium-Catalyzed Synthesis ofSecondary Alkylamines:
Selective Alkylation with Aliphatic Amines
Sebastian Bähn,a Dirk Hollmann,a Annegret Tillack,a and Matthias Bellera,*
a
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax : (+49)-381-1281-51113; e-mail: matthias.beller@catalysis.de
Received: June 6, 2008; Published online: August 13, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800353.
Abstract: The chemoselective N-alkylation of tert-
alkylamines applying aliphatic amines is described
for the first time. In the presence of the Shvo cata-
lyst 1, tert-octylamine 4 and 1-adamantylamine 5
are alkylated using primary, secondary, and even
tertiary amines to give the corresponding monoal-
kylated tert-alkylamine in moderate to very good
yields and excellent selectivity. This novel reaction
proceeds without an additional hydrogen source
and ammonia is formed as the only by-product.
product.[12] Based on these reactions, we also became
interested in the selective alkylation ofaliphatic
amines (Scheme 1). The resulting tert-alkylamines are
ofinterest as intermediates; for example, this structur-
al element is found in pharmaceuticals[13] like vilda-
gliptin.[14]
From a mechanistic viewpoint the alkylation of
amines proceeds via a so-called borrowing hydrogen
sequence which is shown in Scheme 2.[15] Initially, the
ruthenium-catalyzed dehydrogenation ofthe alkyl-
AHCTREaUNG mine should occur via coordination and ß-hydride
elimination. Then, nucleophilic attack ofthe tert-al-
kylamine on the resulting imine and elimination of
ammonia yields the corresponding secondary imine.
Subsequent catalytic hydrogenation leads to the alky-
lated tert-alkylamine. Notably, applying secondary or
even tertiary amines, in the first reaction cycle a pri-
Keywords: alkylation; amines; homogeneous cataly-
sis; hydrogen transfer; ruthenium
Amines are of significant importance for the bulk and mary or secondary amine is eliminated instead ofam-
fine chemical industry. Due to their numerous appli- monia.
cations in polymers, dyes, agrochemicals, and pharma-
In the case oftertiary amines, we assume that ini-
ceuticals,[1] there is an ongoing interest for improved tially an iminium ion is generated by ß-hydride elimi-
and new synthetic preparations.[2] Besides the well nation. Another possible reaction mechanism involv-
[2,3]
[16]
known N-alkylations ofamines with alkyl halides,
ing hydrolysis ofthe amines to of rm ketones
could
catalytic methodologies such as reductive amina- be excluded. For this purpose, reactions under strict
tion,[2,4] hydroaminations,[5] and hydroaminomethyla- water-free conditions and in the presence of small
tions[6] of olefins or alkynes have been developed for amount ofwater (5 mol%) were perof rmed, however
the synthesis ofaliphatic amines within the last
the results do not indicate any influence of water.
decade. In addition, the environmentally friendly N-
[7]
alkylation ofamines using primary
and secondary
alcohols[8,9] has attracted considerable interest.
Recently, we demonstrated that aliphatic amines
can be used as alkylating agents instead ofthe corre-
sponding alcohol. Although this transformation – al-
kylation ofamines with amines – seems to be unusual
at first sight, there is significant industrial interest in
analogous transalkylations.[10] More specifically, we
discovered that anilines are converted in high yield to
N-alkylanilines.[11] This atom-efficient alkyl transfer
proceeds with primary as well as secondary and terti-
ary aliphatic amines leaving ammonia as the only by- Scheme 1. Selective N-alkylation of tert-alkylamines.
Adv. Synth. Catal. 2008, 350, 2099 – 2103
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2099

Sebastian Bähn et al.
UPDATES
Scheme 2. Catalytic hydrogen transfer in N-alkylation of tert-alkylamines with aliphatic amines.
The formed alkylamine reacts further until all alkyl
As model system the alkylation of tert-octylamine 4
chains are transferred to the tert-alkylamine. Clearly, (1,1,3,3-tetramethylbutlamine) was performed with
dehydrogenation ofthe tert-alkyl group is not feasible phenethylamine. Different ruthenium complexes were
because ß-hydride elimination is not possible. Hence, tested by applying 1 mol% ruthenium catalyst and 2
a selective alkyl transfer takes place.
equivalents of tert-octylamine 4 at 1608C in a pressure
tube without additional solvent (Table 1). The differ-
ent pre-catalysts investigated included the ruthenium/
TsDPEN system 3 reported by Noyori and co-work-
ers[17] (Table 1, entry 7), the ruthenium/dppfsystem of
Hamid and Williams[7c] (Table 1, entry 8), and our
ruthenium carbonyl/phosphine system (Table 1,
entry 9).[9a] However, similar to the alkylation ofani-
Table 1. Influence of the catalyst on the reaction of tert-oc-
tylamine 4 and phenethylamine.[a]
lines[11]
C4CO)]2H}Ru2(CO) CTHREUNG
the
Shvo
catalyst
{[2,3,4,5-Ph4ACHTREUNG
(h5-
4A(m-H) 1, shown in Scheme 3, pro-
Entry Catalyst
Yield [%][b]
vided the best result (Table 1, entry 1). Surprisingly,
catalyst 2 was less reactive. So far, we cannot explain
this observation.
Next, we investigated the influence of different re-
action conditions (Table 2). Without solvent, the opti-
1
2
3
4
5
6
7
8
9
Shvo 1
Shvo-H2 2
49
19
14
12
<1
–
–
–
<1
Shvo PPh3
Shvo cataCXiumꢁPCy[e]
[Ru[(+)-BINAP](Cl)2][e]
[{Ru
[{Ru
[{Ru
ACHTREUNG
(p-cymene)(Cl)2}2][c]
A
A
A
[a]
Reaction conditions: 1 mmol phenethylamine, 2 mmol
tert-octylamine 4, 1 mol% ruthenium catalyst relative to
phenethylamine, 24 h, 1608C.
Yields were determined by GC with hexadecane as inter-
nal standard and are based on phenethyl-(1,1,3,3-tetra-
methylbutyl)-amine 6.
4 mol% K2CO3.
2 mol% ligand, 4 mol%K2CO3.
BINAP=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl,
TsDPEN=N-(4-toluenesulfonyl)-1,2-diphenylethylenedi-
[b]
[c]
[d]
[e]
A
dppf=1,1’-bis(diphenyl-phosphanyl)ferrocene,
cataCXiumꢁPCy=N-phenyl-2-(dicyclohexylphosphino)-
Scheme 3. Different ruthenium catalysts for the alkylation
of tert-alkylamines.
pyrrole.
2100
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Adv. Synth. Catal. 2008, 350, 2099 – 2103

Ruthenium-Catalyzed Synthesis ofSecondary Alkylamines
UPDATES
[a]
Table 2. Optimization ofthe reaction conditions.
action with tert-octylamine 4. The results are summar-
ized in Table 3. Primary amines as well as secondary
ones gave the desired products in good to excellent
yield. Remarkably, even tertiary amines such as trioc-
tylamine can be used as alkylating agents, although
activation ofthese substrates is known to be diifcult.
However, tribenzylamine is less reactive and no reac-
tion with tert-octylamine 4 or 1-adamantylamine 5 is
observed (Table 3, entries 6 and 17). The more elec-
tron-rich 4-methoxybenzylamine showed increased re-
activity compared to benzylamine (Table 3, entries 4
and 11). Moreover, aliphatic amino ethers are con-
verted selectively to the secondary amines (Table 3,
entry 10). We were pleased to find that 1-adamantyla-
mine reacted with primary, secondary, and tertiary
amines providing excellent yields ofthe correspond-
ing N-alkyl-1-adamantylamines (Table 2, entries 12–
14). In all cases, the reaction was highly selective to-
wards monoalkylation. Neither the formation of dia-
lkylated tert-alkylamines nor ofthe alkyl-di- tert-alkyl-
amines was observed.
Entry T
[8C]
Solvent Shvo 1
tert-Octylamine Yield
[mol%]
4 [equiv.]
[%][b]
1
2
3
4
5
6
7
8
140
150
160
170
–
–
–
–
1
1
1
1
2
2
2
2
2
2
2
2
2
2
1
3
2
2
2
2
2
2
3
16
35
49
34
38
48
44
60
69
35
23
55
41
48
44
70
60
51
75
160 Heptane 1
160 DME
160 NMP
170 Heptane 1
170 DME
170 NMP
160
160
160
160
1
1
9
1
1
1
1
0.5
2
1
1
1
10
11
12
13
14
15[c]
–
–
–
–
170 DME
16[d] 170 DME
17[e] 170 DME
In conclusion, we present the first selective alkyla-
tion ofaliphatic amines using amines. Proceeding
under transfer hydrogenation conditions, no addition-
al hydrogen is needed for the alkylation. In the pres-
ence ofthe Shvo catalyst 1, selective alkyl transfer,
using primary as well as secondary and tertiary ali-
phatic amines to tert-alkylamines proceeds selectively
in high yield.
18[f]
19
170 DME
170 DME
1
1
[a]
Reaction conditions: 2 mmol phenethylamine, 24 h,
0.5 mL solvent.
[b]
Yields were determined by GC with hexadecane as inter-
nal standard and are based on phenethyl-(1,1,3,3-tetra-
methylbutyl)-amine 6.
12 h.
48 h.
0.25 mL solvent.
1 mL solvent.
[c]
[d]
[e]
[f]
Experimental Section
General Procedure for the Selective Monoalkylation
of tert-Alkylamines
mal yield is obtained at 1608C (Table 2, entry 3). At
lower temperature more diphenethylamine is formed,
while a higher temperature gave triphenethylamine as
In an ACE-pressure tube under an argon atmosphere alkyl-
amine (2 mmol mono-, 1 mmol di-, or 0.67 mmol trialkyl-
AHCTREaUNG mine) and Shvo catalyst (21.7 mg, 0.02 mmol, 1 mol% per
alkyl group) were dissolved in DME (0.5 mL) and tert-alkyl-
amine (6 mmol, 3 equiv. per alkyl group). The pressure tube
was fitted with a Teflon cap and stirred at 1708C for 24 h.
The solvent was removed under vacuum, and the crude
product was purified by column chromatography.
by-product.
Applying
1-methyl-pyrrolidin-2-one
(NMP) as solvent decreased the chemoselectivity and
significantly more triphenethylamine is obtained
(Table 2, entries 7 and 10). In heptane as non-polar
solvent the catalyst is less reactive but more selective
and a moderate yield of60% at 170 8C is achieved
(Table 2, entry 8). An improved yield of69% is ob-
served in dimethoxyethane (DME) (Table 2, entry 9)
and the best yield (75%) is achieved using an excess
Supporting Information
Experimental details and characterization data for com-
pounds 6–12 are given in the Supporting Information.
of3 equiv.
entry 19).
tert-octylamine 4 in DME (Table 2,
Reactions in DMSO, 2-methylbutan-2-ol, dioxane,
and toluene are comparable. Variation ofthe catalyst
loading (Table 2, entries 13 and 14), reaction time
(Table 2, entries 15 and 16), and solvent concentration
(Table 2, entries 17 and 18) did not lead to any further
improvement.
Acknowledgements
This work has been supported by the State of Mecklenburg-
Western Pomerania, the BMBF (Bundesministerium für Bil-
dung und Forschung), and the Deutsche Forschungsgemein-
schaft (DFG BE 1931/16–1, Leibniz prize). We thank all
members of the analytical group (LIKAT) for their support.
In order to demonstrate the generality ofthe alkyl
transfer, different amines were investigated in the re-
Adv. Synth. Catal. 2008, 350, 2099 – 2103
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2101

Sebastian Bähn et al.
UPDATES
Table 3. Catalytic N-alkylation of tert-alkylamines.[a]
[a]
Reaction conditions: 2 mmol mono-, 1 mmol di-, or 0.67 mmol trialkylamine, 6 mmol tert-
alkylamine, 1 mol% Shvo catalyst 1 per alkyl group, 24 h, 0.5 mL DME.
Yields were determined by GC with hexadecane as internal standard and are based on
alkyl groups. Isolated yields in brackets.
[b]
[c]
1 mL DME.
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Ruthenium-Catalyzed Synthesis ofSecondary Alkylamines
UPDATES
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