Developments in the Reactivity of 2-Methylimidazolium Salts

Article abstract of DOI:10.1021/acs.joc.7b00807

Unexpected and unusual reactivity of 2-methylimidazolium salts toward aryl-N-sulfonylimines and aryl aldehydes is here reported. Upon reaction with aryl-N-sulfonylimines, the addition product, arylethyl-2-imidazolium-1-tosylamide (3), is formed with moderate to good yields, while upon reaction with aldehydes, the initial addition product (6) observed in NMR and HPLC-MS experimental analysis is postulated by us as an intermediate to the final conversion to carboxylic acids. Studies in the presence and absence of molecular oxygen allow us to conclude that the imidazolium salts is crucial for the oxidation. A detailed mechanistic study was carried out to provide insights regarding this unexpected reactivity.

Full text of DOI:10.1021/acs.joc.7b00807

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Article
DEVELOPMENTS IN THE REACTIVITY OF 2-METHYL IMIDAZOLIUM SALTS
Daniela Peixoto, Margarida Figueiredo, Manoj B. Gawande, Marta C. Corvo, Gerd
Vanhoenacker, Carlos A. M. Afonso, Luisa Maria Ferreira, and Paula Serio Branco
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 31 May 2017
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DEVELOPMENTS IN THE REACTIVITY OF 2-METHYL IMIDAZOLIUM
SALTS
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Daniela Peixoto‡, Margarida Figueiredo‡, Manoj B. Gawande,§ Marta C. Corvo,¥ Gerd
Vanhoenacker,ψ Carlos A. M. Afonso,† Luisa M. Ferreira* and Paula S. Branco*
LAQV, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de
Lisboa, 2829-516 Caparica, Portugal.
§Regional Centre of Advanced Technologies and Materials, Faculty of Science, Department of Physical Chemistry,
Palacky University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
¥Univ Nova Lisboa, Faculdade Ciências e Tecnologia, CENIMAT I3N, P-2829516 Caparica, Portugal.
†Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av.
Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
ψResearch Institute for Chromatography, President Kennedypark 26, 8500 Kortrijk, Belgium.
ABSTRACT: Unexpected and unusual reactivity of 2-methyl imidazolium salts towards aryl-N-sulfonylimines and aryl
aldehydes is here reported. On reaction with aryl-N-sulfonylimines the addition product, arylethyl-2-imidazolium-1-
tosylamides (3) is formed with moderate to good yields while on reaction with aldehydes, the initial addition product (6)
observed in NMR and HPLC-MS experimental analysis is postulated by us as an intermediate to the final conversion to
carboxylic acids. Studies in the presence and absence of molecular oxygen allow us to conclude that the imidazolium salts
is crucial for the oxidation. A detailed mechanistic study was carried out to provide insights to this unexpected reactivity.
Although the extensive work done with the frequently
studied class of imidazolium-based ionic liquids very little
has been published concerning the reactivity of these
azolium salts when functionalized at the C2 position.19
Nevertheless this is one of the most relevant substitution
positions which is shown to be associated with the biolog-
ical activities of azoles.20,21 In the presence of a base the
C2-substituted imidazolium salt forms a 1,3-dipolar specie
that can act as a nucleophile reacting with aldehydes and
the heteroarylvinyl imidazolium thus formed have inter-
esting antitumoral activity.22,23 This type of 1,3-dipolar
specie have also been studied as captors and catalyst in
reactions with CO2.24,25 These NHC−CO2 adducts were
found to catalyze the cyclization of CO2 and propargylic
alcohols at mild conditions giving α-alkylidene cyclic
carbonates.25 Interesting reactivity was also observed with
alkyl imidazolium salts when in-situ generated. The so
produced N-heterocyclic olefins (NHO) were involved in
oxidative processes and coupling reactions.26,27 Initially we
had proposed ourselves to evaluate the application of 1,2-
dimethyl-3-ethyl imidazolium salts (1) as a reagent for the
condensation and/or methylene transfer reagent to elec-
trophilic species such as imines and aldehydes. The in-
teresting results obtained with the reactivity of 1 acting as
an oxidant lead us to here present our results.
INTRODUCTION
The unique properties of ionic liquids are responsible for
its numerous and potential applications.1-3 Among several,
they have been used successfully in many catalytic reac-
tions, not only as the solvent but in some cases as the
catalyst for N-heterocyclic carbene (NHC) catalyzed reac-
tions.4,5 Due to its characteristics, the NHC species has
had an important role for the development of new syn-
thetic methods. Transesterification, nucleophilic aromatic
substitution, cycloaddition and C-C bond formation, are
examples in which NHCs can play an important role.6-11
These metal-free catalyzed processes are interesting al-
ternatives to classical organic transformations since they
are often more economical and environmentally friendly.
The NHC-based reactive species is usually obtained by
deprotonation of azolium salts, through a base (NaOH,
NaH, DBU, K2CO3, MeONa, Et3N, etc.). The benzoin con-
densation reaction, is a model reaction catalyzed by these
NHC intermediate species.
12-16
For these and other im-
portant organic transformations imidazolium-based ionic
liquids have been used often as catalyst, as sol-
vent/catalyst, under microwave irradiation and ultrasonic
activation,13 in solventless conditions or in classical organ-
ic solvents.16,17 In all these methodologies the presence of
a base plays a key role in the generation of the NHC from
the azolium salts but electrogenerated NHC18 have also
been reported.
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Ts
N
( )
RESULTS AND DISCUSSION
Et
N
R
1
2
3
4
Et
R
2
Ts
N
Et
X
N
N
Whereas the 1,2-dimethyl-3-ethyl imidazolium iodide (1b)
was easily prepared through N-ethylation of 1,2-
dimethylimidazole with ethyl iodide28,29 the analogue (1a)
was purchase from a commercial agent. From our previ-
ously experience with aryl-N-sulfonylimines (2),30 we
decide to test the reactivity of 1,2-dimethyl-3-ethyl imid-
azolium chloride (1a) with 2. As expected, the 2-
substituted methyl group is quite reactive in the presence
of a base due to the strong electron withdrawing effect of
the adjacent positively charged nitrogen atom on the
imidazole ring. Our main purpose was a methylene group
transfer from 1a to the aryl-N-sulfonylimines (2) with
concomitant by elimination of an imidazolium-based
NHC to attain the aziridine ring (Scheme 1). However, it
was only observed the formation of the zwiterrionic ad-
duct, arylethyl-2-imidazolium-1-tosylamides (3) with low
to moderate yields. The low yields observed for com-
pounds 3c and 3d could be due to the high instability of
the aryl-N-sulfonylimines 2c and 2d. Titration of 3b with
silver nitrate shows that the compound is present as an
internal salt since the value of chloride detected is equal
to the blank assay of MiliQ™ water. Although the few
reports in literature concerning the reaction of 2-
substituted imidazolium salts with electrophiles22,31 this is
the first report on the reaction with imines. Due to the
high polar nature of the zwitterionic species 3, its isola-
tion could only be achieved through reverse phase chro-
matography using a water: methanol gradient. All the
attempts using either acidic or basic conditions to trans-
form 3 into the corresponding aziridine ring were unsuc-
cessful. The NMR data including bidimensional experi-
ments attest the proposed structure as also the mass spec-
tra analysis. The rapid H/D exchange of the 2-methylene
group could be observed on the NMR and MS spectra (see
supporting information) with the corresponding isotopic
pattern present. The ability of 2-substituted imidazolium
ILs to endeavor in this H/D exchanged was very recently
reported by others.32 The compounds obtained were
found to be quite stable and no special care was required
with them. As these compound present himself as oils at
room temperature, it is possible to infer that these ad-
ducts may have characteristics similar to ionic liquids.
Studies are underway. Next we turn our attention to the
reaction with aldehydes. From what we were able to ob-
serve and isolate in the reaction medium, here again, no
methylene group transfer from the imidazolium salt to
the aldehyde occur. We start our study with the reaction
of 1,2-dimethyl-3-ethylimidazolium iodide (1b) with ben-
zaldehyde (4a). Our first attempt with Cs2CO3 as base in
dry THF allowed us to obtain the benzoic acid in 50%
yield after 24h (Table 1, entry 1a). The work up of the reac-
tion was performed the following way: the reaction mix-
ture was evaporated to dryness and the residue washed
out with ethyl ether to remove unreacted benzaldehyde
and/or other products formed. To the residue was added
water and after acidification with HCl 1M the mixture was
extracted with CH2Cl2, dried with sodium sulfate and
evaporated to dryness to leave pure benzoic acid.
Cs2CO3
N
+
Ts
N
N
R
N
THF
(3)
5
6
7
8
1a X = Cl
1b X = I
R
3a Ph
3b p-MeOC6H4 71
3c p-BrC6H4
Yield (%)
66
22
33
3d p-NO2C6H4
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Scheme 1. Reaction of 1,2-dimethyl-3-ethyl imidazolium
chloride (1a) with aryl-N-sulfonylimines (2) to attain ar-
ylethyl-2-imidazolium-1-tosylamides (3).
The aqueous phase was also evaporated and analyzed.
The products profile changed according to the reaction
time. After 24 h no benzaldehyde was recovered, the ben-
zoic acid was obtained as mention above in 50% and the
aqueous phase shows only the adduct 6 in nearly 50%
yield taking into account the recovered benzaldehyde and
benzoic acid (Table 1, entry 1a). Although the reaction was
performed with equimolar amounts of benzaldehyde and
imidazolium salt (1b) no traces of the later one could be
observed after 24h. Using the same procedure the out-
come of the reaction was analyzed after 48, 72 and 192h in
independent reactions. The results are presented in table
1 (entries 1a to 1d). Repeatedly, the yield of formation of
benzoic acid decreased in the following days but attain
the highest yield (82%) after 192h with the benzaldehyde
being identified in vestigial amounts. We proposed that
the benzaldehyde appeared from the reverse reaction of
formation of 6 to the starting materials. The phenylvinyl
imidazolium iodide 7a results from water elimination of
6. Analogs of the arylvinyl imidazolium salts 7 were also
observed by others on reaction of imidazolium salts with
aldehydes.22,23 Compounds 1b, 6 and 7 were identified by
1H NMR and HPLC-ESI analysis of the crude of the aque-
ous polar fractions (see supporting information). In order
to clarify the outcome of this reaction, the experimental
conditions were reproduced in an NMR tube. To the ini-
tial mixture of 1,2-dimethyl-3-ethylimidazolium iodide
(1b) and base in CD3OD, 1.0 equivalents of benzaldehyde
were added. Diffusion-ordered spectroscopy (DOSY)
allows the separation of the NMR signals of different
species according to their diffusion coefficients.33,34 In
figure 1 it´s possible to observe the DOSY spectra of the
initial mixture (I) and after benzaldehyde addition (II).
Before benzaldehyde (I) addition only the imidazolium
and methanol diffusion pattern were distinguished,
whereas after benzaldehyde addition, the immediate
formation of adduct 6, takes place as can be seen by the
1
respective diffusion coefficient with H signals. This ad-
duct presents chemical shifts between and 7.26-7.42 ppm,
as well as the imidazolium side chains (figure 1.II). The
reaction was followed throughout 24 h and it was possible
to identify in the H, C HMBC NMR spectra correlations
between the benzylic signal at 5.2 ppm and C2 (144 ppm)
from the imidazolium, as well as with the aromatic car-
bon from benzaldehyde addition (125 ppm) (see SI).
1
13
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1
Figure 1. H DOSY spectra (400 MHz, CD3OD) of 1,2-dimethyl-3-ethylimidazolium iodide (1b) and base mixture in CD3OD (I),
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and immediately after the addition of 1.0 equivalents of benzaldehyde (II) acquired with bipolar LED pulse sequence
and K2CO3 (Table 1, entries 5a to 5d) only moderate
yields were observed. Using an organic base as NEt3 the
Formation of benzoic acid in this conditions is residual
and not observed on the NMR spectra after 24h. Also
observed in this spectra is a correlation between a signal at
7.95 ppm and a carbonyl group at 174 ppm which is compatꢀ
ible with another intermediate species (see mechanism furꢀ
ther ahead). The reaction was tested with other solvents
and the formation of benzoic acid was observed to be
residual in methylene chloride (4%) and very low in
methanol (9%) and water (22%) (Table 1, entries 7-9). In
the absence of 1b, benzoic acid was obtained in vestigial
amounts so that we can´t exclude an ordinary oxidation
reaction of benzaldehyde % (Table 1, entries 17). No
benzyl alcohol has ever been observed and as so, the
Cannizarro reaction was not involved in the oxidation
process. Since the best results were observed in THF,
other bases were tested. The yields are reported in Table
1. Using NaH as base (Table 1, entries 2a to 2d) the yield
of benzoic acid range from 42 to 47%. With NaOH (Ta-
ble 1, entries 3a to 3d) a very good yield was obtained
after 192h while with Na2CO3 (Table 1, entries 4a to 4d)
highest yield was obtained after 24h (85%) although
decreased substantially in the assays preformed with
more time of reaction (Table 1, entries 6a to 6d). The
reaction was extended to other aromatic, heteroaro-
matic and aliphatic aldehydes. With aliphatic aldehydes
as phenylacetic aldehyde the expected aldol condensa-
tion product was formed (5%) together with recovered
aldehyde. With p-cyanobenzaldehyde (4b) the respec-
tive acid 5b was obtained in 59 and 44% yield after 24h
and 192h respectively (Table 2, entry 1a and 1b). It was
also identified the elimination product 7b in 14% after
192h (Table 2, entry 1b). As for the p-
bromobenzaldehyde (4c), the amount of p-
bromobenzoic acid 5c found was 27% (Table 2 entry 2a).
After 192h it was obtained the adduct 7c in 36% yield
(Table 2, entry 2b). As for p-metoxybenzaldehyde (4d)
the formation of the corresponding carboxylic acid (5d)
was obtained in 13 and 43% yield after 24h and 192h
respectively
(Table
2,
entry
3a
and
3b).
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Table 1. Conditions for the reaction of 1,2-dimethyl-3-ethyl imidazolium iodide mediated oxida-
tion with benzaldehyde
1
2
Et
3
4
5
6
Et
Et
O
O
I
I
1) Base
2) HCl
N
O
N
N
+
+
H
OH
(5a)
+
N
N
N
7a
)
7
(
(4a)
(6a)
(1b)
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5a)
η %
(4a),
1eq
Base
(1.2 eq)
(7a)
Entry
Solvent
Reaction time (h)
η %
1a
1b
1c
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaH
NaH
NaH
NaH
NaOH
NaOH
NaOH
NaOH
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NEt3
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
MeOH
H2O
24
48
72
192
24
48
72
192
24
48
72
192
24
48
72
192
24
48
72
192
24
48
72
192
192
192
192
192
192
24
50
17
-
-
23
82
42
43
47
42
40
19
37
81
30
21
-
i)
1d
2a
2b
2c
2d
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
7
8
9
10
11
12
13
14
15
16
17
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
12
24
43
20
21
35
85
5
6
47
4
NEt3
NEt3
NEt3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaH
9
22
20iii)
20iii)
93
40
70
57iv)
72iv)
THF
THF
THF / O2
THF degassed
THF / O2
THF
NaH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
24
24
24
192
24
THF
THF
v)
-
i) identified by NMR in the crude mixture of the aqueous phase; ii) identified in the 24h reaction, iii) general procedure with 20
mol% of 1b; iv) general procedure with 2 equivalents of benzaldehyde; v) without 1b, vestigial amounts of 5a.
Mainly it was recovered the aldehyde 4d and in the
crude of the aqueous phase the compound 6d , was
identified by 1H NMR which is not a surprise taking into
consideration the formation of a fully conjugated system
assisted by the methoxyl substituent (Table 2, entry 3b).
With p-nitrobenzaldehyde (4e) the corresponding oxi-
dation product (5e) was obtained in yields ranging from
21 to 48% (Table 2, entry 4a and 4b) as also the elimina-
tion adduct 7e. As for the m-hydroxybenzaldehyde (4f),
no carboxylic acid was observed (Table 2, entries 5),
instead, a 1:1 mixture of 6f and starting material 1b was
identified. The m-hydroxybenzaldehyde (4f) was recov-
ered in 50% yield. As for the m-chlorobenzaldehyde (4g)
the formation of the corresponding carboxylic acid 5g
was obtained in 87% yield (Table 2, entries 6). The elim-
ination compound 7g was also identified but on the 24h
reaction (Table 2, entries 6). With heteroaromatic alde-
hydes as 2-furaldehyde (4h) the corresponding carbox-
ylic acid (5h) was obtained in 46 and 52% yield after 24h
and 192h respectively (Table 2, entry 7a and 7b). The
elimination compound 7h was also identified. In the
presence of a catalytic amount (20%) of 1b the for-
mation of benzoic acid never exceed the 20% either with
Cs2CO3 or NaH as base, which point to a stoichiometric
role for this reagent (Table 1, entry 10 and 11). When the
reaction was conducted with a degassed solution (free of
oxygen) only a slightly reduction on the yield from 50 to
40% was observed (Table 1, entry 1a vs 13).
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Table 2. 1,2-Dimethyl-3-ethyl imidazolium iodide mediated oxidation of aromatic aldehydes
1
2
3
4
5
6
7
8
9
(5)
(4),
1eq
(7)
η %
-
Entry
Solvent
Reaction time (h)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
η %
1a
1b
2a
2b
3a
3b
4a
4b
5
4b
4b
4c
4c
4d
4d
4e
4e
4f
4g
4h
4h
4c
4d
4e
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF/O2
THF/O2
THF/O2
24
192
24
192
24
192
24
192
192
192
24
59
44
27
-
13
43
21
14
-
36
27
3
48
-
6
87
46
52
37.5
12
11i)
14
8
7a
7b
8
9
10
192
24
24
18
24
27
27
i) identified in the 24h reaction.
In the presence of oxygen, the yield of the reaction after
24h increase from 50 to 70% with Cs2CO3 as base and
from 42 to 93% with NaH (Table 1, entries 1a vs 14 and 2a
vs 12). With other aryl aldehydes a possible role of O2
was not as conclusive nor did it support the results with
benzaldehyde (Table 2 entries 2a vs 8, 3a vs 9 and 4a vs
10). The yields were more or less in the same order of
magnitude when no O2 was present. To elucidate the
mechanism, the reaction was performed in the presence
of 2 equivalents of benzaldehyde. The benzoic acid was
obtained in 57% and in 72% yield after 24h and 192h of
reaction respectively (Table 1, entry 15 and 16). These
results are in the same order of magnitude as those with
a 1:1 proportion of reagents (Table 1, entry 1a and 1d). As
expected, in these conditions with two equivalents, 50%
of benzaldehyde was recovered after 24h. Although the
formation of benzoic acid was consistently observed
though with different outcome, it wasn’t possible to see
such a reproducibility with other minor products isolat-
ed from the organic phase. It was possible in some in-
stances to proceed to the isolation and characterization
of some of these compounds whose structures were
postulated by comparison with spectroscopic data in the
literature while others were identified by GC-MS and
evaluation with data bases. Those compounds that we
were able to identify (8-12)35-39 are presented below in
Figure 2. Our proposed mechanism is presented in
Scheme 2. Taking as example the benzaldehyde we pro-
posed the formation of the intermediate (6) based on
NMR experimental and HPLC-ESI analysis as mentioned
above. Every attempt to purify this intermediate by
reverse phase column chromatography lead to the aryl-
vinyl imidazolium (7) as also the imidazolium (1b).
Since after 24h only the benzoic acid (5a) and the in-
termediate 6 were identified points us to establish an
oxidative role for 1b that lead to the formation of the
acyl derivative (14, corresponding signals observed on
the diffusion experiments – Figure 1 ) and the reduce
form of 1b, the specie (15).
Figure 2. Minor compounds isolated on the 1,2-
dimethyl-3-ethyl imidazolium iodide mediated oxida-
tion of benzaldehyde. Unless otherwise mention the
base reaction conditions were: 1b (1.0 equiv.), benzal-
dehyde (1.0 equiv.), Cs2CO3 (1.2 equiv.), r.t., THF; a)base
reaction conditions 12 days; b)CDCl3 15 days; c)24h; d)r.t.,
CD3OD; e) THF-d8.
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Et
I
1
2
O
N
+
O2
3
4
5
6
Ph
H
N
(4)
(1b)
Et
Et
Cs2CO3
I
N
N
7
8
9
Et
N
O
Et
N
O
N
I
N
Et
I
O
(15)
O2
O H
Ph
Ph
N
O
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
(6)
(14)
N
(16)
(1b)
-
-HO2
H2O
Et
(6)
(14)
O
O
I
N
Ph
O OH
Ph
OH
+
N
(5a)
O
50%
CsOH
after 24h
HO
O Cs
Et
Et
O
O
I
N
N
+
OH
Ph
OH
Ph
N
(5a)
N
82%
after 192h
Scheme 2. Proposed mechanism for the oxidation reaction promoted by 1,2-dimethyl-3-ethyl imidazolium iodide (1b).
This postulated intermediate 15 must be quite unstable
since whenever in the mixture of an organic fraction,
were identified in the NMR signals that could corre-
spond to 15, its isolation was impossible. Nevertheless in
one case it was possible to obtain an organic phase
(from the ethyl ether extraction) which analysis by NMR
presented signals at higher filed than the imidazolium
ring and could be attributed to the structure of 15. This
was further confirmed by the CG-MS with a molecular
ion of m/z of 126 (see supporting information). As ex-
pected after 48h the NMR spectrum showed an intrac-
table mixture which was also confirmed by the GC-MS
with the absence of the peak corresponding for the pre-
viously identified and postulated compound 15. The
nucleophilic attack of the hydroxide ion or water onto 14
maybe the responsible for the benzoic acid formation.
The conversion of 6 to 14 is an equilibrium as also from
6 to 1b since in the following days the yield of benzoic
acid decrease and 1b was identified. The highest yield
obtained for benzoic acid after 1 week (192h) can in our
view be justified by the nucleophilic attack of the hy-
droxide ion as presented in scheme. When the reaction
is conducted in the presence of molecular oxygen the
yield is 70% after 24h which is the result of the shift of
the equilibrium of 6 / 14 to the last one. As for the good
yield when NEt3 is used as base we can postulate an
attack of NEt3 to 14, thus shifting the equilibrium 6 / 14
to the right, that upon 1b elimination gives a very reac-
tive and highly electrophilic acylium cation intermediate
that on work up with water give the benzoic acid. The
low yields obtained in the following days (Table 1 entry
7b to 7c) should result from the instability if this
acylium cation intermediate in the reaction medium.
Our proposed mechanism involving as key step a redox
reaction between the species 6 and 14 was reinforced by
the result obtained when the reaction was run in the
presence of oxygen (table 1, entry 21) which could favor
this transition step. Even so, we can’t exclude that the
intermediate 6 reacts with dioxygen to form the peroxy-
species (16) which has already been postulated by others
when NHC is involved40 although radical species report-
ed by others41 cannot be excluded. We have also previ-
ously detected radical species in the redox reaction in-
volving aromatic nitroso compounds and thiazolium
salts.42 The decomposition of this unstable compound as
presented in scheme 2 may be happening in two ways
leading to two different compounds. It can decompose
-
to form the activated ketone 14 by abstraction of HO2 or
in a second possible pathway the formation of the per-
oxy acid by abstraction of 1b. This peroxy acid is a
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The Journal of Organic Chemistry
was carried out to provide insights to this unexpected
strong oxidant agent itself and thereby able to shift the
1
2
3
4
5
6
7
8
equilibrium of 6 / 14 to the right under formation of
benzoic acid and 14. Here we can’t roll out the possible
reaction of the peroxy acid with the aldehyde to give
benzoic acid. To support this equilibrium, the reaction
of crude 6 with benzaldehyde in the presence of cesium
carbonate allowed benzoic acid to be obtained in 44%
yield after 72h which means that 6 is in the reaction
conditions, in equilibrium with 1b. The formation of the
acyl intermediate (14) was postulated in similarly to the
NHC-based azolium salts which catalyze the oxidation
of unactivated aldehydes to esters or acids.40 The au-
thors reported the reaction proceeding through a transi-
ent activated alcohol which is then converted to the
NHC-acyl intermediate by manganese(IV) oxidation43 or
by oxygen.40,44
The benzoin condensation product 12 and the deriva-
tives 10 and 8 can be justified by the mechanism pre-
sented in scheme 3 where 1b has a catalytic role similar
to that reported for NHC.45 Here again, the formation of
8 may reinforce the postulated intermediate 14 as repre-
sented in scheme 3. The fact that we have observed by
HPLC-ESI a compound whose m/z of 217 u.m.a. may
correspond to the Breslow intermediate (see supporting
information) does not allow us to exclude a possible role
of this intermediate in the formation of the minor ben-
zoin condensation product 12.
reactivity.
EXPERIMENTAL SECTION
General methods and materials: All the reagents and
solvents were obtained commercially and these were used
without further purification. The solvents used were dried
using current laboratory techniques. Thin layer chromatog-
raphy (t.l.c.) was carried out on aluminium backed Kie-
selgel 60 F254 silica gel plates (Merck). Plates were visual-
ized either by UV light (254 and/or 366nm). Preparative
layer chromatography (PLC) was performed on Merck
Kieselgel GF 254 silica gel plates with a thickness of 0.5 mm
or 1 mm. Column chromatography were carried out silica
gel Kieselgel 60 (Merck), 70 - 230 mesh particle size as
stationary phase, in normal phase chromatography or Li-
Chroprep RP-18 (Merck) silica, with a particle size of 40-63
μm as the stationary phase in reverse phase chromatog-
raphy. The reverse phase columns were eluted using water-
methanol mixtures in order to decrease the polarity of the
mixture (from 0% methanol, 10%, 20% and successively up
to 100% methanol). Ultraviolet spectroscopy (UV) was
recorded on a Thermo Corporation spectrophotometer,
Helius γ, on quartz cell support. Absorption spectrum
measurements were made in the range of 190 to 320 nm. 1H
and 13C NMR spectra were recorded on a Brucker ARX400
at 400 and 100 MHz, respectively. Mass spectrum (MALDI-
TOF) were run on a Voyager-DE ™ PRO Workstation mass
spectrometer, in positive reflector mode (unless otherwise
noted), with 2,5-dihydroxybenzoic acid (DHB) as matrix.
HPLC-MS-ESI was acquired on a Agilent 1200 Series LC
with quaternary pump, ALS, TCC, DAD and Agilent G6130B
LC/MSD with API-ES source. HRMS was acquired on a
G6545A Q-TOF with Agilent JetStream technology source
(ESI) LC is 1290 Infinity II LC system (UHPLC) with High
Speed Pump, Multisampler and Multicolumn Thermostat.
Chromatographic conditions (see supporting information).
Mass spectra (MS) using the EI-TOF technique were ob-
tained from Unidade de Masas e Proteómica, the University
of Santiago de Compostela, Spain. Infrared (IR) spectrosco-
py was performed on a Perkin Elmer spectrophotometer,
Spectrum 1000FT-IR, in support of KBr pellets. Melting
points (m.p.) (uncorrected) were measured on the Reichert
Thermovar. Gas chromatography-mass spectrometry (GC-
MS) was done on an Agilent 6890N chromatograph cou-
pled to a Thermo DSQ electronic impact detector (EI).
Chromatographic conditions: VF5-ms column, 0.25mm ID,
0.25μm film; 250 ° C-injector temperature; Temperature
program: 50ºC (1min), 10ºC / min up to 300ºC; Split ratio
1:20; 1mL / min of drag gas flow; 1μL of sample injected;
5min of solvent delay. DIONEX ion chromatography was
acquired on a DIONEX ion chromatograph, ICS3000, with
IonPack® AS15 4x250mm column, coupled with pre-
column. The analysis was done at 30 °C with 38 mM NaOH.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Proposed mechanism for the formation of
benzaldehyde oxidation products.
CONCLUSIONS
While the use of ILs may offer superior physical proper-
ties relative to more traditional and volatile aprotic
solvents, their potential reactivity must not be over-
looked. Here we have demonstrated that 2-methyl im-
idazolium salts may in the presence of a base react with
electrodeficient species such as aryl-N-sulfonylimines
and aldehydes. On reaction with imines, arylethyl-2-
imidazolium-1-tosylamides (3) are formed with moder-
ate to good yields. The reaction with aldehydes had an
unexpected result with the oxidation to the correspond-
ing carboxylic acid taking place. Although the conver-
sion of aldehydes to carboxylic acids can happen rather
spontaneously, efficient methods to achieve this trans-
formation without hazardous oxidants or harmful sol-
vents are still scarce. Here we have demonstrated that 2-
methyl imidazolium salts can promote the oxidation of
aromatic aldehydes in the presence of a mild base, in
good to excellent yields. A detailed mechanistic study
Synthesis of the 3-ethyl-1,2-dimethyl imidazolium
iodide (1b)
:
In a flask equipped with a magnetic stir bar
and
a
reflux condenser, equimolar amounts of 1,2-
dimethylimidazole and iodoethane (11 x 10-3 mol) were
added in 20 mL of dry THF. The mixture was stirred and
refluxed under a nitrogen atmosphere for 15h. The solid
obtained was washed with dry ethyl ether, dissolved in
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methanol and recrystallized by addition of dry ethyl ether
General procedure for the synthesis of arylethyl-2-
1
2
3
4
5
6
7
8
in an ice-salt bath (-20 °C). The white solid obtained was
imidazolium-1-tosylamides (3): In a round bottom flask
equipped with magnetic stir bar was added 1,2-dimethyl-3-
ethylimidazolium chloride (1a) (0.0257 g, 0.16 x 10-3 mol)
and cesium carbonate (1.2 equiv.) in dry THF. The reaction
mixture was stirred at room temperature under nitrogen
for 1 h. Subsequently, under a nitrogen atmosphere, the
corresponding imine (2a-d) (see supporting information) (1
equiv.) was added, and the reaction proceeded under the
same conditions until consumption of the imine (approxi-
mately 1-2 h). The reaction was followed by t.l.c., eluting
with a mixture of hexane: ethyl acetate (8: 2). The reaction
mixture was evaporated to dryness, and the crude product
was washed with ethyl ether. The mixture was diluted in
water (either dissolved in acetone and adsorbed onto celite)
and applied to a reverse phase column (RP-18) for purifica-
tion. Elution was done using water-methanol mixtures, in
order to decrease the polarity of the blend (from 0% meth-
anol, 10%, 20% to 100% methanol - 20 ml of each mixture).
The collected fractions were analyzed by UV-Vis spectros-
copy, with scanning between 190 and 320 nm. The fractions
exhibiting identical absorption maxima were pooled and
evaporated to dryness to give the product 3a-d.
filtered and dried under vacuum. 74.6 %; UV-Vis λmax
1
223,50 nm; H NMR (D2O, 400 MHz) δ: 7.38 (d, J = 2.0 Hz,
1H), 7.32 (d, J = 2.0 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.78 (s,
3H), 2.60 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H) ppm; 13C NMR
(D2O, 100 MHz): δ 143.9 (C), 122.1 (CH), 121.7 (C), 119.9 (CH),
43.3 (CH2), 34.5 (CH3), 14.1 (CH3), 8.7 (CH3) ppm; IR ʋmax
(cm-1): 3095 (aromatic C-H), 1586 (C=N). HRMS-CI(+) calcd
for C7H13N2 [M]+ 125.1073 found 125.1083.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of aryl-N-
sulfonylimines (2):46 In a round bottom flask equipped
with a magnetic stirrer and reflux condenser, equimolar
amounts (3 x 10-3 mol) of p-toluenesulfonamide and the
corresponding aldehyde, 0.05 g of Amberlyst 15 and about
0.5 g of the Molecular Sieves 4Å in dry toluene. The reac-
tion mixture was stirred and heated under reflux under a
nitrogen atmosphere until the total consumption of the
aldehyde was verified. This monitoring was by TLC, in an
eluent of hexane: ethyl acetate (6: 4). Subsequently, the
mixture was removed from the heat and decanted into a
new flask, thereby removing the Molecular Sieves. The
mixture was then allowed to cool to room temperature to
give precipitation of the imine. To assist precipitation,
petroleum ether was added, and the sample was filtered
and dried in vacuum.
(2-(3-Ethyl-1-methyl-1H-imidazol-3-ium-2-yl)-1-phenyl-
ethyl)(tosyl)amide (3a): From compound 1a (0.0257g) and
2a (0,041 g) according to the general procedure, compound
3a was obtained as a white oil (0,040g, 66%); UV-Vis λmax
1
N-Benzylidene-4-methylbenzenesulfonamide
(2a):
223 nm; H NMR (MeOD, 400 MHz) δ: 7.45 (d, J = 8.1 Hz,
From benzaldehyde (0.318g) and p-toluenesulfonamide
(0,513g) according to the general procedure, compound 2a
2H), 7.42 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.18 –
7.13 (m, 5H), 7.06 (d, J = 8.0 Hz, 2H), 4.44-4.41 (m, 1H), 4.03
– 3.96 (m, 2H), 3.58 (s, 3H), 3.37 (dd, J = 15.2 and 8.4 Hz,
1H), 3.23 (dd, J = 15.2 and 6.0 Hz, 1H), 2.25 (s, 3H), 1.33 (t, J =
7.2 Hz, 3H’) ppm; 13C NMR (MeOD, 100 MHz) δ: 145.3 (C),
143.1 (C), 142.7 (C), 142.3 (C), 130.1 (2xCH), 129.6 (2xCH),
128.6 (CH), 127.7 (2xCH), 127.6 (2xCH), 124.2 (CH), 121.5
(CH), 58.7 (CH), 44.4 (CH2), 35.7 (CH3), 34.3 (CH2), 21.3
(CH3), 15.2 (CH3) ppm; IR ʋmax (cm-1): 3053 (aromatic C-H),
1329 (symmetric stretching SO2), 1265 (C-N), 1158 (symmet-
ric stretching SO2); MS (MALDI-TOF) ([M+H]+) m/z:
1
was obtained as a white solid (0,358g, 46%); H NMR
(CDCl3, 400 MHz) δ: 9.03 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H),
7.89 (d, J = 8.4 Hz, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.49 (t, J =
7.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 2.44 (s, 3H) ppm; 13C
NMR (CDCl3, 100 MHz) δ: 170.2 (HC=N), 144.6 (C), 139.1 (C),
134.5 (C), 132.4 (CH), 129.8 (2xCH), 129.2 (2xCH), 128.1
(2xCH), 126.4 (2xCH), 21.5 (CH3) ppm.
N-(4-Methoxybenzylidene)-4-methylbenzenesulfona-
mide (2b): From 4-methoxybenzaldehyde (0.408g) and p-
toluenesulfonamide (0,513g) according to the general pro-
cedure, compound 2b was obtained as a white solid
C21H26N3O2S
384.1703;
C21H25DN3O2S
385.1660;
C21H24D2N3O2S 386.1564. FIA-HRMS calcd for C21H26N3O2S
[M+H]+ 384.17457 found 384.17444.
1
(0.443,51%); H NMR (CDCl3, 400 MHz) δ: 8.94 (s, 1H),
7.89-7.89 (m, 4H), 7.31 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.8
Hz, 2H), 3.88 (s, 3H), 2.43 (s, 3H) ppm; 13C NMR (CDCl3, 100
MHz) δ: 169.3 (HC=N), 164.7 (C), 144.3 (C), 139.1 (C’), 129.7
(2xCH), 127.9 (2xCH), 126.5 (C), 125.2 (2xCH), 114.3 (2xCH),
55.6 (OMe), 21.5 (CH3) ppm.
N-(4-Bromobenzylidene)-4-methylbenzenesulfonami-
de (2c): From 4-bromobenzaldehyde (0.555g) and p-
toluenesulfonamide (0,513g) according to the general pro-
cedure, compound 2c was obtained as a white solid (0.517g,
51%); 1H NMR (CDCl3, 400 MHz) δ: 8.98 (s, 1H), 7.87 (d, J =
8.1 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.3 Hz,
2H), 7.35 (d, J = 8.0 Hz, 2H), 2.44 (s, 3H) ppm.
(2-(3-Ethyl-1-methyl-1H-imidazol-3-ium-2-yl)-1-(4-
methoxyphenyl)ethyl)(tosyl)amide (3b): From com-
pound 1a (0.0257g) and 2b (0,047 g) according to the gen-
eral procedure, compound 3a was obtained as a colorless oil
1
(0.047g, 71%); UV-Vis λmax 227 nm; H NMR (MeOD, 400
MHz) δ: 7.44 (d, J = 8.0 Hz, 2H), 7.39 (d, J =2.0 Hz, 1H), 7.29
(d, J = 2.4 Hz, 1H), 7.08 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 8.0
Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 4.34 (t, J = 7.2 Hz, 1H),
4.03-3.99 (m, 2H), 3.69 (s, 3H), 3.56 (s, 3H), 3.28 (dd, J = 15.2
and 8.0 Hz, 1H), 3.14 (dd, J = 15.0 and 6.4 Hz, 1H), 2.26 (s,
3H), 1.34 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (MeOD, 100
MHz) δ: 160.1 (C), 146.1 (C), 144.4 (C), 141.2 (C), 137.4 (C),
129.7 (2xCH), 128.9 (2xCH), 127.5 (2xCH), 123.9 (CH), 121.2
(CH), 114.6 (2xCH), 59.0 (CH), 55.7 (OMe), 44.4 (CH2), 35.6
(CH3), 35.3 (CH2), 21.3 (CH3), 15.2 (CH3) ppm; IR ʋmax (cm-1):
3053 (aromatic C-H), 1421 (methyl C-H), 1327 (symmetric
stretching SO2), 1265 (C-N), 1159 (symmetric stretching
SO2); MS (MALDI-TOF) ([M+H]+) m/z: C22H28N3O3S
414.1884; C22H27DN3O3S 415.1979; C22H26D2N3O3S 416.2016;
Determination of the chloride ion by ion chromatography
4-Methyl-N-(4-nitrobenzylidene)benzenesulfonamide
(2d): From 4-bromobenzaldehyde (0.453g) and p-
toluenesulfonamide (0,513g) according to the general pro-
cedure, compound 2d was obtained as a yellow solid (0.420,
1
46%); H NMR (CDCl3, 400MHz) δ: 9.11 (s, 1H), 8.33 (d, J =
8.4 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 8.4 Hz,
2H), 7.38 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H) ppm.
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The Journal of Organic Chemistry
DIONEX
C22H27DN3O3S [M+H]+ 415.19141 found 415.19043.
(2-(3-Ethyl-1-methyl-1H-imidazol-3-ium-2-yl)-1-(4-
(mg/Kg):
10.55.
FIA-HRMS
calcd
for
MHz) δ: 8.13 (br d, J = 8.4 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H),
7.49 (t, J = 7.6 Hz, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ:
171.7 (C=O), 133.9 (CH), 130.4 (2xCH), 129.4 (C), 128.6
(2xCH) ppm.
1
2
3
4
5
6
7
8
bromophenyl)ethyl)(tosyl)amide (3c): From compound
1a (0.0257g) and 2c (0,054 g) according to the general pro-
cedure, compound 3a was obtained as a colorless oil (0.016,
4-Cyanobenzoic acid (5b): From compound 1b (0.050g)
and 4b (0,026 g) according to the general procedure, com-
pound 5b was obtained as a white solid (0.017g, 59% after
24h; 0.013g, 44% after 192h); m.p. 215.216 °C (Lit47 215-217
1
22%); UV-Vis λmax 228 nm; H NMR (MeOD, 400 MHz) δ:
7.45 (br s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.36-7.33 (m, 3H),
7.17 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 4.41 (dd, J =
9.2 and 5.2 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.72 (s, 3H),
3.33-3.29 (m, 1H), 3.19 (dd, J = 14.8 and 5,2 Hz, 1H), 2.30 (s,
3H), 1.41 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (MeOD, 100 MHz)
δ: 146.0 (C), 144.7 (C), 144.3 (C), 141.4 (C), 132.3 (2xCH), 129.9
(2xCH), 129.8 (2xCH), 127.3 (2xCH), 124.0 (CH), 121.6 (C),
121.3 (CH), 59.0 (CH), 44.5 (CH2), 35.8 (CH3), 35,1 (CH2), 21.2
(CH3), 15.1 (CH3) ppm; IR ʋmax (cm-1): 3131 (Aromatic C-H),
1331 (symmetric stretching SO2), 1265 (C-N), 1148 (symmet-
ric stretching SO2), 739 (C-Br); MS (MALDI-TOF) ([M+H]+)
m/z: C21H2579BrN3O2S 462.0362; C21H2581BrN3O2S 464.0954 ;
C21H24D79BrN3O2S 463.0571; C21H24D81BrN3O2S 465.0500;
C21H23D279BrN3O2S 464.0954; C21H24D281BrN3O2S 466.0550.
FIA-HRMS calcd for C21H22D2BrN3O2S [M+H]+ 464.09764
found. 464.09509.
1
°C); H NMR (CDCl3, 400 MHz) δ: 8.21 (d, J = 8.0 Hz, 2H),
7.79 (d, J = 8.0 Hz, 2H) ppm.
9
4-Bromobenzoic acid (5c): From compound 1b (0.050g)
and 4c (0,037 g) according to the general procedure, com-
pound 5c was obtained as a yellow solid (0.011g, 27% after
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
24h); m.p. 248-249 °C (Lit47 248-250 °C); H NMR (Ace-
tone-d6, 400 MHz) δ: 7.95 (d, J = 8.4 Hz, 2H), 7.70 (d, J =
8.40 Hz, 2H) ppm; 13C NMR (Acetone-d6, 100 MHz) δ: 166.9
(C=O), 132.6 (2xCH), 132.3 (2xCH), 130.7 (C), 128.1 (C) ppm.
MS (M+) m/z: C7H579BrO2 199.9; C7H581BrO2 201.8.
4-Methoxybenzoic acid (5d): From compound 1b (0.050g)
and 4d (0,027 g) according to the general procedure, com-
pound 5d was obtained as a yellow solid (0.004g, 13% after
24h; 0.013g, 43% after 192h); m.p. 181-182 °C (Lit47 180-182
1
°C); H NMR (CDCl3, 400 MHz) δ: 8.06 (d, J = 8.4 Hz, 2H),
6.94 (d, J = 8.4 Hz, 2H), 3.88 (s, 3H) ppm.
(2-(3-Ethyl-1-methyl-1H-imidazol-3-ium-2-yl)-1-(4-
nitrophenyl)ethyl)(tosyl)amide (3d): From compound 1a
(0.0257g) and 2d (0,049 g) according to the general proce-
dure, compound 3a was obtained as a yellow oil (0.023g,
4-Nitrobenzoic acid (5e): From compound 1b (0.050g)
and 4e (0,030 g) according to the general procedure, com-
pound 5e was obtained as a yellow solid (0.007g, 21% after
24h; 0.016g, 48% after 192h); m.p. 232-233 °C (Lit47 232-234
1
33%); UV-VIS λmax 220 and 269 nm; H NMR (MeOD, 400
1
°C); H NMR (CDCl3, 400 MHz) δ: 8.32 (d, J = 8.4 Hz, 2H),
MHz) δ: 8.07 (d, J = 8.4 Hz, 2H), 7.53 – 7.50 (m, 3H), 7.44-
7.42 (m, 3H), 7.09 (d, J = 8.0 Hz, 2H), 4.65 – 4.61 (m, 1H),
4.21 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.70 – 3.57 (m, 1H), 3.41-
8.27 (d, J = 8.8 Hz, 2H) ppm.
3-Chlorobenzoic acid (5g): From compound 1b (0.050g)
and 4g (0,028 g) according to the general procedure, com-
pound 5g was obtained as a white solid (0.027g, 87% after
13
3.36 (m, 1H), 2.31 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H) ppm; C
NMR (MeOD, 100 MHz) δ: 151.8 (C), 148.4 (C), 145.4 (C),
143.1 (C), 142.3 (’), 130.0 (2xCH), 129.1 (2xCH), 127.4 (2xCH),
124.4 (2xCH), 124.3 (CH), 121.5 (CH), 58.5 (CH), 44.7 (CH2),
35.9 (CH3), 34.0 (CH2), 21.2 (CH3), 15.2 (CH3) ppm; MS
(MALDI-TOF) ([M+H]+) m/z: C21H25N4O4S 429.1864;
C21H24DN4O4S 430.1786; C21H23D2N4O4S 431.1869. FIA-
HRMS calcd for C21H24DN4O4S [M+H]+ 430.16593 found.
430.16501.
1
192h); m.p. 155-157 °C (Lit48,49 154-158 °C); H NMR (CDCl3,
400 MHz) δ: 9.32 (br s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.59 (d,
J = 7.2 Hz, 1H), 7.43 (t, J = 8.0 Hz) ppm.
Furan-2-carboxylic acid (5h): From compound 1b
(0.050g) and 4h (0,019 g) according to the general proce-
dure, compound 5h was obtained as a beige solid (0.010g,
46% after 24h; 0.012g, 52% after 192h); m.p. 128-129 °C (Lit50
128-132 °C); 1H NMR (CDCl3, 400 MHz) δ: 7.64 (br s, 1H),
7.31 (d, J = 3.2 Hz, 1H), 6.56 (br s, 1H) ppm; 13C (CDCl3,
100MHz) δ: 163.0 (C=O), 147.5 (CH), 143.9 (C), 120.2 (CH),
112.4 (CH) ppm.
General procedure for the synthesis of the compounds
5-12: In a round bottom flask equipped with magnetic stir
bar was added 1,2-dimethyl-3-ethylimidazolium iodium (1b)
(0,050 g, 0.20 x 10-3 mol) and cesium carbonate (1.2 equiv.)
in dry THF. The flask was kept closed with a stopper and
the reaction mixture was stirred at room temperature for 1
h and then the corresponding aldehyde (4a-h) (1 equiv) was
added. Following and depending the reaction conditions
used the following procedure were applied: i) To the reac-
tion under oxygen atmosphere, we used a take-off and an
oxygen balloon. Ii) For degassed reactions, they were con-
ducted using degassed solvent and under a nitrogen at-
mosphere. In both cases and upon completion of the reac-
tion, the mixture was evaporated under reduced pressure
and the crude was washed with ethyl ether. The reaction
mixture was diluted with water, acidified with HCl (1M)
and extracted with dichloromethane. The organic phase
was dried (Na2SO4) and filtered. The organic and aqueous
phase were evaporated under reduced pressure to dryness
to give the following products.
3-Ethyl-2-(2-hydroxy-2-phenylethyl)-1-methyl-1H-
imidazol-3-ium (6a): identified on the crude aqueous
1
fraction. H NMR (D2O, 400 MHz) δ: 7.42-7.40 (m, 4H),
7.33-7.26 (m, 3H), 5.17 (t, J = 6.0 Hz, 1H), 3.94 (q, J = 7.6 Hz,
2H), 3.54 (s, 3H), 3.48 (t, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz,
3H) ppm; 13C NMR (D2O, 100 MHz) δ: 142.8 (C), 141.0 (C),
129.0 (2xCH), 128.7 (CH), 125.5 (2xCH), 123.1 (CH), 120.4
(CH), 71.0 (CH), 43.3 (CH2), 34.8 (CH3), 32.3 (CH2), 14.1
(CH3) ppm.
3-Ethyl-2-(2-hydroxy-2-(4-methoxyphenyl)ethyl)-1-
methyl-1H-imidazol-3-ium (6d): identified on the crude
1
aqueous fraction. H NMR (D2O, 400 MHz) δ: 7.47 (d, J =
2.0 Hz, 1H), 7.33 (br s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.98 (d, J
= 8.8 Hz, 2H), 5.23 (t, J = 6.4 Hz, 1H), 4.054 (q, J = 7.6 Hz,
2H), 3.89 (s, 3H), 3.67 (s, 3H), 3.61-3.49 (m, 2H), 1.34 (t, J =
7.2 Hz, 3H) ppm.
3-Ethyl-2-(2-hydroxy-2-(3-hydroxyphenyl)ethyl)-1-
methyl-1H-imidazol-3-ium (6f): identified on the crude
Benzoic acid (5a): Yields in accordance with table 1; white
solid; m.p. 121-122 °C (Lit47 121-125 °C); 1H NMR (CDCl3, 400
1
aqueous fraction. H NMR (D2O, 400 MHz) δ: 7.49 (br s,
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1H), 7.39-7.32 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.88 (d, J =
129.6 (2xCH), 128.8 (2xCH), 128.8 (2xCH), 128.7 (2xCH),
1
2
3
8.0 Hz, 1H), 6.80 (brs, 1H), 5.19 (t, J = 6.4 Hz, 1H), 4.00 (q, J
= 7.2 Hz, 2H), 3.62 (s, 3H), 3.53 (t, J = 6.0 Hz, 2H), 1.40 (t, J =
7.2 Hz, 3H) ppm.
127.0 (CH), 45.6 (CH2). According to the literature.
Benzil (10): GC-MS: rt = 17.23 min :105 m/z [C7H5O]+, 210
m/z ([M+H]+).
3-Ethyl-1-methyl-2-styryl-1H-imidazol-3-ium (7a): iden-
tified on the crude aqueous fraction. H NMR (D2O, 400
1,2-Diphenylethan-1-ol (11): GC-MS: rt = 18.76 min: 197
([M+H]+).
2-Hydroxy-1,2-diphenylethan-1-one (12): GC-MS: rt =
28.46 min: 105 m/z [C7H5O]+, 107 m/z [C7H7O]+, 212 m/z
[M+H]+.
4
5
6
7
8
9
1
MHz) δ: 7.73-7.72 (m, 2H), 7.52-7.49 (m, 4H), 7.37 (br s, 1H),
7.30 (br s, 1H), 7.04 (d, J = 16.8 Hz, 1H), 4.25 (q, J = 7.2 Hz,
2H), 3.89 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H) ppm.
2-(4-Cyanostyryl)-3-ethyl-1-methyl-1H-imidazol-3-ium
(7b): 14% calculated by NMR; 1H NMR (CDCl3, 400 MHz) δ:
7.94 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.69 (br s,
1H), 7.59 (br s, 1H), 7.54 (d, J = 16.4 Hz, 1H), 7.41 (d, J = 16.4
Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 1.57 (t, J = 7.2
Hz, 3H) ppm.
1-Ethyl-2,3-dimethyl-2,3-dihydro-1H-imidazole (15): GC-
MS: rt = 8.96 min: 126 m/z [C7H14N2]+.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
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59
60
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via
the Internet at http://pubs.acs.org
NMR experiments; NMR spectra of the compounds; Mass
spectra and GC-MS.
(2-(4-Bromostyryl)-3-ethyl-1-methyl-1H-imidazol-3-ium
1
(7c): beige solid (0.030g, 36% after 192h); H NMR (CDCl3,
400 MHz) δ: 7.69-7.68 (m, 3H), 7.62 (d, J = 2.0 Hz, 1H), 7.49
(d, J = 8.0 Hz, 2H), 7.41 (d, J = 16.8 Hz, 1H), 7.20 (d, J = 16.8
Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.04 (s, 3H), 1.49 (t, J = 7.2
Hz, 3H) ppm; 13C NMR (CDCl3, 100MHz) δ: 143.5 (HC=CH),
142.1 (C), 132.7 (C), 132.3 (2xCH), 130.0 (2xCH), 125.3 (C),
124.7 (CH), 121.6 (CH), 107.9 (HC=CH), 45.0 ( CH2), 37.8
(CH3), 15.6 (CH3) ppm. HRMS-CI(+) calcd for C14H1679BrN2
[M]+ 291.0491 found 291.0497.
3-Ethyl-1-methyl-2-(4-nitrostyryl)-1H-imidazol-3-ium
(7e): 27 and 3% yield after 24h and 192h, calculated by
NMR; 1H NMR (CDCl3, 400 MHz) δ: 8.28 (d, J = 8.8 Hz, 2H),
8.00 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.62 (d, J =
16.8 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 16.8 Hz, 1H),
4.43 (q, J = 7.6 Hz, 2H), 4.14 (s, 3H), 1.61 (t, J = 7.2 Hz, 3H)
ppm.
AUTHOR INFORMATION
Corresponding Author
* Email: paula.branco@fct.unl.pt
* Email: lpf@fct.unl.pt
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
This work was supported by the Associated Laboratory for
Sustainable Chemistry - Clean Processes and Technogies
LAQV which is financed by national funds from
FCT/MEC(UID/QUI/50006/2013) and cofinanced by the
ERDF under the PT2020 Partnership Agreement (POCI-01-
0145-FEDER-007265). The NMR spectrometers are part of
The National NMR Facility, supported by Fundacão para a
(2-(3-Chlorostyryl)-3-ethyl-1-methyl-1H-imidazol-3-ium
1
(7g): beige solid (0.008g, 11% after 24h); H NMR (MeOD,
400 MHz) δ: 7.85 (br s, 1H), 7.70-7.68 (m, 2H), 7.64 (d, J =
2.0 Hz, 1H), 7.48-7.44 (m, 3H), 7.22 (d, J = 16.4 Hz, 2H), 3.97
(s, 3H), 1.52 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (MeOD, 100
MHz) δ: 144.1 (CH). 143.5 (C), 137.8 (C), 136.2 (C), 131.7 (CH),
131.6 (CH), 128.7 (CH), 127.5 (CH), 125.2 (CH). 122.6 (CH),
109.9 (CH), 45.3 (CH2), 36.9 (CH3), 15.4 (CH3). HRMS-CI(+)
calcd for C14H1635ClN2 [M]+ 247.0997 found 247.1006.
Ciência
e Tecnologia (RECI/BBB-BQB/0230/2012). La-
boratório de Análises REQUIMTE for the technical support
on mass spectrometry analyses.
3-Ethyl-2-(2-(furan-2-yl)vinyl)-1-methyl-1H-imidazol-3-
ium (7h): 14 and 8% yield after 24h and 192h, calculated
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100 MHz) δ: 197.7 (C=O), 136.8 (C), 134.7 (C), 133.3 (CH),
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1
2
3
Table of Contents
4
5
6
7
8
O
8 Carboxilic acids
(13-99% yield)
O
Et
Ts
Et
R
OH
R
N
N
R
R
H
(5)
X
N
Et
Cs2CO3
Cs2CO3
N
O
N
Diffusion-ordered spectroscopy
Mechanistic study
9
N
Et
X = Cl
Ts
N
I
X = I
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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33
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N
N
(3)
(6)
R
N
4 New compounds
(22-71% yield)
(7)
12
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