Ionic-liquid-assisted metal-free oxidative coupling of amines to give imines

Article abstract of DOI:10.1002/ejoc.201402530

An oxidative coupling of amines to give imines in ionic liquids (ILs) under metal-free aerobic conditions has been developed. The high efficiency achievable in ILs is mechanistically explained in terms of activation of the starting materials (benzylamine and molecular oxygen) by an initial electron transfer, promoted by the ionic nature of the solvent. Reactivity data of variously p-substituted benzylamines show a general deactivating effect, which would imply a change in the rate-determining step in the reaction mechanism.

Full text of DOI:10.1002/ejoc.201402530

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201402530
Ionic-Liquid-Assisted Metal-Free Oxidative Coupling of Amines To Give Imines
Antonio Monopoli,*[a] Pietro Cotugno,[a] Francesco Iannone,[a] Francesco Ciminale,*[a]
Maria Michela Dell’Anna,[b] Piero Mastrorilli,[b] and Angelo Nacci[a,c]
Dedicated to C.I.N.M.P.I.S on the occasion of its 20th anniversary
Keywords: Ionic liquids / Imines / Amines / Oxidation / Oxygen / Green chemistry
An oxidative coupling of amines to give imines in ionic
liquids (ILs) under metal-free aerobic conditions has been
tron transfer, promoted by the ionic nature of the solvent.
Reactivity data of variously p-substituted benzylamines show
developed. The high efficiency achievable in ILs is mechan- a general deactivating effect, which would imply a change
istically explained in terms of activation of the starting mate-
rials (benzylamine and molecular oxygen) by an initial elec-
in the rate-determining step in the reaction mechanism.
In this field, the oxidative homocoupling of primary
amines to give imines is of particular interest [Equation (1)].
Very promising metal-free protocols based on biomimetic
systems[11] have been proposed to achieve this transforma-
tion, as have photocatalysts[12] and also efficient methods
using inexpensive and recyclable transition metal catalysts
and new materials.[10b,13]
Introduction
Imines are important and versatile intermediates in or-
ganic chemistry as they represent useful building blocks for
the synthesis of biologically active molecules, agrochem-
icals, dyes, fine chemicals, and pharmaceuticals.[1] Classi-
cally, imines are synthesized by condensation of a carbonyl
compound with a primary amine.[2] However, due to prob-
lems related to the high reactivity of aldehydes or ketones,
which often result in the formation of unwanted products,
in the last decade, a number of alternative protocols have
been developed, including oxidation of secondary amines,[3]
(1)
However, despite the number of protocols devoted to the
catalytic condensation of primary amines with alcohols,[4] oxidative homocondensation of amines, carrying out these
and homocondensation of amines under oxidative condi- reactions in environmentally friendly solvents remains un-
tions.[5]
explored, and, to the best of our knowledge, no examples
However, these methods can suffer from drawbacks con- of successful methods performed in ionic liquids (ILs)[14]
nected with the use of expensive catalysts,[5a,6] harsh reac- have been reported until now. Continuing our interest in
tion conditions,[7] stoichiometric amounts of unstable oxi- the use of ILs in organic synthesis,[15] we recently found
dant species,[3a,8] radical initiators,[5b,9] toxic reactants, or that the N-alkylation of arylamines with alkyl chlorides can
harmful and non-environmentally-friendly solvents.[10] As a be performed in high yields and with high selectivities in
consequence, the search for milder and greener conditions molten tetraalkylammonium salts at 100 °C.[15d] However,
for the synthesis of imines is still an open challenge for this reaction is not applicable to benzylamines, since ap-
chemists.
preciable amounts of the corresponding homocondensed
imines were detected in addition to the alkylation product.
As confirmed by repeating the reaction in the absence of
the alkyl chloride, the formation of the homocondensed im-
ine of benzylamine might have been the result of simple
aerobic heating of the amine dissolved in the molten salt,
apparently without the need for any catalyst or additive.
A general survey of the literature devoted to this subject
showed that the oxidative homocondensation of benzyl-
amines generally requires the presence of special oxidising
agents,[3a,11] or metal catalysts,[6,16,17] and a sole recent ex-
ample reports on a thermally promoted aerobic oxidation
[a] Department of Chemistry, University of Bari “Aldo Moro”,
Via Orabona 4, 70126 Bari, Italy
E-mail: antomono@libero.it
antonio.monopoli@uniba.it
francesco.ciminale@uniba.it
www.chimica.uniba.it
[b] DICATECh, Politecnico di Bari,
Via Orabona, 4, 70126 Bari, Italy
[c] CNR – ICCOM, Department of Chemistry, University of Bari
“Aldo Moro”,
Via Orabona, 4, 70126 Bari, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402530.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
A. Monopoli, F. Ciminale et al.
FULL PAPER
in water.[18] Due to the synthetic importance of this reac- of the four metals cited above to the reaction mixture. This
tion, we decided to investigate the role of the molten salt in revealed that none of them promotes the oxidative coupling
promoting this process.
in TBABr (Table 1, runs 6–12). In particular, in the case of
iron and copper, the addition of 3 mol-% of FeCl3 (Table 1,
run 10) or copper salts (Table 1, runs 6 and 7) seemed to
have rather a detrimental effect compared to when the reac-
tion was run without any metal (Table 1, run 5).
By carrying out reactions under an oxygen or inert atmo-
sphere in addition to those carried out under air, we found
that the reaction conversions increased with the partial
pressure of O2. Reactions run under O2 gave higher conver-
sions than those run under air or under an inert atmosphere
(Table 1, runs 5, 13, and 14). These findings suggest that
oxygen is likely to be involved in the rate-determining step
of the oxidative coupling (see Scheme 1).
Results and Discussion
We first carried out a screening of oxidation conditions
using the model substrate phenylmethanamine (1) in tetra-
butylammonium bromide (TBABr) (Table 1). To evaluate
the real ionic liquid effect, we compared the oxidation in
TBABr with that carried out in molecular solvents (DMA,
toluene, and H2O) in the absence of catalysts or any other
additive (Table 1, runs 2–5).
Table 1. Aerobic oxidative homocoupling of benzylamine in TBA-
Br.[a]
Run
Solvent Catalyst/oxidant
Conv. [%][b] Selectivity [%][b]
1
2
3
4
5
6
7
8
–
air
air
10
12
7
99
98
98
92
98
97
98
96
97
95
81
95
96
98
DMA
toluene air
H2O air
6
TBABr air
57
39
45
38
53
51
58
53
98
28[d]
TBABr CuBr2 (0.2 mol-%)
TBABr CuBr2 (1 mol-%)
TBABr Cu(OAc)2 (1 mol-%)
TBABr FeCl3 (1 mol-%)
TBABr FeCl3 (3 mol-%)
TBABr Pd(OAc)2 (0.1 mol-%)
TBABr Pt/Al2O3
9
10
11
12
13[c]
14[c]
TBABr O2
TBABr N2
[a] Reaction conditions: 1 (0.25 mmol), molten TBABr (0.4 g) or
solvent (3 mL), stirred under air at 100 °C for 5 h. [b] Conversions
and selectivities were evaluated by GLC and 1H NMR spec-
troscopy. [c] Reactions under O2 (or N2) at atmospheric pressure.
[d] Obtained under N2 in non-deaerated IL.
These initial experiments confirmed that the molten salt
assisted the oxidative coupling. In TBABr, benzylamine (1)
was selectively converted into the homocondensed product
N-benzylidene-(phenyl)-methanamine (2) in 57% yield,
whereas oxidation in the molecular solvents was unproduc-
Scheme 1. Plausible pathways for the oxidative coupling of
benzylamine in ILs.
Investigations were extended to other ionic liquids such
tive and virtually comparable to the solventless process as several tetraalkylammonium-, butylpyridinium (Bupy)-,
(Table 1, run 1). and butylmethylimidazolium (Bmim)-based ILs. Table 2
Next, we paid attention to the possible presence of metal summarizes the most representative results obtained using
contaminants that could be responsible for the activation in p-methylbenzylamine (3) as the model substrate.
TBABr. Conscious that chemicals can contain small
The reaction temperature was chosen depending on the
amounts of metals (especially molten salts), and that cross- melting point of the solvent salts. In most of the ILs tested,
contamination is always a pernicious possibility that must the reactions were carried out at 100 °C. At this tempera-
be taken into account,[19] after completion of the coupling ture, conversions were almost complete within 1 h (Table 2,
experiments, we carried out ICP analyses of the reaction runs 1–6). The occurrence of side-reactions involving the
mixture, searching for detectable amounts of metals such as solvent, such as Hofmann elimination, discouraged us from
Fe,[10b] Pd,[6b,16,17] Pt,[6c] and Cu,[13b] which are known to using higher temperatures with tetraalkylammonium salts
promote these reactions. Only Fe (53 ppb) and Cu (81 ppb) (Table 2, run 14). In low-melting ILs bearing AcO– and Cl–
were found at detectable levels. Notwithstanding this, in or- anions, the reactions could be carried out at 50 °C to give
der to exclude the contribution by any metal to the reaction excellent yields of the coupling product in double the reac-
mechanism, catalytic tests were carried out by adding each tion time (Table 2, runs 15–17).
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
Metal-Free Oxidative Coupling of Amines To Give Imines
Table 2. Oxidative coupling of p-tolylamine in ILs (TEA = tetraeth- water in tetrabutylammonium hydroxide (TBAOH·H2O)
ylammonium).[a]
can explain the disappointing results observed in this ionic
medium (Table 2, run 13). However, it cannot be excluded
–
–
that poor results obtained in BF4 and PF6 based ILs
might also be wholly or partly due to protonation of the
benzylamine by the HF that it is known to be generated in
these ionic liquids at high temperatures.[24]
Run
IL
T [°C]
Time [h]
Yield [%][b]
With the aim of extending the scope of the method, we
examined a series of substituted benzylamines (p-Me, p-
MeO, p-F, p-Cl, o-Me), α-naphthylmethanamine, and a few
non-benzylic alkylamines, evaluating both the effect of any
substituents on the aromatic ring and the influence of the
amine skeleton on the efficiency of the homocoupling reac-
tion. For each substrate, the reaction conditions (IL, tem-
perature, and reaction time) were varied to try to obtain the
maximum yield under the mildest conditions.
The results listed in Table 3 show that non-benzylic alk-
ylamines, such as hexylamine and cyclohexylamine, were
practically inert towards oxidative coupling, producing only
traces of the imines after longer reaction times (Table 3,
runs 10 and 11). In contrast to this, and very surprisingly,
cyclohexylmethanamine reacted at 50 °C in 3 h to give the
oxidative coupling product (i.e., 13) in good yield (Table 3,
run 12).
1
TBAOAc
TBACl
TBABr
TEAOAc
[Bmim]OAc
[Bmim]Cl
[Bmim]Br
[Bmim]BF4
[BuPy]Br
[BuPy]PF6
TBABr (wet)
TBACl (wet)
TBAOH·xH2O
TBAOAc
100
100
100
100
100
100
100
100
100
100
100
100
100
120
50
0.5
1
1
0.5
0.5
1
1
1
0.5
1
1
1
1
0.5
1
2
98
93
95
96
98
98
74
43
95
5
51
65
10
93
95
95
88
2[c]
3
4
5
6
7
8
9
10
11[d]
12[e]
13
14
15
16
17
TEAOAc
[Bmim]OAc
[Bmim]Cl
50
50
2
[a] Reaction conditions: IL (0.4 g), p-methylbenzylamine
(0.25 mmol) heated at the appropriate temperature under an oxy-
gen atmosphere. [b] GLC yields. [c] The salt was previously dried
under vacuum for 8 h at 50 °C. [d] Water (25 μL) was added to the
TBABr before starting the reaction. [e] The salt was exposed to the
air.
The results of the reactions of the benzylamines, includ-
ing α-naphthylmethanamine, show that the oxidative cou-
pling is sensitive to both electronic and steric effects. The
latter can clearly be seen in the fact that some sterically
hindered amines, such as o-tolylmethanamine, α-naphthyl-
Results pertaining to the screening of ionic solvents show methanamine, and particularly diphenylmethanamine pro-
that the nature of the IL cation has only a negligible effect vided the corresponding coupling products (i.e., 8, 9, and
on the reactivity (Table 2, runs 1, 4, and 5). The reactivity 10) less efficiently than unsubstituted benzylamine (Table 3,
appears to be principally influenced by the anion. The runs 1 and 7–9). As expected,[12c] inert alkylamines and an-
AcO–, Cl–, and Br– anions (Table 2, runs 1–7, 9, and 14–17) ilines Ϫ the latter are incompatible with homocoupling as
–
were found to promote the coupling much better than BF4
and PF6 (Table 2, runs 8 and 10).
a result of their lack of an α hydrogen Ϫ could be success-
fully used in cross-coupling reactions with benzylamines
–
Recently, we interpreted a similar solvent effect, observed (Table 4). In reactions with anilines (Table 4, entries 1–5),
for the N-alkylation of arylamines in ionic liquids,[15d] as however, the longer reaction times and lower yields indi-
reflecting the capability of the solvent to accept a hydrogen cated a slower formation of cross-coupling products. This
bond. Such a hydrogen-bond basicity of ILs is largely a is consistent with the considerably weaker nucleophilicity of
function of the anion, and is quantitatively expressed by its aromatic amines than aliphatic amines; coupling with the
Kamlet–Taft β parameter: 1.16 (AcO–), 1.00 (Cl–), 0.67 latter resulted in fact in almost complete conversions and
–
–
(Br–), 0.37 (BF4 ), 0.21 (PF6 ).[20] However, a closer inspec- very good yields (Table 4, entries 6–8). Exploiting the elec-
tion of the reactivity data pertaining to reactions in TBA- tronic effect of the substituents on the nucleophilicity, we
based ILs (Table 2, runs 1–3) reveals that the qualitative could obtain higher yields of cross-coupling products with
correlation with β fails in the case of TBACl, which, judg- anilines bearing electron-donating groups. For instance, a
ing from β values, should have been better performing than 60% yield was obtained for p-OMe-substituted substrate,
TBABr. Control experiments (Table 2, runs 11 and 12), vs. 25% for a p-F-substituted aniline (Table 4, entries 4 and
which were planned after considering the higher hygroscop- 2).
icity of TBACl[21] and the difficulty in handling this solvent
We also observed that the cross-coupling product, N-
under anhydrous conditions, confirmed that the water con- benzylideneaniline (14), was forming after the homocou-
tent in the ILs was important, and that it had a detrimental pling product, N-benzylidenebenzylamine (2), apparently
effect on the coupling reaction.
by exchange of aniline for benzylamine. This process would
This can be easily understood in terms of competition reasonably start with nucleophilic addition of aniline to the
between hydrogen bonding of water to the anion – which homocoupled product (i.e., 2). Moreover, in the case of an-
contributes significantly to the hydrophilicity of the IL[14a]
–
ilines, steric effects also seem to be important, as evidenced
and the essential benzylamine/anion hydrogen bonding. by the fact that cross-coupling with o-bromoaniline was un-
Consistent with these findings, the massive presence of successful (Table 4, entry 5).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
A. Monopoli, F. Ciminale et al.
FULL PAPER
Table 3. Oxidative homocoupling of various amines in ILs.[a]
Table 4. Oxidative cross-coupling of benzylamine in TBABr.[a]
[a] General reaction conditions: IL (0.4 g), benzylamine
(0.25 mmol), amine (0.5 mmol) heated at 100 °C under an oxygen
atmosphere. [b] GLC yields.
show that all p-substituents (MeO, Me, F, and Cl), regard-
less of their electronic character, exert a general deactivating
effect. This would typically imply a change in rate-de-
termining step in a two-step reaction sequence.[23]
Table 5. Reactivity data for p-substituted benzylamines.
Substituent X (σp)
Conversion [%] after 15 min
p-Cl (+0.23)
p-F (+0.06)
H (0)
p-Me (–0.17)
p-MeO (–0.27)
67
93
95
88
61
[a] General reaction conditions: IL (0.4 g), amine (0.25 mmol)
heated at the appropriate temperature under an oxygen atmo-
sphere. [b] GLC yields. [c] In TEAOAc, 1-naphthylamide was the
major product (81%).[22]
Returning to the homo-coupling reaction, (see Table 3),
Consistent with this unusual electronic substituent effect,
the results with para-substituted benzylamines relative to and with the other results described above, we propose the
benzylamine show that oxidative coupling in ILs is disfa- mechanism shown in Scheme 1. In the first step, a one-elec-
voured by both electron-donating (p-MeO) and electron- tron transfer from amine 1 to dioxygen generates the radical
withdrawing (p-Cl) substituents (Table 3, runs 1, 3, and 6).
ion pair 1+· O2–·, which would be particularly stabilized by
Reactivity data more reliable for mechanistic interpret- solvation in IL as a result of ion–ion interactions with the
ation are reported in Table 5 as conversions in TBABr at ionic components of the solvent, and specific hydrogen
100 °C after a shorter reaction time (15 min). These clearly bonds between the aminium radical 1+· and the IL anions.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
Metal-Free Oxidative Coupling of Amines To Give Imines
Such a stabilization, which could be the reason behind potentials were found to give a good Hammett correlation,
the observed activating effect of ILs, has precedent in two with a negative ρ value of –0.94.[29] On the other hand,
recently reported reactions of amines to give ionic products, step b would become rate-determining in the presence of
namely N-alkylations of anilines,[15d] and protonation equi- electron-donating groups. In fact, substituents such as p-
libria of aliphatic amines.[25]
OMe and p-Me (σ Ͻ 0) may reasonably be expected to have
Moreover, various catalytic oxidative couplings of a retarding effect on the radical cation dehydrogenation that
benzylamine are reported to involve the same radical ions would amount to a deprotonation along with a hydrogen-
–· [12a,13c,13d]
1+· and O2
.
However, in those cases, the forma- atom abstraction.
tion of the radical ions does not occur by direct electron
transfer as in the case of the ILs, but is instead mediated
by the catalyst. Apart from this difference, our mechanistic
proposal parallels that of the literature.
Conclusions
In conclusion, we have developed a protocol for the aero-
bic oxidation of amines to give imines using ionic liquids
as reaction media. The high efficiency achievable in ILs is
mechanistically explained in terms of activation of the start-
ing materials (benzylamine and molecular oxygen) by an
initial electron transfer, which may be promoted by the
ionic nature of the solvent.
Therefore, the presented process, which does not require
the use of any metal catalyst or organic oxidizing agent,
competes favourably with most of the reported protocols,
which require higher temperatures, catalysts, additives, and
longer reaction times. To the best of our knowledge, this
represents the first example of metal-free oxidative coupling
of amines to give imines in ionic liquids.
Furthermore, concerning our thought that ILs could be
capable of promoting the direct one-electron oxidation of
an amine by O2, it is interesting to note that in TBABr, we
have been able to use p-toluidine as a redox mediator in a
radical thiol–ene addition without the ruthenium poly-
pyridyl photocatalyst[26] that, in the original reaction car-
ried out in MeCN,[27] was reported to be necessary to cata-
lyse the oxidation of the amine by O2. After generation of
the active species by single-electron transfer, the oxidative
coupling would proceed by dehydrogenation of aminium
radical 1+· by superoxide, giving rise to an imine intermedi-
ate and H2O2 (path b). Then, the final imine product would
simply be the result of a condensation of the imine interme-
diate with the starting benzylamine, in the case of homo-
coupling (path c), or of an aliphatic amine or aniline, in the
case of heterocoupling reactions. Qualitative detection of
H2O2 by means of a colorimetric assay[28] provided good
direct evidence for the dehydrogenation pathway described
above, but an oxygenation pathway could not be completely
excluded as a viable alternative.
According to this alternative pathway, the coupled imine
might originate from an oxygenative C–N bond cleavage of
the aminium radical to give hydroxylamine and benzalde-
hyde, followed by condensation of the latter with benzyla-
mine (steps e and f). A similar question was already posed
regarding aerobic photocatalytic oxidation on TiO2, and
the oxygenative pathway was determined to be preferred,
based on the fact that a significant amount of benzaldehyde
was detected in the reaction of dibenzylamine.[12c]
Experimental Section
General Information: All the starting amines, TBAOH·H2O (40%
in H2O), and metal derivatives (listed in Table 1) were sourced com-
mercially and used as received. Molecular solvents (toluene, DMA,
and water) were distilled before use. Ionic liquids TBABr,
TBAOAc, [Bmim]Cl, [Bmim]BF4, [BuPy]Br (from Fluka), [Bmim]-
Br, TEAOAc, TBACl (from Aldrich), [Bmim]OAc, and [BuPy]PF6
(from ABCR) were dried before use, yields of the imine products
were determined by GLC using decane as an internal standard. To
identify the reaction products, first they were isolated by column
chromatography on neutral aluminum oxide (Al2O3, 50–200 μm,
from Baker). Next, the products were identified by comparison of
their GC–MS and NMR spectroscopic data with those reported in
the literature (see below and Supporting Information). NMR spec-
tra are recorded in CDCl3 with a 400 MHz spectrometer.
However, the fact that we did not detect benzaldehyde in
the reaction of dibenzylamine in TBABr (Table 3, run 13)
testifies for a preferred dehydrogenative pathway. On the
other hand, this result also indicates that our experimental
conditions are unfavourable for imine hydrolysis, thus rul-
ing out that the possibility that the coupled imine can derive
from hydrolysis of the intermediate imine (Scheme 1,
step d), followed by condensation of the resulting benzalde-
hyde with the starting benzylamine.
Typical Homocoupling Procedure: In a vial (5 mL) equipped with a
screw cap and a magnetic stirrer bar, and connected by a side-arm
to an oxygen line, IL (0.4 g), benzylamine (0.25 mmol), and decane
(internal standard, for GLC yields) were stirred and heated for the
appropriate reaction time (see Tables 1, 2, and 3). The mixture was
washed with aqueous NaHCO3 and then extracted with Et2O (5ϫ
1 mL). Then the combined organic layers were dried with anhy-
drous MgSO4, the solvent was removed in vacuo, and the crude
mixture was purified by chromatography on a short pad of Al2O3
(eluent hexane/diethyl ether). The isolated products were identified
Finally, concerning the observed substituent effect, it is
worth considering that a change in the rate-determining
step may occur between steps a and b, which have different by comparison of their spectroscopic data with those reported in
the literature.
electronic demands. Step a would be made rate-determining
by the presence of electron-withdrawing substituents (e.g.,
p-F and p-Cl, σ Ͼ 0). These are predicted to slow down a
one-electron oxidation, as demonstrated in the electrochem-
(E)-N-Benzylidene-1-phenylmethanamine (2): 1H NMR: δ = 4.82 (s,
2 H), 7.15–7.45 (m, 8 H), 7.8 (d, J = 4.5 Hz, 2 H), 8.35 (s, 1 H)
ppm. 13C NMR: δ = 65.09, 127.04, 128.04, 128.33, 128.54, 128.63,
ical oxidation of N,N-dimethylbenzylamines whose peak 130.79, 136.27, 139.39, 161.89 ppm; see ref.[30]
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
A. Monopoli, F. Ciminale et al.
151.9, 132.6 (d, JC,F = 2.9 Hz), 130.8 (d, JC,F = 8.9 Hz), 129.2,
FULL PAPER
(E)-N-(4-Methylbenzylidene)-1-p-tolylmethanamine (4): 1H NMR: δ
= 2.35 (s, 3 H), 2.39 (s, 3 H), 4.80 (s, 2 H), 7.25 (m, 6 H), 7.7 (d, J 126.1, 120.9, 116.0 (d, JC,F = 21.9 Hz) ppm.
= 8.2 Hz, 2 H), 8.38 (s, 1 H) ppm. 13C NMR: δ = 21.22, 21.61,
64.92, 128.09, 128.37, 129.27, 129.42, 133.82, 136.55, 136.61,
141.06, 161.76 ppm; see ref.[30]
(E)-N-Benzylidenehexan-1-amine (19): 1H NMR: δ = 0.89 (t, J =
6.9 Hz, 3 H), 1.35 (m, 6 H), 1.75 (m, 2 H), 3.60 (m, 2 H), 7.40 (m,
3 H), 7.50 (m, 2 H), 8.30 (s, 1 H) ppm. 13C NMR: δ = 14.81,
22.99, 27.84, 31.30, 31.92, 62.52, 128.61, 128.82, 130.64, 136.71,
160.89 ppm; see ref.[35]
(E)-N-(4-Methoxybenzylidene)-1-(4-methoxyphenyl)methanamine
1
(5): H NMR: δ = 3.75 (s, 3 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 4.75
(s, 2 H), 6.78–6.90 (m, 4 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.70 (d, J
= 8.3 Hz, 2 H), 8.30 (s, 1 H) ppm. 13C NMR: δ = 55.31, 55.39,
64.43, 113.97, 114.04, 129.23, 129.29, 129.86, 131.76, 158.72,
160.97, 161.74 ppm; see ref.[30]
(E)-N-Benzylidenedodecan-1-amine (20): 1H NMR: δ = 8.27 (s, 1
H), 7.72 (d, J = 3.0 Hz, 2 H), 7.40 (t, J = 3.0 Hz, 3 H), 3.60 (t, J
= 6.0 Hz, 2 H), 1.69 (t, J = 6.0 Hz, 2 H), 1.29 (d, J = 20.6 Hz, 18
H), 0.88 (t, J = 6.0 Hz, 3 H) ppm. 13C NMR: δ = 160.6, 136.5,
130.5, 128.6, 128.1, 61.9, 31.9, 31.1, 29.70, 29.65, 29.60, 29.50,
29.36, 27.5, 22.7, 14.2 ppm.
1
(E)-N-(4-Fluorobenzylidene)-1-(4-fluorophenyl)methanamine (6): H
NMR: δ = 4.75 (s, 2 H), 7.00–7.15 (m, 4 H), 7.25 (m, 2 H), 7.75
(m, 2 H), 8.32 (s, 1 H) ppm. 13C NMR 64.31, 115.50 (d, JC,F
=
1
(E)-N-Benzylidene-2-phenylethanamine (21): H NMR: δ = 8.14 (s,
21.1 Hz): δ = , 115.95 (d, JC,F = 22.0 Hz), 129.50 (d, JC,F = 8.1 Hz),
130.40 (d, JC,F = 8.5 Hz), 132.52 (d, JC,F = 3.1 Hz), 135.11 (d, JC,F
1 H), 7.70–7.68 (m, 2 H), 7.39–7.38 (m, 3 H), 7.29–7.17 (m, 5 H),
3.85 (t, J = 7.0 Hz, 2 H), 3.01 (t, J = 7.5 Hz, 2 H) ppm. 13C NMR:
δ = 161.4, 139.9, 136.2, 130.5, 129.0, 128.5, 128.3, 128.0, 126.0,
63.1, 37.5 ppm.
= 3.3 Hz), 160.55, 162.83 (d, JC,F = 243.8 Hz), 164.33 (d, JC,F
=
250.5 Hz) ppm; see ref.[31]
(E)-N-(4-Chlorobenzylidene)-1-(4-chlorophenyl)methanamine (7): 1H
NMR: δ = 4.75 (s, 2 H), 7.15–7.40 (m, 6 H), 7.65 (m, 2 H), 8.30
(s, 1 H) ppm. 13C NMR: δ = 64.25, 128.76, 129.05, 129.38, 129.60,
132.95, 134.59, 137.00, 137.78, 160.00 ppm; see ref.[30]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR and mass spectra of the reaction products.
(E)-N-(2-Methylbenzylidene)-1-o-tolylmethanamine (8): 1H NMR: δ
= 2.30 (s, 3 H), 2.51 (s, 3 H), 4.83 (s, 2 H), 7.10–7.31 (m, 7 H), 7.90
(m, 1 H), 8.71 (s, 1 H) ppm. 13C NMR: δ = 19.85, 19.48, 63.52,
126.22, 126.33, 127.28, 127.92, 128.47, 130.25, 130.39, 130.99,
134.41, 136.27, 137.76, 137.88, 160.05 ppm; see ref.[31]
Acknowledgments
Partial financial support for this work from the Ministry of Univer-
sity and Scientific Research of Italy (MIUR) and from the Univer-
sity of Bari is gratefully acknowledged.
(E)-1-(Naphthalen-1-yl)-N-(naphthalen-1-yl-methylene)methan-
1
amine (9): H NMR: δ = 5.39 (s, 2 H), 7.42–7.60 (m, 7 H), 7.80–
[1] a) M. A. Fox, J. N. Younathan, Tetrahedron 1986, 42, 6285–
6291; b) S. I. Murahashi, Angew. Chem. Int. Ed. Engl. 1995,
34, 2443–2465; Angew. Chem. 1995, 107, 2670–2693; c) H.
Wang, R. E. Partch, Y. Li, J. Org. Chem. 1997, 62, 5222–5225;
d) J. P. Adams, J. Chem. Soc. Perkin Trans. 1 2000, 2, 125–139;
e) P. G. Cozzi, Chem. Soc. Rev. 2004, 33, 410–421; f) J. S. M.
Samec, A. H. Ell, J. E. Bäckvall, Chem. Eur. J. 2005, 11, 2327–
2334; g) H. Sun, F. Z. Su, J. Ni, Y. Cao, H. Y. He, K. N. Fan,
Angew. Chem. Int. Ed. 2009, 48, 4390–4393; Angew. Chem.
2009, 121, 4454–4457; h) O. Rios-Bern, S. O. Flores, I.
Cordova, M. A. Valenzuela, Tetrahedron Lett. 2010, 51, 2730–
2733; i) B. Gnanaprakasam, J. Zhang, D. Milstein, Angew.
Chem. Int. Ed. 2010, 49, 1468–1471; Angew. Chem. 2010, 122,
1510–1513; j) Y. Shiraishi, Y. Sugano, S. Tanaka, T. Hirai, An-
gew. Chem. Int. Ed. 2010, 49, 1656–1660; Angew. Chem. 2010,
122, 1700–1704; k) Y. Shiraishi, M. Ikeda, D. Tsukamoto, S.
Tanaka, T. Hirai, Chem. Commun. 2011, 47, 4811–4813; l) S.
Furukawa, Y. Ohno, T. Shishido, K. Teramura, T. Tanaka,
ACS Catal. 2011, 1, 1150–1153.
[2] a) S. Nieto, J. M. Dragna, E. V. Anslyn, Chem. Eur. J. 2010, 16,
227–232; b) L. R. Reddy, M. Prashad, Chem. Commun. 2010,
46, 222–224; c) B. Miriyala, S. Bhattacharyya, J. S. Williamson,
Tetrahedron 2004, 60, 1463–1471; d) R. S. Varma, R. Dahiya,
S. Kumar, Tetrahedron Lett. 1997, 38, 2039–2042.
[3] a) K. C. Nicolaou, C. J. N. Mathison, T. Montagnon, Angew.
Chem. Int. Ed. 2003, 42, 4077–4082; Angew. Chem. 2003, 115,
4211–4216; b) K. Yamaguchi, N. Mizuno, Angew. Chem. Int.
Ed. 2003, 42, 1480–1483; Angew. Chem. 2003, 115, 1518–1521;
c) H. Choi, M. P. Doyle, Chem. Commun. 2007, 745–747; d)
A. Dhakshinamoorthy, M. Alvaro, H. Garcia, ChemCatChem
2010, 2, 1438–1443; e) L. Aschwanden, T. Mallat, M. Macie-
jewski, F. Krumeich, A. Baiker, ChemCatChem 2010, 2, 666–
673.
7.95 (m, 5 H), 8.25 (d, J = 8.4 Hz, 1 H), 8.95 (d, 1 H), 9.09 (s, 1
H) ppm. 13C NMR: δ = 63.65, 124.52, 124.65, 125.42, 125.80,
125.89, 126.10, 126.21, 126.31, 127.40, 128.01, 128.82, 128.93,
129.39, 131.34, 131.58, 131.86, 131.93, 134.05, 134.13, 135.75,
162.51 ppm; see ref.[32]
1
N-(Diphenylmethylene)-1,1-diphenylmethanamine (10): H NMR: δ
= 5.55 (s, 1 H), 7.05 (m, 2 H), 7.10–7.45 (m, 16 H), 7.8 (m, 2 H)
ppm. 13C NMR: δ = 70.00, 126.85, 127.79, 127.97, 128.20, 128.53,
128.60, 128.66, 128.94, 130.25, 136.94, 140.05, 145.20, 167.17 ppm;
see ref.[33]
(E)-1-Cyclohexyl-N-(cyclohexylmethylene)methanamine (13): This
product could not be purified satisfactorily by chromatography be-
cause of its ease of hydrolysis. It was identified by GC–MS (EI):
m/z (%) = 207 (1) [M]+, 152 (18), 139 (8), 124 (100), 95 (17), 55
(27); see ref.[34]
1
(E)-N-Benzylideneaniline (14): H NMR: δ = 7.20 (m, 3 H), 7.35–
7.45 (m, 5 H), 7.88–7.91 (m, 2 H), 8.48 (s, 1 H) ppm. 13C NMR: δ
= 121.05, 126.00, 128.92, 128.99, 129.32, 131.54, 136.42, 152.29,
160.38 ppm; see ref.[30]
1
(E)-N-Benzylidene-4-methoxybenzenamine (15): H NMR: δ = 8.48
(s, 1 H), 7.90–7.87 (m, 2 H), 7.47–7.45 (m,3 H), 7.52–7.21 (m, 2
H), 6.95–6.92 (m, 2 H), 3.83 (s,3 H) ppm. 13C NMR: δ = 158.4,
158.3, 144.9, 136.4, 131.0, 128.7, 128.6, 122.2, 114.4, 55.5 ppm.
(E)-N-Benzylidene-4-methylbenzenamine (16): 1H NMR: δ = 8.46
(s, 1 H), 7.91–7.88 (m, 2 H), 7.46 (m, 3 H), 7.21–7.12 (m, 4 H),
2.37 (s, 3 H) ppm. 13C NMR: δ = 159.6, 149.5, 136.4, 135.8, 131.2,
129.8, 128.74, 128.72, 120.8, 21.0 ppm.
[4] a) M. S. Kwon, S. Kim, S. Park, W. Bosco, R. K. Chidrala, J.
Park, J. Org. Chem. 2009, 74, 2877–2879; b) J. W. Rigoli, S. A.
Moyer, S. D. Pearce, J. M. Schomaker, Org. Biomol. Chem.
2012, 10, 1746–1749.
(E)-N-Benzylidene-4-fluorobenzenamine (17): 1H NMR: δ = 8.41 (s,
1 H), 7.90 (dd, J = 8.5, 5.5 Hz, 2 H), 7.40–7.37 (m, 2 H), 7.24–7.13
(m, 5 H) ppm. 13C NMR: δ = 164.8 (d, JC,F = 250.8 Hz), 158.8,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
Metal-Free Oxidative Coupling of Amines To Give Imines
[5] a) K. Shimizu, K. Ohshima, Y. Tai, M. Tamura, A. Satsuma,
Catal. Sci. Technol. 2012, 2, 730–738; b) T. Mukaiyama, A.
Kawana, Y. Fukuda, J. Matsuo, Chem. Lett. 2001, 30, 390–391;
c) S. I. Murahashi, Y. Okano, H. Sato, T. Nakae, N. Komiya,
Synlett 2007, 1675–1678; d) M.-H. So, Y. Liu, C.-M. Ho, C.-
M. Che, Chem. Asian J. 2009, 4, 1551–1561; e) S. Kodama, J.
Yoshida, A. Nomoto, Y. Ueta, S. Yano, M. Ueshima, A.
Ogawa, Tetrahedron Lett. 2010, 51, 2450–2452.
[6] a) E. R. Klobukowski, R. J. Angelici, L. K. Woo, Catal. Lett.
2012, 142, 161–167; b) K. Shimizu, K. Ohshima, K. Shimura,
M. Tamura, A. Satsuma, Green Chem. 2011, 13, 3096–3100; c)
W. He, L. Wang, C. Sun, K. Wu, S. He, J. Chen, P. Wu, Z. Yu,
Chem. Eur. J. 2011, 17, 13308–13317; d) L. Aschwanden, B.
Panella, P. Rossbach, B. Keller, A. Baiker, ChemCatChem 2009,
1, 111–115; e) A. Grirrane, A. Corma, H. Garcia, J. Catal.
2009, 264, 138–144.
Dell’Anna, A. Monopoli, J. Organomet. Chem. 2014, 752, 1–
5.
[16] S.-I. Murahashi, T. Hirano, T. Yano, J. Am. Chem. Soc. 1978,
100, 348–350.
[17] M. C. Lubinu, L. D. Luca, G. Giacomelli, A. Porcheddu,
Chem. Eur. J. 2011, 17, 82–85.
[18] L. Liu, S. Zhang, X. Fu, C.-H. Yan, Chem. Commun. 2011, 47,
10148–10150.
[19] a) N. Leadbeater, M. Marco, J. Org. Chem. 2003, 68, 5660–
5667; b) R. Arvela, N. Leadbeater, M. Sangi, V. Williams, P.
Granados, R. A. Singer, J. Org. Chem. 2005, 70, 161–168; c) N.
Leadbeater, Nature Chem. 2010, 2, 1007–1009.
[20] For Kamlet–Taft parameters of IL ions, see: L. Crowhurst,
P. R. Mawdsley, J. M. Perez-Arlandis, P. A. Salter, T. Welton,
Phys. Chem. Chem. Phys. 2003, 5, 2790–2794.
[21] J. G. Huddleston, A. E. Visser, W. M. Reichert, H. D. Willauer,
G. A. Broker, R. D. Rogers, Green Chem. 2001, 3, 156–164.
[22] 1-Naphthylamide was the major product in TEAOAc, as a re-
sult of an overoxidation of secondary imine 9, which was
formed by the coupling of naphthylmethanamine. As a further
confirmation, a certain amount of pure 9 was placed in
TEAOAc under the reaction conditions, and this gave 1-
naphthylamide in 2 h.
[23] a) R. A. Jones, Physical and Mechanistic Organic Chemistry,
2nd ed., Cambridge University Press 1984, p. 43–45; b) N. S.
Isaacs, Physical Organic Chemistry, Longman Scientific &
Technical, 1987, p. 146–148.
[7] S. M. Landge, V. Atanassova, M. Thimmaiah, B. Toeroek, Tet-
rahedron Lett. 2007, 48, 5161–5164.
[8] G. Chu, C. Li, Org. Biomol. Chem. 2010, 8, 4716–4719.
[9] L. Liu, Z. Wang, X. Fu, C.-H. Yan, Org. Lett. 2012, 14, 5692–
5695.
[10] a) L. Aschwanden, T. Mallat, F. Krumeich, A. Baiker, J. Mol.
Catal. A 2009, 309, 57–62; b) R. I. Khusnutdinov, A. R. Baygu-
sina, R. I. Aminov, Russ. J. Org. Chem. 2012, 48, 1059–1061.
[11] a) H. Yuan, W. J. Yoo, H. Miyamura, S. Kobayashi, J. Am.
Chem. Soc. 2012, 134, 13970–13973; b) A. E. Wendlandt, S. S.
Stahl, Org. Lett. 2012, 14, 2850–2853; c) M. Largeron, M. B.
Fleury, Angew. Chem. Int. Ed. 2012, 51, 5409–5412; Angew.
Chem. 2012, 124, 5505–5508.
[12] a) J. H. Park, K. C. Ko, E. Kim, N. Park, J. H. Ko, D. H. Ryu,
T. K. Ahn, J. Y. Lee, S. U. Son, Org. Lett. 2012, 14, 5502–5505;
b) X. Lang, W. Ma, Y. Zhao, C. Chen, H. Ji, J. Zhao, Chem.
Eur. J. 2012, 18, 2624–2631; c) X. Lang, H. Ji, C. Chen, W.
Ma, J. Zhao, Angew. Chem. Int. Ed. 2011, 50, 3934–3937; An-
gew. Chem. 2011, 123, 4020–4023; d) N. Li, X. Lang, W. Ma,
H. Ji, C. Chen, J. Zhao, Chem. Commun. 2013, 49, 5034–5036.
[13] a) H. Huang, J. Huang, Y.-M. Liu, H.-Y. He, Y. Cao, K.-N.
Fan, Green Chem. 2012, 14, 930–934; b) R. D. Patil, S. Adimur-
thy, Adv. Synth. Catal. 2011, 353, 1695–1700; c) C. Su, M.
Acik, K. Takai, J. Lu, S.-J. Hao, Y. Zheng, P. Wu, Q. Bao, T.
Enoki, Y. J. Chabal, K. P. Loh, Nature Commun. 2012, 3, 1–9;
d) F. Su, S. C. Mathew, L. Mohlmann, M. Antonietti, X.
Wang, S. Blechert, Angew. Chem. Int. Ed. 2011, 50, 657–660;
Angew. Chem. 2011, 123, 683–686; e) Z. Zhang, F. Wang, M.
Wang, S. Xu, H. Chen, C. Zhang, J. Xu, Green Chem. 2014,
DOI: 10.1039/c3gc42312c.
[24] a) P. Wasserscheid, T. Welton (Eds.), Ionic Liquids in Synthesis,
2nd ed., Wiley-VCH, Weinheim, Germany, 2008; b) E. S. Puti-
lova, G. V. Kryshtal, G. M. Zhdankina, N. A. Troitskii, S. G.
Zlotin, Russ. J. Org. Chem. 2005, 41, 512–516.
[25] F. D’Anna, S. Marullo, P. Vitale, R. Noto, J. Org. Chem. 2009,
74, 6224–6230.
[26] In a typical experiment, cyclohexene (0.5 mmol) and benz-
ylthiol (2.5 equiv.) were stirred at 100 °C in the presence of
TBABr (0.4 g) and p-toluidine (0.25 mmol), under an oxygen
atmosphere. After 2 h, GC–MS analysis revealed a 75% con-
version to the expected thiol–ene addition product [i.e., benzyl-
(cyclohexyl)sulfane, 70% yield] and small percentages of the
dibenzyl disulfide (20%) and the dibenzyl sulfide (10%). The
same reaction performed in the absence of p-toluidine gave a
similar degree of conversion, the disulfide was the sole product.
[27] E. L. Tyson, Z. L. Niemeyer, T. P. Yoon, J. Org. Chem. 2014,
79, 1427–1436.
[28] G. Su, Y. Wei, M. Guo, AJAC 2011, 2, 879–884.
[29] J. R. Lindsay Smith, D. Masheder, J. Chem. Soc. Perkin Trans.
2 1976, 47–51.
[14] a) J. P. Hallett, T. Welton, Chem. Rev. 2011, 111, 3508–3576; b)
C. D. Hubbard, P. Illner, R. van Eldik, Chem. Soc. Rev. 2011,
40, 272–290.
[15] a) V. Calo, A. Nacci, A. Monopoli, J. Organomet. Chem. 2005,
690, 5458–5466; b) A. Monopoli, A. Nacci, V. Calò, F. Cimin-
ale, P. Cotugno, A. Mangone, L. C. Giannossa, P. Azzone, N.
Cioffi, Molecules 2010, 15, 4511–4525; c) P. Cotugno, A. Mon-
[30] H. Yuan, W.-J. Yoo, H. Miyamura, S. Kobayashi, J. Am. Chem.
Soc. 2012, 134, 13970–13973.
[31] E. Zhang, H. Tian, S. Xu, X. Yu, Q. Xu, Org. Lett. 2013, 15,
2704–2707.
[32] K. Onto, T. Hatakeyama, M. Takeo, S. Uchiito, M. Tokuda,
H. Suginome, Tetrahedron 1998, 54, 8403–8410.
opoli, F. Ciminale, N. Cioffi, A. Nacci, Org. Biomol. Chem. [33] P. Eisenberger, A. M. Bailey, C. M. Crudden, J. Am. Chem.
2012, 10, 808–813; d) A. Monopoli, P. Cotugno, M. Cortese,
C. D. Calvano, F. Ciminale, A. Nacci, Eur. J. Org. Chem. 2012,
3105–3111; e) A. Monopoli, P. Cotugno, G. Palazzo, N. Dita-
ranto, B. Mariano, N. Cioffi, F. Ciminale, A. Nacci, Adv.
Synth. Catal. 2012, 354, 2777–2788; f) V. Calò, V. Fiandanese,
A. Nacci, A. Scilimati, Tetrahedron 1994, 50, 7283–7292; g) P.
Cotugno, M. Casiello, A. Nacci, P. Mastrorilli, M. M.
Soc. 2012, 134, 17384–17387.
[34] E. Gebauer-Henke, W. Leitner, A. Prokofieva, H. Vogta, T. E.
Müller, Catal. Sci. Technol. 2012, 2, 2539–2548.
[35] Z. Zhu, J. H. Espenson, J. Am. Chem. Soc. 1996, 118, 9901–
9907.
Received: May 13, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42530
/KAP1
Date: 13-08-14 18:04:37
Pages: 8
A. Monopoli, F. Ciminale et al.
FULL PAPER
Oxidative Coupling
An oxidative coupling of amines to give im-
ines in ionic liquids (ILs) under metal-free
aerobic conditions has been developed. The
efficiency achievable in ILs is explained in
terms of activation of the reactants (benz-
ylamine and O2) by an initial electron
transfer, promoted by the ionic medium.
A. Monopoli,* P. Cotugno, F. Iannone,
F. Ciminale,* M. M. Dell’Anna,
P. Mastrorilli, A. Nacci ..................... 1–8
Ionic-Liquid-Assisted Metal-Free Oxidative
Coupling of Amines To Give Imines
Keywords: Ionic liquids / Imines / Amines /
Oxidation / Oxygen / Green chemistry
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0