Metal-free aerobic oxidative coupling of amines to imines

Article abstract of DOI:10.1039/c1cc13202d

Oxidative coupling of primary amines to imines is achieved with high to moderate yields by refluxing suspensions of amines and water under one atmosphere dioxygen without any additives. Tandem acid-free aza Diels-Alder reactions for synthesis of N-alkyl-4-pyridones are also accomplished. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13202d

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COMMUNICATION
Metal-free aerobic oxidative coupling of amines to iminesw
Lianghui Liu, Siyu Zhang, Xuefeng Fu* and Chun-Hua Yan
Received 31st May 2011, Accepted 27th July 2011
DOI: 10.1039/c1cc13202d
Oxidative coupling of primary amines to imines is achieved with
high to moderate yields by refluxing suspensions of amines and
water under one atmosphere dioxygen without any additives.
Tandem acid-free aza Diels–Alder reactions for synthesis of
N-alkyl-4-pyridones are also accomplished.
amount of N-(4-methylbenzylidene)-p-methylbenzylamine is
formed after refluxing the biphasic water and amine suspen-
sion under one atmosphere dioxygen for two days. The highest
yield is obtained when the ratio of the volume of water to the
amine is 8 (Table 1, entry 5). When the ratio of water to amine
increases, the yield of imine decreases dramatically (Table 1,
entries 6–8). The yield of imine is effectively unchanged by use
of a Teflon-reactor to avoid contact with light and glass
surfaces. These observations exclude the possibility of light-
induced or glass-catalyzed processes, and indicate that the
presence of water and dioxygen is essential.
Highly efficient, selective and metal-free oxidation of organic
substrates that utilize dioxygen as the terminal oxidant is one
of the most important current challenges for synthetic organic
chemistry.1 Oxidation of amines provides an alternative strat-
egy to prepare imines which are versatile synthetic intermedi-
ates in a variety of organic transformations.2 Great progress
has been made in recent years in developing mild and practical
methods for oxidation of secondary amines to imines.3 But
oxidation of primary amines utilizing green oxidants (dioxygen
and peroxide) to imines is much less developed.4 Notable
examples include vanadium-,4i,5 gold-,6 ruthenium-,7 copper-,8
tyrosine-derived quinone-,9 and polyaniline-catalyzed10 aerobic
oxidation of amines, and photo-induced aerobic oxidative
coupling of amines by TiO2,11 carbon nitride,12 and uracil-
annulated heteroazulene derivatives.13 Metal-free catalytic
systems are quite rare.9,10,12,13 Landge et al. reported a micro-
wave-assisted solvent-free system catalyzed by K-10 mont-
morillonite requiring a very high temperature (150 1C).14 Chu
and Li first achieved oxidative coupling of amines to imines in
water using V2O5 as catalyst at room temperature. However,
excessive H2O2 was used as the terminal oxidant and the scope
of the substrates was limited to benzylamines with electron
withdrawing groups.15 This article reports on an unprece-
dented metal-free aerobic oxidative coupling of amines to
imines using dioxygen as the sole oxidant and water as the
reaction medium.
Prolonging the refluxing time results in higher yield (up to
83%, Table 2, entry 1) although the selectivity declines due to
the overoxidation of imine to oxime, amide and carboxylate
salt, which are detected by GC-MS and 1H NMR. A variety of
substituted benzylamine derivatives are also observed to form
imines in moderate to high yields (Table 2). Electronic effects
associated with electron donating and electron withdrawing
substituents on the phenyl ring have little effect on the
efficiency of the oxidation reaction (Table 2, entries 3–7).
The thiophen-2-ylmethanamine is effectively coupled to form
imine P8 indicating good tolerance of heteroatoms (Table 2,
entry 8). A noteworthy feature of our method is the formation
of imine P9 (Table 2, entry 9) which is a significant improve-
ment over previously reported methods for the preparation
of sterically hindered imines.16 Aliphatic amines, allylic- or
propargylic-amines do not produce measurable quantities of
imine products under the same reaction conditions and the
yields for secondary amines are very low. Oxidative coupling of
aliphatic amines usually gives relatively low yield,5b,6e,f,8 and
reports on the oxidative coupling of allylic- and propargylic-
amines are very rare.
The imine products are observed in equilibrium with free
amines and aldehydes in water. Heating the mixture of P2
and P4 leads to immediate formation of two new species
N-benzylidene-p-methoxylbenzylamine and N-(4-methoxyl-
benzylidene)-benzylamine.
Heating the homogeneous solution of 4-methylbenzylamine
(0.60 mmol) in organic solvents such as acetonitrile, toluene or
xylene (0.6 ml) under one atmosphere dioxygen results in trace
amounts of the product (Table 1, entries 1–3). There is no
imine observed when 0.6 ml of water and one atmosphere of
nitrogen are used (Table 1, entry 4). However, a notable
Although anilines could not undergo homo-coupling reac-
tion due to lack of the a-carbon hydrogen, it is feasible to
obtain cross-coupling products with benzylamines through the
tandem reaction of homo-coupling of benzylamines to form
imines, hydrolysis to form aldehydes, and condensation with
excess anilines to give cross-coupling products (Scheme S1,
ESIw). Their cross-coupling products N-aryl imines are thermo-
dynamically more stable than N-benzylidene–benzylamine
which drives the coupling of benzylamines with anilines
Beijing National Laboratory for Molecular Sciences,
State Key Lab of Rare Earth Materials Chemistry and Applications,
College of Chemistry and Molecular Engineering, Peking University,
Beijing, 100871, China. E-mail: fuxf@pku.edu.cn;
Fax: +86 10-6275-1708; Tel: +86 10-6275-6035
w Electronic supplementary information (ESI) available: The general
procedure of the reactions, the preparation of imines and their spectral
data. See DOI: 10.1039/c1cc13202d
c
10148 Chem. Commun., 2011, 47, 10148–10150
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Table 1 Optimization of the oxidation conditionsa
Table 3 Oxidative cross-coupling of aminesa
Entry Amine 1 Amine 2
Product
Time/h Yieldb (%)
Entry Sol. (vol./ml) System status Yieldb (%) Selectivityb (%)
1
2
3
36
36
36
77
73
66
1
2
CH3CN (0.6) Homogeneous o1
—
Toluene (0.6) Homogeneous
4
5
495
495
—
495
495
495
495
3c
4d
5
Xylene (0.6)
H2O (0.6)
H2O (0.6)
H2O (5)
Homogeneous
Biphase
Biphase
Oil-in-water
Oil-in-water
Homogeneous
o1
49
36
18
4
6
7
H2O (10)
H2O (20)
8e
4
5
48
56
53
45
a
Reaction conditions: 4-methylbenzylamine 0.60 mmol, 1 atm of O2,
e
b
c
d
reflux for 48 hours. GC results. 120 1C. 1 atm of N2. 150 ml flask.
a
Reaction conditions: 0.6 mmol of amine 1, 1.8 mmol of amine 2,
b
0.6 ml of water, and 1 atm of O2. GC yield, the conversions of
benzylamine are over 95%.
Table 2 Aerobic oxidation of various aminesa
catalyst in aqueous solution.15 Since Sharpless and co-workers
reported that water insoluble reactants stirred vigorously in
pure water gave a faster reaction rate compared to that in an
organic solution or in neat conditions in 2005,17 performing
organic reactions ‘‘on water’’ has received intense attention due
to the high efficiency, low pollution, low economic costs, facile
separation processes, and safety considerations.18 Recently,
Aubry and co-workers developed two or three-liquid-phase
microemulsion systems for the oxidation with singlet oxygen
generated in situ;19 Shapiro and co-workers successfully developed
a metal-free system accomplishing aerobic oxidation of aldehydes
on water.20 Beattie et al. observed a rate accelerated reaction
when performed on water and proposed that strong adsorption
of the hydroxide ion at the oil–water interface facilitated the
acid-catalysis process.21 We observe that reduction of the yield
of imine with increase of the ratio of water to amine (Table 1,
entries 5–8) most probably results from switching from
‘‘on water’’ to ‘‘in water’’ conditions where addition of 20 ml
of water to the biphasic water (0.6 ml) and amine (0.6 mmol)
suspension gives a homogeneous solution. Based on our
observations and those mechanisms reported in the literature,
we propose that the amino group may form hydrogen bonds
with water; amines react with oxygen to form peroxide
complexes which subsequently release hydrogen peroxide
which can also act as the oxidant to form imine intermediates;
the imines react with free amines to give the coupling products
or with water to form benzaldehydes which are then converted
to coupling products through condensation with free amines
(Scheme 1–I). Refluxing benzophenone and diphenylmethamine
on water under nitrogen atmosphere results in less than 1% imine
product which indicates that P9 is probably formed from
deamination condensation reaction of diphenylmethimine
and diphenylmethamine (Scheme 1–I, pathway A). The fact
that the substrates are limited to aromatic methylamines and
the substitution on the phenyl ring has small influence suggests
that the oxygen insertion may undergo a radical pathway:
oxygen grabs the a-H of benzylamine to form a benzyl radical,
which reacts with oxygen to form a peroxide complex
(Scheme 1–II). An alternative mechanism has been suggested
by one of the reviewers: the first step is an ene-reaction with
the singlet oxygen to form a hydroperoxide complex, which
Entry Substrate
Product
(P)
Time/h Yieldb (%)
1
2
3
4
(P1) 64
(P2) 28
(P3) 48
(P4) 28
83
75
83
64
5
6
(P5) 28
(P6) 32
79
71
7
(P7) 12
85
8
9
a
(P8) 28
(P9) 48
65
51c
Reaction conditions: 0.6 mmol of amine, 0.6 ml of water, and 1 atm
b
c
of O2. GC yield, the conversions 495%. 15% benzophenone was
formed; selectivity = 77%.
(Table 3, entries 1–3). On the other hand, aliphatic amines
have low activity toward oxidative coupling reaction, but the
cross-coupling of aliphatic amines with benzylamines is viable
with the presence of excess aliphatic amines (Table 3, entries
4 and 5). The real-time monitoring of the reaction between
benzylamine and hexamine indicates that initially N-benzylidene–
benzylamine is the main product which gradually turns to
N-benzylidene–hexamine along with the proceeding of the
reaction (Fig. S2, ESIw).
Landge et al. proposed that a dehydrogenation pathway
occurs after the amine coordinates to the acid center in the
solvent-free system catalyzed by a solid acid.14 Chu and Li
proposed that a benzylic anion intermediate is generated by
deprotonation of benzylaminium when V2O5 is used as the
c
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Scheme 1 Possible mechanisms for oxidative coupling of amines.
Scheme 2 Tandem oxidative aza Diels–Alder reaction.
eliminates a hydrogen peroxide with the recovery of aromaticity
as the driving force (Scheme 1–III).
Encouraged by high yields of the coupling of benzylamines
and the ease of separation of the imines from water, an effort
was initiated to explore the feasibility of integrating such
reactions in transformations of more practical interest such
as aza Diels–Alder reactions. The imine product generated
from amine oxidative coupling is extracted by diethyl ether.
After removal of the solvent, it is mixed with a methanol solution
of Danishefsky’s diene to form an aza Diels–Alder product
(Scheme 2). N-Aryl imines are previously found to undergo
efficient acid-free aza Diels–Alder reaction in methanol.22
Observation of an acid-free aza Diels–Alder reaction of N-alkyl
imines substantially expands the scope of the synthesis of
N-alkyl-4-pyridones.
In summary, we have developed a green protocol for
oxidative coupling of benzylamines to imines by simply refluxing
aerated suspensions of water and benzylamines. This simple
metal-free system which uses dioxygen as the sole oxidant may
find a wide range of applications in green oxidation chemistry.
Mechanistic studies accessible for this ‘‘on water’’ reaction are
on the way to obtain a deeper understanding of the origins of
high efficiency and high selectivity of these aerobic oxidative
coupling reactions.
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We are grateful for support by the starter grant from Peking
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Notes and references
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´
¨
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10150 Chem. Commun., 2011, 47, 10148–10150
This journal is The Royal Society of Chemistry 2011