Amino acid ionic liquids as catalysts in a solvent-free Morita-Baylis-Hillman reaction

Article abstract of DOI:10.1039/c8ra02409j

In the present work, we describe the preparation of ten amino acid ionic liquids (AAILs) formed from ammonium salts as cations, derivatives of glycerol, and natural amino acids as anions. All of them are viscous oils, colorless or pale yellow, and hygroscopic at room temperature. They have appreciable solubility in many protic and aprotic polar solvents. The AAILs were used as catalysts in a Morita-Baylis-Hillman (MBH) reaction. The ionic liquids derivative from l-proline and l-histidine demonstrated the ability to catalyze the reaction between methyl vinyl ketone and aromatic aldehydes differently substituted in the absence of an additional co-catalyst under organic solvent-free conditions. The AAIL derivatives from l-valine, l-leucine, and l-tyrosine catalyzed the MBH reaction only in the presence of imidazole. The MBH adducts were obtained in moderate to good yields. Although the catalytic site in the ILs was in its enantiomerically pure form, all the MBH adducts were obtained in their racemic form.

Full text of DOI:10.1039/c8ra02409j

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Amino acid ionic liquids as catalysts in a solvent-
free Morita–Baylis–Hillman reaction†
Cite this: RSC Adv., 2018, 8, 23903
Mathias Prado Pereira,
Oliveira
Rafaela de Souza Martins,
*
Marcone Augusto Leal de
and Fernanda Irene Bombonato
In the present work, we describe the preparation of ten amino acid ionic liquids (AAILs) formed from
ammonium salts as cations, derivatives of glycerol, and natural amino acids as anions. All of them are
viscous oils, colorless or pale yellow, and hygroscopic at room temperature. They have appreciable
solubility in many protic and aprotic polar solvents. The AAILs were used as catalysts in a Morita–Baylis–
Hillman (MBH) reaction. The ionic liquids derivative from L-proline and L-histidine demonstrated the
ability to catalyze the reaction between methyl vinyl ketone and aromatic aldehydes differently
substituted in the absence of an additional co-catalyst under organic solvent-free conditions. The AAIL
derivatives from L-valine, L-leucine, and L-tyrosine catalyzed the MBH reaction only in the presence of
imidazole. The MBH adducts were obtained in moderate to good yields. Although the catalytic site in the
ILs was in its enantiomerically pure form, all the MBH adducts were obtained in their racemic form.
Received 19th March 2018
Accepted 23rd June 2018
DOI: 10.1039/c8ra02409j
rsc.li/rsc-advances
11
synthons via a catalytic process. Historically, the most
explored catalysts for this MBH reaction include tertiary amines
Introduction
Ionic liquids (ILs) exclusively comprise an organic cation and an or phosphines. The reaction is performed in polar protic
inorganic or organic anion. They are categorized as a green solvents, such as water, and they increase the rate of the reac-
solvent due to their signicant properties, such as good thermal tion. Common protocols involve
a
reaction between
stability, being liquid at/or close to room temperature, negli- a substituted aldehyde and activated alkenes, such as vinyl
gible vapor pressure, and nonammability. In recent years, sulfone, alkyl vinyl ketone, alkyl acrylate or acrylonitrile, in the
a new class of ILs has attracted the interest of several research presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as a catalyst
12–14
groups. These ILs are known as task-specic ionic liquids in a polar solvent.
TSILs) and have a free functional group covalently tethered to
The mechanism proposed in the literature for MBH reac-
(
the cation, or the anion. The presence of a free functional group tions catalyzed by a tertiary amine consists of a nucleophilic
can modify the physicochemical properties of an ionic liquid addition of 1,4 type to the a,b-unsaturated compound, gener-
and also make it capable of acting as a catalyst in organic ating the zwitterionic enolate (I) that acts as a nucleophile
1
2
reactions. In this context, the amino acid ionic liquids (AAILs)
have aroused interest due to the low cost of amino acids and the carbon bond and a new zwitterionic species (II), which aer
presence of a chiral carbon.
a proton transfer followed by decomposition process that
There are two groups of AAILs: the rst one has an amino results in the MBH adduct (III) and regenerates the catalyst
attacking the substituted aldehyde, creating a new carbon–
15
acid as a cation or an anion in its natural form, and the other (Fig. 1).
group has a modied amino acid. In the vast majority of
3
–6
16,17
18,19
Aggarwal
and McQuade
propose a different route the
cases, these AAILs are derivatives from L-proline and they can be a hydrogen transfer in the intermediate II. This stage is
used as an organocatalyst in Aldol, Mannich, Michael, and considered the rate determinate step of the MBH reaction.
7–10
Morita–Baylis–Hillman reactions.
MacQuade proposes that, in polar aprotic solvents, the alkoxide
The Morita–Baylis–Hillman (MBH) reaction is a powerful portion of the intermediate II reacts with another aldehyde
chemical transformation method, in which simple starting molecule, resulting in a deprotonated hemiketal intermediate,
materials are converted into highly functionalized molecular
Group of Studies in Organic Synthesis and Catalysis, Department of Chemistry,
University of Juiz de Fora, S a˜ o Pedro 36036-900, Juiz de Fora, Minas Gerais, Brazil.
E-mail: fernanda.bombonato@uf.edu.br; Fax: +55 32 2102-3310 ext. 30; Tel: +55
3
2 2102-3310 ext. 30
Electronic supplementary information (ESI) available: H and C NMR. See
Fig. 1 Simplified mechanism of the MBH reaction catalyzed by tertiary
amine.
1
13
†
DOI: 10.1039/c8ra02409j
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and in the a hydrogen abstraction, the intermolecular form
occurs due to the attack of the charged oxygen atom. Aer the
hydrogen transfer, the hemiketal is hydrolyzed, resulting in the
intermediate IV (Fig. 2(a)). Aer the elimination of the ammo-
nium portion, the MBH adduct is formed. In Aggarwal's turn,
the author suggests that the hydrogen transfer takes place
between the intermolecular intermediate II and the protic polar
solvent used in the reaction, and oxygen protonation and
abstraction of the a hydrogen occur simultaneously (Fig. 2(b)).
In addition, there are several papers in the literature that Fig. 3 General mechanism proposed for the MBH reaction catalyzed
by L-proline.
describe the results obtained in the reactions of MBH catalyzed
by L-prolines. In this case, the amine used as a catalyst is
integration. Aggarwal et al. go further and claim that benzal-
dehyde reacts with the ionic liquid derived from the imidazo-
lium ion in a side reaction.
a secondary amine and the mechanism described in the works
is based on the reaction of an a,b-unsaturated carbonyl
compound with an L-proline by a nucleophilic addition of 1,2
type. It creates an a,b-unsaturated iminium ion (V), which,
subsequently, suffers from a nucleophilic attack (the nucleo-
philic species at this stage depends on the reaction condition,
such as excess of L-proline, presence of imidazole, base medium
and L-proline) at the b position, resulting in a substituted b-
enamine (VI). Enamine (VI) acts as a nucleophile and attacks
the substituted aldehyde. It creates a condensation product
28,29
Coelho, Eberlin, and Neto
go further into this investiga-
tion and study the origin of the stabilizing effect of imidazolium
IL derivatives in the MBH by ESI-MS(/MS) and DFT calculations.
The author identied an MBH intermediate associated with the
ion pair of the ILs by ESI-MS(/MS). These experimental results
evidenced the formation of an electrostatic intermediate
complex between the ion pair of the IL and the cationic inter-
mediate of the MBH reaction. Additionally, the analysis of
theoretical calculations evidences the occurrence of ion-pairing
and a larger supramolecular organization of the intermediates
of the MBH reactions and the imidazolium IL used as
(VII) which, aer leaving the nucleophile (VIII) and hydrolyzing
the imines, produces the MBH adduct (IX). Finally, it regener-
20–27
ates the catalyst (Fig. 3).
Regardless of the nature of the amino-catalyst used (primary
or tertiary amine), the reactional intermediates formed have
a charge. In this sense, the use of aprotic polar, protic polar or
even ionic polar solvents will inuence the stabilization of these
charged intermediates and, consequently, will affect the speed
of the reaction.
29
a solvent.
These two effects together, the ionic pairing and the supra-
molecular organization caused by imidazolium ionic liquids in
the MBH reaction, changed this reaction faster when compared
to reactions performed in molecular solvents.
28
No work in the literature describes the use of primary amines
as catalysts in MBH reactions. Historically, primary amines are
the least compounds used as catalysts due to the fact that in
most aminocatalyzed reactions. The reaction mechanism
undergoes a balance shi between the imine–enamine forms.
This process is formed by the reaction of the catalyst with
carbonyl compounds. It is disadvantageous when primary
amines are used as catalysts, this phenomenon occurs the
In this sense, Santos et al. describe the inuence of using
a derivative imidazolium IL as a solvent in MBH reaction rate
between methyl acrylate and benzaldehyde. The reaction per-
formed 14.1 times faster in ILs than in acetonitriles. The
authors suggest that a strong stabilization of zwitterionic
intermediates occurs in ILs, affecting the reaction speed.
Aggarwal et al. challenge the results described by Afonso et al.
and question the experimental method used by the authors to
determine the reaction speed. Afonso et al. determine the
reaction rate by gas chromatography experiments, comparing
the integration of the MBH adduct with the aldehyde
30,31
imine form is predominant in equilibrium.
In this sense, the
use of primary amines as catalysts requires special attention
regarding the development of new and efficient catalytic
systems.
In this context, in the present work, we investigate the
synthesis of new AAIL's derivatives from glycerol and natural
amino acids (L-valine, L-leucine, L-proline, L-histidine, and L-
tyrosine). Further, we describe the use of AAILs prepared as
catalysts in MBH reactions between MVK and differently
substituted aldehydes.
Results and discussion
According to the Brazilian National Petroleum Agency (ANP),
3
Brazil produced 3.94 million m of glycerol in 2015 due to the
32
biodiesel production. The Brazilian market exports part of this
production at a reduced cost, but still has a surplus of this raw
material in the domestic market. With this in mind, we chose to
Fig. 2 Intermediate from rate-limiting step proposed by Aggarwal (a)
and MacQuade (b).
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a hydroxide ion. The hydroxide quaternary ammonium salts
were reacted immediately with natural amino acids, L-valine, L-
leucine, L-proline, L-histidine, and L-tyrosine, to result in an
AAIL, as shown in 4a–e and 5a–e of Scheme 1. In this way, two
series of AAILs with different chemical proprieties were
prepared. AAILs 4a–e contained free hydroxyls and were capable
of acting as donors and acceptors for hydrogen bondings. The
AAILs 5a–e were capable of acting as acceptors for hydrogen
bondings because the hydroxyls were protected as ketals.
The AAILs prepared as described above are viscous oils,
colorless or pale yellow, and hygroscopic at room temperature.
They have appreciable solubility in many protic and aprotic
polar solvents, such as water, acetonitrile, dimethyl sulfoxide,
N,N-dimethyl formamide, tetrahydrofuran, methanol, and
chloroform, when compared with pure amino acids, and they
are insoluble in ethyl acetate, diethyl ether, and hexane.
1
13
The AAILs structure was conrmed by H, C NMR, infrared
spectroscopy (IR), and elemental analysis. The deprotonation of
1
3
the acid group of amino acid was clearly evidenced by C NMR
in the signal of carbonyl carbon that has a delocalization to high
shi (Table 1).
Thermal gravimetric analysis (Table 2) showed that the ionic
ꢁ
liquids had a decomposition temperature (Tdec) at ꢀ200 C and
that the ionic liquids 4a–e had a slightly higher temperature
than 5a–e. This difference is due to the free hydroxyl group that
increases the hydrogen bonds in AAIL 5a–e. A negative glass
transition temperature (T ) was observed via differential scan-
g
ning calorimetric measurements.
The AAILs were tested for catalysts in an MBH reaction
between MVK and p-nitrobenzaldehydes. All the prepared ILs
have the active catalytic site in an enantiomerically pure form,
in this sense we expect to obtain the MBH adducts in their
Scheme 1 Synthetic route to AAILs 4a–e and 5a–e. Reagents and
conditions: (i) acetone, TsOH, petroleum ether, Dean-Stark, 32 h,
ꢁ
ꢁ
6
0 C, 80%; (ii) PPh
3
, I
2
, imidazole, toluene, 2 h, 90 C, 81%; (iii) HCl 2 M, enantiomerically enriched form. Initially, the reactions were
acetone, 4 h, 50 C, 63%; (iv) triethylamine, ethanol, 16 h, 60 C, 75%; carried out with 20 mol% of the catalyst, in the absence of
ꢁ
ꢁ
ꢁ
(
v) CH
2
O, TsOH, MeCN, 4 h, 90 C, 77%; (vi) Amberlyst A-26 OH; (vii) L-
organic solvents, additives and at room temperature. The
results of this sequence of experiments are summarized in
Table 3 (entries from 1 to 17).
Since we expect the MBH reaction to be catalyzed by the
amine group and the prepared ionic liquids to have different
amino acid residues, the amine function is classied differently
amino acid, 48 h, r.t. 62–95%.
use a derivative of glycerol as a cation in order to add value to
this raw material that is abundant in our country.
We started the synthesis of the ionic liquids with the prep-
aration of quaternary ammonium salts 2 and 3 in four steps
from glycerol. The intermediates 2 and 3 are described in the
(primary, secondary and heteroaromatic amines). To better
understand the results, we will rst discuss the MBH reactions
catalyzed by the ILs containing primary amines (L-valine, L-
leucine, and L-tyrosine) 4a, b and 5a, b and c, respectively. Later,
we will discuss the results obtained when the ILs derived from
the L-proline (4c and 5c) were used as catalysts. Finally, we will
33,34
1
13
literature,
but the characterization ( H and C NMR and IR)
was incomplete or missing. Subsequently, salts 2 and 3 were
submitted to an anion metathesis, which was mediated using
Amberlyst A-26 OH, where iodide was substituted with
13
Table 1
C NMR shifts of carbonyl carbon in a free amino acid and AAILs
ꢂb
ꢂb
a
AAIL
d (ppm) of R–COO
AAIL
d (ppm) of R–COO
d (ppm) of R–COOH
4
4
4
4
4
a
b
c
d
e
182.7
184.2
183.1
181.5
182.1
5a
5b
5c
5d
5e
182.0
182.0
180.0
182.1
182.2
175.4
176.3
175.4
174.8
175.0
a
35 b 13
Data taken from literature;
2
C NMR performed at 75 and 125 MHz in D O.
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a
Table 2 Thermal gravimetric analysis results
use of protic or aprotic polar organic solvents in the presence of
water as an additive. In this sense, we can affirm that the ILs
used in this work as a solvent, and a catalyst, depending on the
cation used have characteristics of protic or aprotic polar
solvents and the residual water present in the ILs acts as an
additive.
When the ILs 4a, b and e, and 5a, b and e (primary amines)
were used as catalysts in the MBH reactions no formation of the
desired MBH adduct was observed in the absence of solvents,
organic additives and at room temperature. However, we can
observe the consumption of both the MKV and the catalyst. By
means of IR experiments, Calow et al. have observed that the
MVK in the presence of primary amines rapidly undergo
ꢁ
ꢁ
ꢁ
ꢁ
T
g
AAIL
T
dec/ C
T
g
/ C
AAIL
T
dec/ C
/ C
4
4
4
4
4
a
b
c
d
e
226
234
229
233
165
*
5a
5b
5c
5d
5e
189
188
220
228
145
ꢂ40
ꢂ64
ꢂ45
*
ꢂ55
ꢂ44
*
*
ꢂ41
a
*Not determined.
discuss the results in MBH reactions when the ILs derived L-
histidine (4d and 5d) were used as catalysts.
The ionic liquids used also have cations with different
characteristics. The series of ionic liquids 4 have cations
capable of both donating and receiving hydrogen bonds. The
ionic liquids of series 5 have cations capable of only receiving
hydrogen bonds. In this work, we will compare our results with
works described in the literature for MBH reactions where only
amino acids were used as catalysts. In this sense, the reactions
described up to the present moment in the literature report the
a
nucleophilic addition reaction 1,4 type, generating
a substituted b-ketone, which reacts again with another amine
molecule and produces an imine, this species is inactive in the
MBH reactions. In this context, the residues of the amino
acids present in the ILs used in these reactions reacted with
MVK inactivating the catalyst and disrupting the catalytic cycle,
corroborating the results described by Calow and others.
36
a
Table 3 Optimisation of AAIL mediated MBH reaction between p-nitrobenzaldehyde 6a and methyl vinyl ketone (7)
b
c
Entry
AAIL (20 mol%)
Additive (20 mol%)
Solvent (1 mL)
Time (h)
Yield (%)
d
1
Imidazole
—
—
—
—
—
—
—
CHCl
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
3
72
72
72
72
72
72
72
72
72
4
4
5
5
5
5
5
5
5
5
5
5
72
72
4
4
5
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
82
51
68
66
44
35
41
38
30
26
29
23
34
2
3
4
5
6
7
8
9
4a
5a
4b
5b
4e
5e
4c
5c
4d
5d
4a
5a
4b
5b
4e
5e
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
—
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
Imidazole
—
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
O
O
O
24
N.R.
N.R.
40
32
20
—
—
—
Imidazole
Imidazole
5
18
a
b
All reactions were performed with 1.0 mmol MVK, 0.2 mmol p-nitrobenzaldehyde, 20 mol% of AAIL and 20 mol% of imidazole. The reaction was
c
d
monitorated by TLC until complete consumption of the aldehyde. Isolated yield aer column chromatographic purication. Solvent 1 mL.
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Shi et al. described the MBH reaction between the MVK and aer the MBH reaction and observed that the residue of L-
the p-nitrobenzaldehyde, using the L-proline amino acid and the proline of IL 4c and 5c reacted slowly with the MVK excess
20
imidazole as the catalyst separately. The reactions were carried present in the reaction medium, inactivating the catalyst which
out using DMF as a solvent. Under these reaction conditions, it justies the longer reaction time observed when the IL 4c and
was not possible to observe the formation of the desired MBH 5d were used.
adduct. However, when the two catalysts were used in combi-
Gruttadauria et al. and Inani et al. successfully described the
nation, the MBH adduct was obtained in 91% aer 24 hours of MBH reaction catalyzed only by the amino acid L-proline in
reaction at room temperature. The authors proposed that the a mixture of polar aprotic and protic solvents (DMF: water, 9 : 1
24,25
reaction mechanism consists of the formation of an a,b- and water, respectively).
The two authors affirm that the L-
unsaturated imine formed by the reaction between the MVK proline is a bifunctional catalyst and that in the rst stage of the
and the L-proline. This imine undergoes a nucleophilic addition reaction mechanism occurs with the reaction of L-proline with
of the 1,4 type from the imidazole producing an enamine: the the MVK producing an iminium a,b-unsaturated ion and, then
nucleophile from the reaction. It attacks the p-nitro- that a 1,4 type nucleophilic addition occurs. Gruttadauria et al.
benzaldehyde forming the new carbon–carbon bond. Finally, propose that the addition 1,4 is carried out by the carboxylate
this intermediate will consequently produce the MBH adduct.
residue formed by the acid–base reaction between the carbox-
used in the
Based on the results described by Shi et al., it was decided to ylic acid residue of L-proline with the NaHCO
3
cause MBH reactions between the MVK and the p-nitro- reaction medium, to the b-carbon of the imine a,b-unsaturated.
benzaldehyde, in the same reaction condition previously used; Inani et al. propose that the nucleophilic addition of the addi-
however, in the presence of 20 mol% of imidazole. In this new tion 1,4 type is carried out by another L-proline molecule that is
reaction condition, the MBH adducts were formed, aer 5 used in excess in the reaction medium. The reaction time
hours, in yields ranging from 26 to 44%, Table 3 (entries, 12– described in the two studies ranged from 13 to 120 hours. Based
17), and at signicantly lower reaction times when compared to on these results, we can suggest that in the reaction of MBH,
the reaction times described by Shi and others. As previously which was catalyzed by the ionic liquid derived from L-proline
discussed, the ionic medium favors a supramolecular organi- (4c and 5c), occurs via a mechanism similar to that described by
zation. The presence of imidazolium ion, formed during the Inani et al. Since the reaction was performed using only ILs
reaction, favors the formation of ions pairing and both factors derived from the L-proline, that is, we have an excess of L-proline
affect the velocity of the reaction positively. It should be residues in the reaction medium.
observed that no variation of the reaction time was detected
In addition to the work described by Shi and Gruttadauria
when there was an alteration of the cation type, hydrogen and their collaborators, Guo et al. described the use of the
bonding donors/acceptors or only hydrogen bond acceptors.
In order to increase the yield of the MBH adduct and to
decrease the reaction time, we decided to perform an MBH
reaction between MVK and p-nitrobenzaldehyde, using the ILs
amino acid L-proline combined with the L-histidine amino acid
4a, b and e, and 5a, b, and e, in water. Several authors report an
increase in yield and a decrease in reaction time when the
26,37–44
imidazole was used as a catalyst in them MBH reaction.
The results obtained from this sequence of reactions are shown
in Table 3 (entries 18–21 and 26–27). The reaction times
remained the same; however, the yield of the MBH adducts
obtained was lower when compared to the reactions performed
in the absence of water.
However, based on the results described by Calow, we believe
that in the reaction condition used by us the mechanism of the
reaction occurs in a different way to the one proposed by Shi.
Since the addition reaction 1,4 occurs rapidly, it generates
a species that contains an ammonium salt residue (which
would be deprotonated by the imidazole) and an enolate
(capable of acting as a nucleophile in the MBH reaction). It
would be stabilized by forming an ion pair with the imidazole
conjugate acid since the imidazole behaves better as a base than
as a nucleophile.
When analyzing the results obtained using the ILs derived
from the L-proline (4c and 5c), Table 3 (entries, 8–9), the MBH
adducts were obtained without the need for additives in yields
ranging from 51 to 72% aer 72 hours of reaction. When water
was used as a solvent, no reaction was observed (Table 3, entries
Scheme 2 Mechanistic proposal for the reaction of MBH catalyzed by
1
2
2–23). We analysed the ionic liquid by H NMR and ESI(ꢂ)-MS the ionic liquids 4d and 5d.
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in MBH reactions, however, the formation of the MBH adduct equipped with an API-ES ion source, coupled to the Capillary
was not observed when the two amino acids were used sepa- Electrophoresis instrument, Agilent CE 7100 (Agilent Technol-
rately as catalysts. The authors highlighted that the success of ogies, Singapore), used in compounds infusion into the MS by
the catalytic system used is based on the use of a mixture of ush with acetonitrile. The sheath liquid (5 mM of ammonium
protic polar solvents (methanol : water). MBH adducts were acetate dissolved in 1 : 1 (v/v) methanol/water) was delivered at
ꢂ1
obtained in yields that range from moderate to good and long 0.001 mL min ow using an LC isocratic pump (1260 Innity,
reaction times, from 7 to 24 days. Nevertheless, the authors do Agilent Technologies, Waldbronn, Germany). The MS was
not describe a mechanistic proposal for the formation of MBH operated in the negative ionization mode applying electrospray
ꢁ
adducts. Surprisingly, when using ILs derived from the L-histi- voltage of 3.0 kV. Nitrogen was used as drying gas at 250 C, with
ꢂ1
dine 4d and 5d, MBH adducts were obtained with 4 hours of a ow rate of 6 L min ; the pressure of the nebulizer gas was set
reaction in the absence of organic solvents or additives and in at 15 psi. The m/z characterization of the MBH intermediate was
yields ranging from 66 to 68% (Table 3, entries 10–11).
Unfortunately, although all ILs have chiral active sites, no the compounds infusion into the quadrupole MS by a ush with
optical activity was observed in the MBH adducts obtained. acetonitrile, the fused-silica capillary (Polymicro Technologies,
made by the total ion current (TIC) mode. In order to perform
In order to understand more about the performance of the Phoenix, USA) of 70 cm length and an internal diameter of 75
1
AAIL derived from the L-histidine in the MBH reaction, H NMR mm was used. The new capillary was conditioned by ushing
and IR experiments were performed and the results of in situ with 1 M NaOH (10 min), water (10 min), and acetonitrile (15
analyses suggested that the primary amine portion, present at min). Samples were injected hydrodynamically at 50 mbar for
ꢁ
the residue of L-histidine amino acid from the IL 4d, reacts with C10 s and cassette temperature was maintained at 250 C.
MVK by a nucleophilic addition of 1,4 type (as previously Among sample injections, a short preconditioning in the
observed for the IL 4a, b and e and 5a, b, and e) generating capillary was performed by ushing with 1 M NaOH (2 min),
a substituted b enolate. The enolate formed would be stabilized water (2 min) and acetonitrile (2 min). The data processing was
by the imidazole residue by the formation of an ionic pair, see performed with the Agilent ChemStation for CE-MS version
the mechanistic proposal shown in Scheme 2.
soware. The analysis was made within 15 min of reaction, and
We also monitored the reaction across the mass-to-charge the spectra data were shown in Fig. 4. We observed the
(m/z) characterization of the compounds which was made production of a nucleophilic 1,4 addition of amine residue of
with 6120 Quadrupole LC/MS (Agilent Technologies, Singapore) histidine to MVK, forming the MBH nucleophiles
Fig. 4 ESI(ꢂ)-MS after 15 min of reaction between MVK 1.0 mmol (7) and p-nitrobenzaldeyde 0.2 mmol (6a) and the AAIL 4d (20 mol%) as
a catalyst.
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(
intermediates A and B) and the product of the addition of MBH Table 5 Scope of the MBH reaction between methyl vinyl ketone and
a
aromatic aldehydes
nucleophiles to the p-nitrobenzaldehyde (C, D, E, and F) (Fig. 4).
45,46
As described in the literature,
we also observed the side
reactions (electrophilic aromatic substitution, carbene reaction
and N-alquilation) of imidazole residues of histidine with MVK
and not with the aldehyde, as described by Aggarwal et al. This
side reaction could be observed not only ESI(ꢂ)-MS (Fig. 4) but
1
also in H NMR experiments (see ESI†). In view of these results,
we decided to change the proportion between MVK and p-
nitrobenzaldehyde. However, they do not assess the formation
of side reactions in the imidazole residue.
Despite the occurrence of these lateral reactions in the
imidazole residue, the active site of the catalyst (primary amine)
remained free and the catalyst remained active even aer ve
cycles of recycling. The yield of the adduct did not considerably
change (68 to 60%). However, the lateral reactions suffered by
the imidazole residue resulted from a considerable increase in
the volume of the anion, making it difficult to ionic pairing,
which can be observed in the increase in the reaction time when
we reused the catalytic system more than once (Table 4). When
water was used as a solvent (Table 3, entries 24–25), the reaction
time was the same, but the yield decreased drastically, probably
due to the decrease in the organization of the system generated
by the presence of water used as solvents.
b
Entry
R
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
m-NO
o-NO
p-FC H (8d)
p-ClC
o-ClC
p-Cf
3,4,5-(OCH
2-Furyl (8i)
Ph (8j)
2
C
6
H
4
(8b)
(8c)
4
4
66
62
88
81
74
71
51
89
36
39
2
C
6
H
4
6
4
24
24
24
24
72
48
120
120
6
H
4
(8e)
(8f)
6 4
H
3
C
6
H
4
(8g)
3 3 6 2
) C H (8h)
c
9
c
10
3
p-OCH Ph (8k)
a
All reactions were performed with 1.0 mmol MVK, 0.2 mmol of
aromatic aldehydes and 20 mol% AAIL 4d. Isolated yield aer
column chromatographic purication. Reactions were performed
b
c
Although the lateral reactions occurred in the imidazole
portion of ionic liquid 4d, this ILs were selected as the catalyst
to study the scope of the reaction between the MVK and the
aromatic aldehydes differently substituted. Similar to the
results described in the literature, MBH adducts of aldehydes
substituted by electron withdrawing groups were obtained at
higher yields and at shorter reaction times, while the products
of the aldehyde MBH addition, containing electron donating
groups, were obtained with higher reaction times and lower
yields (Table 5). All adducts described above are known
compounds, no optical activity was observed, and their spec-
troscopic data was in accordance with the published literature.
with 1.5 mmol of MVK and 0.5 mmol of aromatic aldehyde and
20 mol% AAIL 4d
Conclusions
AAIL was prepared from glycerol via a simple method using
a clearly dened protocol. All synthesized AAILs were viscous
oils, colorless or pale yellow, and very hygroscopic at room
temperature. Two series of AAILs with different chemical
proprieties were prepared. AAILs 4a–e contained free hydroxyls
and were capable of acting as donors and acceptors for
hydrogen bondings. The AAILs 5a–e were capable of acting as
acceptors for hydrogen bondings because the hydroxyls were
protected as ketals.
Table 4 Recycling of AAIL 4d as a catalyst in MBH reaction between
a
p-nitrobenzaldehyde (6a) and methyl vinyl ketone (7)
Both L-proline and L-histidine ionic liquids catalyzed the
MBH reaction with no addition of additives or organic solvents.
However, the ILs 4a, b and e and 5a, b and e catalyzed the MBH
reaction only in the presence of imidazole. No previous work in
the literature describes the use of primary amines (alone or
associated with a co-catalyst) as a catalyst in the MBH reaction.
The ionic medium and the presence of imidazole (add or
present in the amino acid structure) affect positively the rate of
38,40,42–44,47,48
MBH reactions compared to molecular solvents.
As
b
Recycling
Time (h)
Yield (%)
described in the literature, these two effects added could affect
the rate of the MBH reaction in an ionic medium: a supramo-
lecular organization and a favoring of ion pairing.
Fresh
4
5
6
48
96
68
64
61
60
60
29
nd
2
3
4
5
cycle
cycle
cycle
cycle
rd
th
th
The reactions that the ILs 4c–d and 5d, used as catalysts,
1
were monitored by ESI-(ꢂ)MS and H NMR. In that case, the IL
4d and 5d, derivatives from L-histidine produced by lateral
a
All reactions were performed with 1.0 mmol MVK, 0.2 mmol p- reactions of imidazole portion, were observed (Fig. 4 B, D, E,
b
nitrobenzaldehyde and 20 mol% AAIL. Isolated yield aer column
chromatographic purication.
and F), besides the MBH intermediates expect (Fig. 4 A and C
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and Scheme 2). This lateral reaction did not affect the catalytic
4-Iodomethyl-2,2-dimethyl-1,3-dioxolane. To a solution of
site (primary amine) and the catalysts remained active. An 2,2-dimethyl-1,3-dioxolan-4-yl-methanol (3.92 g, 29.7 mmol) in
increase in time reaction (4 to 96 hours) was observed at most toluene (80.0 mL) was added triphenylphosphine (9.44 g, 38.0
when the catalysts 4d and 5d were used more than once. When mmol), imidazole (3.06 g, 45.0 mmol), and iodine (9.97 g, 39.2
ꢁ
the IL 4c and 5c were used, long-time reactions were observed mmol). The reaction mixture was stirred at 90 C for 2 h. Aer
due to the side reaction detected between the catalysts with the removal of toluene under reduced pressure, the residue was
excess of the MVK used in the MBH reaction, that inactivated dissolved in dichloromethane, washed with saturated Na S O ,
2
2 3
the catalyst site.
brine and dried over Na SO . The solvent was then removed
2 4
The best experimental condition was obtained with the IL 4d under vacuum and the residue was puried by silica gel ash
and it was employed to study the scope of the reaction between column chromatography (hexane/ethyl acetate, 9 : 1) to give the
MVK and substituted aromatic aldehydes to result in different iodide compound as a colorless liquid (5.83 g, 81%). IR (plate,
ꢂ1
1
MBH adducts in good yields. Although all ILs has chiral active NaCl): 2986, 2935, 2877, 1058, 843 cm ; H NMR (300 MHz,
sites, no optical activity was observed in the MBH adducts CDCl ): d 4.30–4.22 (m, 1H); 4.14 (dd, J ¼ 8.7 Hz and J ¼ 6.0 Hz,
3
obtained.
1H), 3.78 (dd, J ¼ 8.7 Hz and J ¼ 5.4 Hz, 1H), 3.23 (dd, J ¼ 9.6 Hz
and J ¼ 4.5 Hz, 1H), 3.14 (dd, J ¼ 9.9 Hz and J ¼ 8.4 Hz, 1H), 1.44
1
3
(
s, 3H), 1.33 (s, 3H); C NMR (CDCl , 75 MHz): d 110.6, 75.8,
3
Experimental
Materials and methods
69.8, 27.3, 25.8, 6.84.
-Iodo-1,2-propanediol (1). To a ice cold solution of 4-
3
iodomethyl-2,2-dimethyl-1,3-dioxolane (2.40 g, 10.0 mmol) in
acetone (10.0 mL), was added HCl 2 M (10.0 mL, 20.0 mmol).
All the amino acids were purchased from Aldrich and the other
chemicals and reagents were treated. The progress of reaction was
monitored by using pre-coated TLC plates (E. Merck Kieselgel 60
F254). Melting points were determined by microqu ´ı mica MQAPF-
ꢁ
The reaction mixture was stirred at 60 C for 4 h. Aer that the
mixture was neutralized with NaHCO saturated solution and
3
extracted with ethyl acetate. The organic layer was dried over
Na SO . The solvent was then removed under vacuum and the
13
1
3
61. C NMR and H NMR were recorded on Bruker DPX-300 and
2
4
DPX-500 spectrometer. Chemical shis are reported in ppm. Peak
multiplicities are designated by the following abbreviations: s,
singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet; br,
broad; and J, coupling constant in Hz. TMS and dioxane were used
as an internal standard. IR spectra were recorded using Bruker FT-
residue was puried by silica gel ash column chromatography
(
hexane/ethyl acetate, 2 : 8) to give the pure product 1 as a yellow
ꢁ
solid (1.28 g, 63%). mp 46–48 C; IR (lm, KBr): 3356, 2925,
1
ꢂ1
1
054, 873 cm ; H NMR (D
2
O, 300 MHz): d 3.67–3.58 (m, 3H),
3
.36 (dd, J ¼ 10.8 Hz and J ¼ 4.3 Hz, 1H), 3.27 (dd, J ¼ 10.8 Hz
ꢂ1
IR in the range of 4000–400 cm and characteristics frequencies
13
and J ¼ 6.0 Hz, 1H); C NMR (D O, 75 MHz): d 70.7, 64.8, 13.2.
2
are expressed. Elemental analysis were recorded using a Perkin
Elmer 2400 series II. Thermogravimetric analysis were performed
under nitrogen atmosphere using an Shimadzu DTG-60 in the
3-(Tri-ethylammonium)propan-1,2-diol iodide (2). Ethanolic
triethylamine solution 4.20 M (24.0 mL, 100 mmol), was cooled
on an ice bath. 3-Iodo-1,2-propanediol (1) (2.02 g, 10.0 mmol)
was solubilized in 50.0 mL of ethanol and was added slowly to
ꢁ
temperature range between 25 and 500 C and a heating rate of
ꢁ
ꢂ1
1
0 C min . Differential scanning calorimeter were performed
ꢁ
the amine solution. The mixture was stirred at 60 C for 16 h,
under nitrogen atmosphere using an Shimadzu DSC-60 in the
and the solvent was removed under vacuum to give a crude
yellow oil. The crude product was washed with a large excess of
cold propanone to afford a white solid 2 (2.27 g, 75%); mp 136–
ꢁ
temperature range between ꢂ90 and 100 C and a heating rate of
ꢁ
ꢂ1
1
0 C min .
ꢁ
ꢂ1
1
1
38 C; IR (lm, KBr) 3422, 2989, 1050, 1002 cm ; H NMR
(
D O, 300 MHz): d 4.24–4.20 (m, 1H), 3.61–3.33 (m, 10H), 1.29 (t,
2
Procedure for the preparation of intermediate compounds
from glycerol
13
J ¼ 6.90 Hz, 9H); C NMR (D
2
O, 75 MHz): d 66.2, 64.3, 59.4,
5
4.3, 7.73.
2
,2-Dimethyl-1,3-dioxolan-4-yl-methanol. Glycerol (20.2 g,
N-((1,3-Dioxolan-4-yl)methyl)-N,N,N-tri-ethylammonium
ꢁ
0
.220 mol), acetone (60.0 mL) in petroleum ether b.p. 60–80 C iodide (3). Ammonium salt (2) (3.03 g, 10.0 mmol), para-
(60.0 mL) and p-toluenesulfonic acid (TsOH) (0.600 g) were formaldehyde (1.50 g, 50.0 mmol) and p-toluenesulfonic acid
mixed and heated under reux for 32 h in which the water (TsOH) (0.360 g) was solubilized in 50.0 mL of acetonitrile. The
ꢁ
formed during the reaction was removed continuously by mixture were mixed and heated under reux at 90 C for 4 h.
a Dean-Stark apparatus. The reaction mixture was cooled to The reaction mixture was cooled to room temperature and
room temperature and Na CO (1.00 g) was added gradually. Na CO (0.400 g) was added gradually. The mixture was stirred
2 3
2 3
The mixture was stirred for 30 min, ltered, and the ltrate was for 30 min, ltered, and the solvent was removed under vacuum
evaporated to dryness to give the crude product. The crude and the residue was puried by silica gel ash column chro-
product was vacuum distilled (10 mm Hg) to give the pure matography (dichloromethane/methanol, 9.5 : 0.5) to give the
ꢁ
acetonide as a colorless liquid (23.2 g, 80%). IR (plate, NaCl): product 3 (2.44 g, 77%) as a yellow solid; mp 142–143 C; IR
ꢂ1
1
ꢂ1
1
3
4
423, 2987, 2937, 1050 cm ; H NMR (CDCl , 300 MHz): d 4.22– (lm, KBr): 3449, 2982, 2875, 1051, 1001 cm ; H NMR (D O,
3
2
.20 (m, 1H), 4.04–3.98 (m, 1H), 3.80–3.67 (m, 2H), 3.59–3.56 300 MHz): d 5.26 (s, 1H) 5.17 (s, 1H), 4.44–4.39 (m, 1H), 3.85–
1
3
(m, 1H), 1.42 (s, 3H), 1.36 (s, 3H); C NMR (CDCl
3
, 75 MHz):
d 109.6, 76.3, 66.0, 63.2, 26.9, 25.4.
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1
3
ꢂ1
1
3
.80 (m, 1H), 3.75–3.49 (m, 9H), 1.49–1.44 (t, J ¼ 6.9 Hz, 9H);
C
1397, 1256, 1052, 792 cm ; H NMR (D
2
O, 300 MHz): d 6.90 (d, J
NMR (D O, 75 MHz): d 96.1, 69.7, 68.2, 58.8, 54.6, 8.09.
¼ 7.20 Hz 2H), 6.52 (d, J ¼ 7.20 Hz, 2H), 3.99 (m, 2H), 3.47–3.08
2
(
1
m, 21H), 2.80–2.72 (m, 1H), 2.60–2.52 (m, 1H), 1.09–1.05 (m,
1
3
8H); C NMR (D O, 75 MHz): d 182.1, 161.4, 131.2, 126.4,
18.0, 66.2, 64.2, 59.4, 58.1, 54.1, 40.5, 7.41; elemental analysis
calcd for C27H N O $1.0H O: C, 58.99, H, 10.08, N, 7.64; found:
53 3 7 2
2
General procedure for the preparation of amino acid ionic
liquids 4a–e, 5a–e
1
3-(Tri-ethylammonium)propan-1,2-diol hydroxide and N-((1,3- C, 58.92, H, 9.64, N, 7.71.
dioxolan-4-yl)methyl)-N,N,N-tri-ethylammonium
hydroxide
N-((1,3-Dioxolan-4-yl) methyl)-N,N,N-tri-ethylammonium L-
aqueous solution was prepared from ammonium salts (2) and valinate (5a). Viscous oil, yield 91%; IV (plate, NaCl) 3385, 2960,
ꢂ1
1
(
3), respectively, using anion exchange resin Amberlyst A-26 1579, 1397, 1160, 1086, 1002 cm ; H NMR (D O, 300 MHz):
2
hydroxide. Hydroxide aqueous solution was added dropwise d 5.03 (s, 1H), 4.93 (s, 1H), 4.63–4.56 (m, 1H), 4.19–4.15 (m, 1H),
to a slightly excess equimolar of L-amino acid aqueous solution 3.61–3.55 (m, 1H), 3.51–3.31 (m, 8H), 3.05 (br, 1H), 1.92–1.90
under cooling. The mixture was stirred under ambient (m, 1H), 1.25 (t, J ¼ 6.90 Hz, 9H), 0.91 (d, J ¼ 6.90 Hz, 3H), 0.84
1
3
temperature and protecting of light for 48 h. Then water was (d, J ¼ 6.90 Hz, 3H); C NMR (D
2
O, 75 MHz): d 182.0, 96.0, 69.7,
ꢁ
evaporated at 60 C. To this reaction mixture were added 68.1, 62.3, 58.6, 54.4, 32.0, 19.8, 17.4, 7.46; elemental analysis
a mixture of acetonitrile : methanol (9 : 1), and it was stirred calcd for C15
32 2 4 2
H N O $1.0H O: C, 55.87, H, 10.63, N, 8.69; found:
vigorously. The mixture was then ltered to remove excess C, 56.26, H, 10.29, N, 8.83.
amino acid. Filtrate was evaporated to remove solvents. The
product was dried in vacuum for 2 days at 60 C.
N-((1,3-Dioxolan-4-yl) methyl)-N,N,N-tri-ethylammonium L-
leucinate (5b). Viscous oil, yield 74%; IR (plate, NaCl): 3374,
(4a). 2954, 2869, 1578, 1399, 1160, 1085, 1002 cm ; H NMR (D O,
2
ꢁ
ꢂ1
1
3-(Tri-ethylammonium)propan-1,2-diol,
L-valinate
Viscous oil, yield 85%; IR (plate, NaCl): 3375, 2960, 1567, 1397, 300 MHz): d 5.01 (s, 1H), 4.92 (s, 1H), 4.62–4.52 (m, 1H), 4.19–
ꢂ1
1
1
3
1
6
5
053, 1002 cm ; H NMR (D O, 300 MHz): d 4.17–4.14 (m, 1H), 4.13 (m, 1H), 3.60–3.53 (m, 1H), 3.48–3.31 (m, 8H), 3.22–3.18
2
.60–3.21 (m, 10H), 3.12 (d, J ¼ 4.20 Hz, 1H), 1.98–1.91 (m, 1H), (m, 1H), 1.65–1.56 (m, 1H), 1.46–1.31 (m, 2H), 1.24 (t, J ¼ 7.2 Hz,
1
3
.24 (t, J ¼ 6.90 Hz, 9H), 0.91 (d, J ¼ 6.30 Hz, 3H), 0.84 (d, J ¼ 9H), 0.88–083 (m, 6H), C NMR (D
2
O, 75 MHz): d 182.0, 96.0,
1
3
.30 Hz, 3H); C NMR (D
9.4, 54.2, 32.1, 19.7, 17.3, 7.38; elemental analysis calcd for analysis calcd for C15
$1.0H
O: C, 54.17, H, 11.04, N, 9.02; found: C, 53.87, 8.33; found: C, 57.10, H, 10.36, N, 8.27.
H, 11.02, N, 8.91.
N-((1,3-Dioxolan-4-yl) methyl)-N,N,N-tri-ethylammonium L-
-(Tri-ethylammonium)propan-1,2-diol L-leucinate (4b). prolinate (5c). Viscous oil, yield 84%; IR (plate, NaCl): 3386,
2
O, 75 MHz): 182.7, 66.3, 64.3, 62.3, 69.7, 68.1, 58.5, 54.9, 54.4, 43.6, 24.9, 23.1, 21.9, 7.48; elemental
H
30
N
O
4
$1.0H O: C, 57.11, H, 10.78, N,
2
2
C
14
H
32
N
2
O
4
2
3
ꢂ1
1
2
Viscous oil, yield 62%; IR (plate, NaCl): 3373, 2956, 1575, 1365, 2957, 1587, 1394, 1161, 1085, 1002 cm ; H NMR (D O, 300
052 cm ; H NMR (D O, 300 MHz): d 4.18–4.15 (m, 1H), 3.60– MHz): d 4.98 (s, 1H), 4,90 (s, 1H), 4.56–4.53 (m, 1H), 4.14–4.09
ꢂ1
1
1
3
6
2
.22 (m, 11H), 1.63–1.57 (m, 1H), 1.44–1.37 (m, 2H), 1.25 (t, J ¼ (m, 1H), 3.57–3.51 (m, 1H), 3.41–3.26 (m, 8H), 3.07–3.01 (m,
1
3
2
.90 Hz, 9H), 0.90–0.85 (m, 6H); C NMR (D O, 75 MHz): 1H), 2.82–2.79 (m, 1H), 2.09–2.07 (m, 1H), 1.74–1.68 (m, 3H),
1
3
d 184.2, 66.3, 64.3, 59.4, 55.1, 54.2, 44.7, 25.0, 23.1, 22.0, 7.38; 1.20 (t, J ¼ 6.9 Hz, 9H); C NMR (D
elemental analysis calcd for C15 $0.5H
O: C, 57.11, H, 69.0, 67.5, 61.4, 57.8, 53.7, 46.0, 30.2, 24.8, 6.75, elemental
1.18, N, 8.88; found: C, 57.18, H, 11.35, N, 8.79.
-(Tri-ethylammonium)propan-1,2-diol L-prolinate (4c). 8.74; found: C, 56.22, H, 9.93, N, 9.16.
O, 75 MHz): d 180.0, 95.3,
2
H
34
N
2
O
4
2
1
analysis calcd for C15
H
30
N
2
O
4
$1.0H
2
O: C, 56.23, H, 10.07, N,
3
Viscous oil, yield 93%; IR (plate, NaCl): 3382, 2981, 1584, 1394,
N-((1,3-Dioxolan-4-yl)methyl)-N,N,N-tri-ethylammonium L-
ꢂ1
1
1
3
054 cm ; H NMR (D O, 300 MHz): d 4.17–4.12 (m, 1H), 3.66– histidinate (5d). Viscous oil, yield 95%; IV (plate, NaCl): 3374,
2
ꢂ1
1
2
.21 (m, 11H), 3.16–3.07 (m, 1H), 2.92–2.84 (m, 1H), 2.14–2.10 2993, 2891, 1574, 1403, 1161, 1088 cm ; H NMR (D O, 500
1
3
(
(
m, 1H), 1.81–1.74 (m, 3H), 1.23 (t, J ¼ 7.2 Hz, 9H); C NMR MHz): d 7.62 (s, 1H), 6.88 (s, 1H), 5.02 (s, 1H), 4.92 (s, 1H), 4.60–
D
2
O, 75 MHz): d 183.1, 67.0, 65.2, 62.1, 60.7, 54.1, 46.6, 31.4, 4.54 (m, 1H), 4.18–4.14 (dd, J ¼ 9.00 Hz and J ¼ 7.00 Hz, 1H),
2
5.9, 7.43; elemental analysis calcd for C14
H
30
N
2
O
4
$1.3H
2
O: C, 3.60–3.57 (dd, J ¼ 9.00 Hz and J ¼ 6.50 Hz, 1H), 3.49–3.30 (m,
9H), 2.94–2.90 (m, 1H), 2.76 (dd, J ¼ 15.0 Hz and J ¼ 8.00 Hz,
53.58, H, 10.47, N, 8.93; found: C, 53.51, H, 9.92, N, 8.74.
1
3
3
-(Tri-ethylammonium)propan-1,2-diol L-histidinate (4d). 1H), 1.23 (t, J ¼ 7.50 Hz, 9H); C NMR (D
2
O, 125 MHz): d 182.1,
Viscous oil, yield 92%; IR (plate, NaCl): 3252, 2989, 2891, 1588, 136.3, 133.9, 118.7, 96.0, 69.7, 68.1, 58.4, 56.7, 54.3, 32.4, 7.39;
ꢂ1
1
1
6
5
3
470, 1396, 1050 cm ; H NMR (D O, 500 MHz): d 7.65 (s, 1H), elemental analysis calcd for C16
H
30
N
4
O
4
$0.5H
.90 (s, 1H), 4.19–4.17 (m, 1H), 3.60 (dd, J ¼ 11.5 Hz and J ¼ 8.89, N, 15.94; found: C, 54.42, H, 8.69, N, 15.77.
.50 Hz, 1H), 3.52 (dd, J ¼ 11.5 Hz and J ¼ 6.00 Hz, 1H), 3.46– N-((1,3-Dioxolan-4-yl)methyl)-N,N,N-tri-ethylammonium L-
.28 (m, 9H), 2.95 (dd, J ¼ 14.5 Hz and J ¼ 5.00 Hz, 1H), 2.80 (dd, tyrosinate (5e). Viscous oil, yield 91%; IR (plate, NaCl): 3385,
2
O: C, 54.68, H,
2
1
3
ꢂ1
1
J ¼ 14.5 Hz and J ¼ 7.50 Hz 1H), 1.27 (t, J ¼ 7.0 Hz, 9H); C NMR 2993, 2959, 1579, 1396, 1252, 1087, 1002 cm ; H NMR (D
O, 125 MHz): d 182.5, 136.3, 133.9, 118.7, 66.2, 64.2, 59.3, 300 MHz): d 7.00 (d, J ¼ 7.8 Hz, 2H), 6.60 (d, J ¼ 7.8 Hz, 2H), 5.00
6.6, 54.1, 32.4, 7.31; elemental analysis calcd for C15
(s, 2H), 4.88 (s, 2H), 4.52–4.49 (m, 2H), 4.13–4.08 (m, 2H), 3.55–
1.0H O: C, 51.71, H, 9.26, N, 16.08; found: C, 51.38, H, 9.51, N, 3.27 (m, 20H), 2.87–2.81 (m, 1H), 2.70–2.65 (m, 1H), 1.21–1.16
O,
2
(D
2
5
30 4 4
H N O -
$
2
1
3
1
6.20.
-Propanaminium, N,N,N-triethyl-2,3-dihydroxy, L-tyrosinate 118.0, 96.0, 69.7, 68.1, 58.4, 58.0, 54.3, 40.0, 7.38; elemental
4e). Viscous oil, yield 70%; IR (plate, NaCl): 3374, 2950, 1572,
2
(m, 18H); C NMR (D O, 75 MHz): d 182.2, 161.4, 131.2, 126.2,
1
(
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analysis calcd for C29
found: C, 60.08, H, 9.42, N, 7.51.
H
53
N
3
O
7
$1.3H
2
O: C, 60.14, H, 9.68, N, 7.26;
3-[Hydroxy(furan-2-yl-phenyl)methyl]but-3-en-2-one (8i). Brown
1
oil, yield 89%; H NMR (CDCl , 500 MHz): d 7.36 (s, 1H), 6.33–6.32
3
(
2
m, 1H), 6.25–6.24 (m, 2H), 6.10 (s, 1H), 5.63 (s, 1H), 3.29 (br s, 1H);
.38 (s, 3H); C NMR (CDCl , 125 MHz): d 200.1, 154.4, 147.4,
3
13
General procedure for the Baylis–Hillman reaction
142.4, 127.4, 110.6, 107.3, 67.3, 26.5.
The p-nitrobenzaldehyde 6a (0.200 mmol) was added to catalyst
3-[Hydroxy(phenyl)methyl]but-3-en-2-one (8j). Colourless oil,
1
4d (0.0400 mmol) and methyl vinyl ketone 7 (1.00 mmol) in yield 36%; H NMR (CDCl , 500 MHz): d 7.35–7.25 (m, 5H), 6.19
3
a 2.00 mL vial. The reaction mixture was stirred for 4 h at room (s, 1H), 6.00 (s, 1H), 5.61 (d, J ¼ 5.0 Hz, 1H), 3.13 (d, J ¼ 5.5 Hz,
1
3
temperature. The residue was puried using silica gel ash 1H), 2.34 (s, 3H); C NMR (CDCl , 125 MHz): d 200.6, 150.1,
3
column chromatographic (ethyl acetate/hexane, 1 : 4) to give the 141.7, 128.6, 127.9, 127.0, 126.7, 73.0, 26.7.
product 8a 68% yield (30.0 mg).
3-[Hydroxy(4-methoxyphenyl)methyl]but-3-en-2-one (8k).
1
3-[Hydroxy(4-nitrophenyl)methyl]but-3-en-2-one (8a). Pale Yellow oil, yield 39%; H NMR (CDCl , 500 MHz): d 7.27 (d, J
3
ꢁ
1
yellow solid, yield 68%; mp. 65–67 C; H NMR (CDCl
3
, 500 ¼ 8.5 Hz, 2H), 6.87 (d, J ¼ 8.5 Hz, 2H), 6.17 (s, 1H), 6.00 (s,
MHz): d 8.18 (d, J ¼ 8.50 Hz,2H), 7.55 (d, J ¼ 8.5 Hz, 2H), 6.27 (s, 1H), 5.57 (d, 1H, J ¼ 4.0 Hz), 3.80 (s, 3H), 2.99 (d, J ¼ 4.5 Hz,
1
3
1
2
1
H), 6.04 (s, 1H), 5.68 (d, J ¼ 3.5 Hz 1H); 3.38 (d, J ¼ 5.0 Hz, 1H), 1H), 2.33 (s, 3H); C NMR (125 MHz, CDCl ) d 200.6, 159.3,
3
13
.36 (s, 3H); C NMR (CDCl
47.5, 128.0, 127.4, 123.8, 72.3, 26.5.
-[Hydroxy(3-nitrophenyl)methyl]but-3-en-2-one (8b). Yellow
3
, 125 MHz): d 200.2, 149.2, 149.1, 150.3, 133.9, 128.8, 126.4, 114.0, 72.6, 55.4, 26.7.
3
General procedure for amino acid ionic liquid recycle
experiments
1
oil, yield 66%; H NMR (CDCl
3
, 500 MHz): d 8.22 (s, 1H), 8.14–
8
1
6
1
.11 (m, 1H), 7.74–7.72 (m, 1H), 7.51 (t, J ¼ 8.0 Hz, 1H), 6.29 (s,
Following extraction with ethyl acetate, the AAIL solution was
subjected to vacuum to remove traces of ethyl acetate and water
and charged with further portions of p-nitrobenzaldehyde 6a
0.200 mmol) and methyl vinyl ketone 7 (1.00 mmol) at room
temperature.
H), 6.09 (d, J ¼ 1.0 Hz, 1H), 5.68 (d, J ¼ 5.5 Hz, 1H), 3.37 (d, J ¼
1
3
.0 Hz, 1H), 2.37 (s, 3H); C NMR (CDCl , 125 MHz): d 200.3,
3
49.1, 148.5, 144.1, 132.9, 129.5, 128.0, 122.8, 121.6, 72.3, 26.6.
(
3
-[Hydroxy(2-nitrophenyl)methyl]but-3-en-2-one (8c). Brown
1
oil, yield 62%; H NMR (CDCl
3
, 500 MHz): d 7.98 (d, J ¼ 8.0 Hz,
1
7
3
H), 7.78 (d, J ¼ 8.0 Hz, 1H), 7.66 (t, J ¼ 7.5 Hz, 1H), 7.47 (t, J ¼
.0 Hz, 1H), 6.23 (br s, 1H), 6.18 (s, 1H), 5.80 (d, J ¼ 1.0 Hz, 1H), Conflicts of interest
1
3
3
.49 (br s, 1H), 2.39 (s, 3H); C NMR (CDCl , 125 MHz):
There are no conicts to declare.
d 200.1, 149.0, 148.2, 136.6, 133.7, 129.0, 128.7, 126.8, 124.9,
7.8, 26.2.
-[Hydroxy(4-uorphenyl)methyl]but-3-en-2-one (8d). Yellow
6
3
Acknowledgements
1
oil, yield 88%; H NMR (CDCl
3
, 500 MHz): d 7.34–7.31 (m, 2H),
We would like to thank Fundaç ˜a o de Amparo `a Pesquisa do
Estado de Minas Gerais (FAPEMIG) for their nancial support to
the project research number CEX-APQ-03842-10, CEX-APQ-
7
.03–7.00 (m, 2H), 6.19 (s, 1H), 5.97 (s, 1H), 5.60 (br s, 1H), 3.10
1
3
(
d, J ¼ 3.0 Hz, 1H), 2.34 (s, 3H); C NMR (CDCl
d 200.5, 163.4, 161.4, 150.0, 137.4, 128.4, 127.0, 115.5, 115.3,
2.4, 26.7.
-[Hydroxy(4-chlorophenyl)methyl]but-3-en-2-one (8e). Yellow
3
, 125 MHz):
0
1283-14 and CEX–RED-00010-14. Coordenaç ˜a o de Aperfeiçoa-
7
mento de Pessoal de N ´ı vel Superior (CAPES), and Rede Mineira
de Qu ´ı mica and MCT/FINEP/CT-INFRA 01/2013-REF 0633/13.
3
1
oil, yield 81%; H NMR (CDCl , 500 MHz): d 7.30 (s, 4H), 6.20 (s,
3
13
1H), 6.00 (s, 1H), 5.60 (s, 1H), 2.34 (s, 3H); C NMR (CDCl , 125
3
MHz): d 200.5, 149.8, 140.2, 133.7, 128.8, 128.1, 127.1, 72.4, 26.7.
-[Hydroxy(2-chlorophenyl)methyl]but-3-en-2-one (8f). Yellow
Notes and references
3
1
oil, yield 74%; H NMR (CDCl
3
, 500 MHz): d 7.60–7.57 (m, 1H),
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.36–7.23 (m, 3H), 6.18 (s, 1H), 6.00 (d, J ¼ 4.50 Hz, 1H), 5.67 (s,
121.
13
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3
1
(
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3
(
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, 125 MHz): d 200.4, 149.6, 145.8, 127.8,
3
1
(
8h). Yellow oil, yield 51%; H NMR (CDCl , 500 MHz): d 6.60 (s,
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2
3
1
H), 6.20 (s, 1H), 6.00 (s, 1H), 5.57 (s, 1H), 3.85 (s, 6H), 3.82 (s,
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50.0, 137.4, 137.2, 127.0, 103.7, 72.9, 61.0, 56.3, 26.7.
1
3
3
, 125 MHz): d 200.7, 153.4,
23912 | RSC Adv., 2018, 8, 23903–23913
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RSC Adv., 2018, 8, 23903–23913 | 23913