Angewandte
Chemie
conditions to form carboxylate salts catalyzed by a bipyridyl-
based pincer Ru complex.[12] Longer reflux times resulted in
a decrease of the yield of hexanol and an increase of the yield
of the hexanoate salt at higher conversions of amine (entry 3).
To prevent dehydrogenation of alcohol product to hexanoate,
the reaction of hexylamine in water/dioxane was performed in
a closed system at 1358C. After 24 hours, hexanol was formed
more selectively, in 62% yield and 80% overall selectivity
(entry 4). However, at longer reaction times the amine
conversion slowed down, while the yield of hexanol slightly
decreased owing to the irreversible formation of carboxylate
(entry 5). To stabilize the alcohol product against dehydro-
genative oxidation to carboxylate, the reaction was performed
under H2 (5 bars) leading to the selective formation of
hexanol in 93% yield (entry 6). Overall, although H2 is not
required by the reaction, deamination under an atmosphere
of H2 improved the reaction by increasing the selectivity and
the yield of the desired alcohol product and also suppressed
the formation of carboxylates.
Similarly, heating solutions of phenethylamine, 2-
methoxyethylamine, tryptamine, cis-myrtanylamine, and ben-
zylamine in water/dioxane in a closed system resulted in
formation of the corresponding alcohol product in 56–66%
yield (entries 8,10–13). Substituted benzylamines with elec-
tron-donating and electron-withdrawing substituents were
well-tolerated under the reaction conditions (entries 14–16).
Substrates that can act as chelating ligands, such as ethyl-
enediamine, diethylenetriamine, 2-(aminomethyl)pyridine,
and the Na salt of phenylalanine, were not reactive towards
deamination, likely owing to strong coordination to the metal
center, while furfurylamine underwent non-selective reac-
tions to give a mixture of products. Deamination of allylamine
generated n-propanol in 17% yield, which indicated the
Scheme 2. Proposed mechanisms of deamination.
ketone and alcohol products (Table 1, entries 17,19, and 21).
Although oxidation of cycloalkylamines to ketones has been
reported, it typically requires the use of a stoichiometric
amount of oxidant.[7,13] Examples of amine-to-ketone trans-
formations in the absence of oxidants are exceedingly rare.[14]
The cycloalkyl alcohol products were obtained with high
selectivity in good yields when the reaction was carried out
under H2 pressure (entries 18 and 20).
This deamination reaction can be used for facile and
selective, entropy-driven cyclization of diamines to cyclic
secondary amines at 1008C in water/dioxane with 70–88%
yield (Table 2, entries 1–4). Although such catalytic reactivity
is not unique, it typically requires harsh conditions: high
temperatures (150–1808C) and/or the presence of a reduc-
tant.[15]
Table 2: Cyclization of diamines catalyzed by 1.
Entry
Substrate
t [h]
Conv. [%][c]
Product
[% yield][c]
=
hydrogenation a C C bond under these conditions.
Deamination of phenethylamine under H2 (5 bars) lead to
the more selective formation of phenethyl alcohol in 89%
yield (entry 9). The deamination of tryptamine and phene-
thylamine resembles the metabolism of these and analogous
substrates in biological systems.[9,10]
1[a]
2[b]
22
22
88
78
By analogy with the reported reactivity of complex 1 in
alcohol amination by NH3,[11a] the deamination reaction likely
proceeds by way of an initial dehydrogenation of the primary
amine to an imine and H2 (Scheme 2). The imine then
undergoes a nucleophilic attack by water to form a hemi-
aminal intermediate, from which ammonia can be liberated to
produce an aldehyde. Eventually, the resulting aldehyde
intermediate is reduced to an alcohol using an H2 molecule
from the imine formation.
Interestingly, formation of dialkylamines (Path B in
Scheme 2)[11a] is only a minor side reaction, and dihexylamine
is formed in less than 4% yield from hexylamine. Therefore,
water successfully competes as a nucleophile with both the
primary amine and NH3 under the conditions of this reaction
(Path A versus Path B in Scheme 2).
3[a]
23
40
88
93
4[a]
[a] Substrate (1 mmol), 1 (0.01 mmol), H2O (3 mL), and dioxane (3 mL)
were heated in a closed system at 1008C or [b] in an open system at reflux
at 1008C. [c] Conversion and product yields were determined by NMR
spectroscopy or GC and shown as an average of 2–3 runs.
The mechanism for the cyclic imine formation likely
occurs by way of dehydrogenation of one of the amino
functional groups (catalyzed by 1) followed by the entropy-
driven intramolecular attack of another amine group (Path A,
Scheme 3) or via the formation of an aldehyde intermediate
(Path B, Scheme 3).
In accordance with the proposed mechanism, the presence
of a b-hydrogen atom is necessary for deamination; no
reactivity was observed in the reaction of tBuNH2 under
analogous conditions. Deamination of cycloalkylamines gave
a complete conversion after 48 hours, with a mixture of
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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