Iridium-catalysed amine alkylation with alcohols in water

Article abstract of DOI:10.1039/b923083a

Amines have been directly alkylated with alcohols using 1 mol% [Cp*IrI₂]₂ catalyst in water in the absence of base or other additives. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b923083a

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COMMUNICATION
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Iridium-catalysed amine alkylation with alcohols in waterw
Ourida Saidi,a A. John Blacker,b Mohamed M. Farah,b Stephen P. Marsdenb and
Jonathan M. J. Williams*a
Received (in Cambridge, UK) 5th November 2009, Accepted 8th January 2010
First published as an Advance Article on the web 22nd January 2010
DOI: 10.1039/b923083a
Amines have been directly alkylated with alcohols using 1 mol%
[Cp*IrI2]2 catalyst in water in the absence of base or other
additives.
catalyst. Water is usually considered to be a preferred solvent
from an environmental perspective.12 It is certainly non-toxic
and cheap, and we were interested in examining the use of
water as a solvent for the alkylation of amines by alcohols,
since the presence of an excess of water may have had
an adverse effect on the position of the aldehyde–imine
equilibrium that underpins this process.
There has been significant recent interest in the transition
metal-catalysed alkylation of amines by alcohols as a more
benign alternative to potentially genotoxic alkyl halides.1 An
alcohol can be activated by temporary transfer of hydrogen to
the metal catalyst, generating an aldehyde, followed by in situ
imine formation. Reduction of the imine by return of the
hydrogen affords the amine, in an overall process that we have
termed borrowing hydrogen.2 The proposed reaction pathway
is outlined in Scheme 1.
In trial reactions, we chose to react 1-phenylethylamine 1
with propan-1-ol 2 using 1 mol% [Cp*IrI2]2 (i.e. 2 mol% in Ir)
as the catalyst, to give the secondary amine 3, as shown in
Scheme 2. These trial reactions were most successful in the
absence of base, and the addition of potassium carbonate
to the reaction led to a reduction in conversion. The use of
[Ru(p-cymene)Cl2]2 or the Ru-based Shvo catalyst under
identical conditions led to the formation of either no product
or trace amounts of product respectively.13,14
Since the first examples of homogeneous catalysts for these
reactions,3 several ruthenium complexes have been shown to
be active for this transformation.4 Iridium complexes have
also proved to be successful,5 including the achievements of
Fujita et al. in this area using [Cp*IrCl2]2, which is typically
used in toluene at reflux in the presence of K2CO3 to activate
the catalyst.6
Having established conditions for the alkylation of amines
in water, we examined the reaction of a range of amines with
propanol. An amine 4 was reacted with 1.2 equivalents of
propan-1-ol 2 in water for 10 h, and we were pleased to find
that the reaction was successful to give a range of propylated
products 5 (Scheme 3).
Recently, we have been using the related catalyst, [Cp*IrI2]2
(SCRAMt), for the oxidation of amines7 or aldehydes8 to
benzoxazoles. The same catalyst is also effective for the
coupling of two primary amines to give a secondary amine.9
One of us (A.J.B.) has also reported the use of this catalyst for
the racemisation of amines by a reversible loss of hydrogen.10
Herein we report that [Cp*IrI2]2 is also an effective catalyst
for the direct alkylation of amines with alcohols, and that
when the reaction is run in water, there is no requirement for
the addition of carbonate11 or any other base to activate the
The results are summarised in Table 1. Several primary
unbranched benzylamines (Table 1, entries 1–5) were
converted into the propylated secondary amine product, with
up to 94% isolated yield. There was no clear trend relating
isolated yield to the electronic or steric nature of the amine,
and we suspect that variation in the isolated yield is simply a
consequence of the relative ease of isolation. Whilst we used a
10 h reaction time for the standard conditions, we found that
in one case that we examined more closely (Table 1, entry 6),
a good isolated yield could be obtained after only 4 h.
Interestingly, when this reaction was repeated neat in the
absence of water, only 48% conversion was obtained after 5 h.15
Scheme 1 Borrowing hydrogen in the alkylation of amines with
alcohols.
a Department of Chemistry, University of Bath, Claverton Down,
Bath, UK BA2 7AY. E-mail: j.m.j.williams@bath.ac.uk;
Fax: +44 (0)1225 386231; Tel: +44 (0)1225 383942
b School of Chemistry and Institute of Process Research and
Development, University of Leeds, UK LS2 9JT
Scheme 2 Model reaction for borrowing hydrogen.
w Electronic supplementary information (ESI) available: Experi-
mental procedures and spectroscopic data are provided. See DOI:
10.1039/b923083a
Scheme 3 Coupling of amines with propan-1-ol.
Chem. Commun., 2010, 46, 1541–1543 | 1541
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Table 1 Ir-catalysed propylation of amines
Entry
1
Amine product 5
Yielda (%)
72
2
3
4
68
94
89
Scheme 4 Coupling of 1-phenylethylamine with alcohols.
Table 2 Ir-catalysed alkylation of amine 1 with alcohols
Entry
1
Amine product
Yielda (%)
98
5
82
6
7
74b
67
2
3
4
5
6
78
82
79
76
72
8
68
75
60
9
10
11
12
71
18c
23c
7
8
86
75
13
a
Isolated yield after extraction into ethyl acetate and purification by
b
column chromatography. 4 h. 22 h.
c
9
82
97
91
85
91
The propylation of a secondary amine into a tertiary amine
was also successful (Table 1, entry 7), although overalkylation
of primary amines was not a problem when only 1.2 equi-
valents of propan-1-ol were used. The use of a larger excess of
propan-1-ol did lead to the dialkylation of primary amines.
There was not a requirement for the substrate to be a benzylic
amine, as demonstrated by the alkylation of 2-phenylethyl-
amine (Table 1, entry 8) and anilines (Table 1, entries 9–13).
However, for electron-deficient anilines (Table 1, entries 12
and 13), the reactivity was considerably lower.
10
11
12
13
When 4-(MeO2C)–C6H4NH2 was used as a substrate there
was no conversion into product under these conditions, and
similarly no alkylation of PhCONH2 was observed. However,
unreacted nitrile (from Table 1, entry 12), ester and amide
were recovered without transformation of these functional
groups, demonstrating the compatibility of these groups with
the reaction conditions.
14
68
95
Our attention then turned to the use of alternative alcohols
as alkylating agents. We chose 1-phenylethylamine 1 as a
suitable amine substrate (Scheme 4), and this was alkylated
with various alcohols 6 to afford the products 7 shown in
Table 2. Again, we were pleased to see that the reaction was
15
a
Isolated yield after extraction into ethyl acetate and purification by
column chromatography.
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successful for a range of alcohols. Benzylic alcohols (Table 2,
entries 1–6) were effective alkylating agents, giving the
secondary amine products with up to 98% isolated yield.
The furan-containing substrate (Table 2, entry 7) survived
the reaction conditions, and various non-benzylic alcohols
were also used successfully (Table 2, entries 7–12), including
the use of secondary alcohol substrates isopropanol (Table 2,
entry 13) and cyclohexanol (Table 2, entry 14). When amine 1
was reacted with 1,5-pentanediol, cyclisation occurred to give
the corresponding piperidine (Table 2, entry 15).
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In summary, amine alkylation has been achieved using
alcohols as the alkylating agents using 1 mol% [Cp*IrI2]2 in
water in the absence of any other additives. Water is generated
as the only by-product and the use of potentially genotoxic
alkylating agents is avoided.
We thank the EPSRC for funding through grant
EP/F038321/1 and Piramal Healthcare for further support.
Notes and references
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Chem. Commun., 2010, 46, 1541–1543 | 1543