Internal redox amidation of α,β-unsaturated aldehydes in ionic liquids. The electrochemical route

Article abstract of DOI:10.1016/j.electacta.2012.11.061

A simple, N-heterocyclic carbene (NHC) activated synthesis of amides has been performed via electrolysis, carried out under galvanostatic control, of an ionic liquid (Bmim-BF₄) followed by addition to the catholyte of an α,β-unsaturated aldehyde and amine. Amides have been isolated, in good to elevated yields, in the absence of any base, co-catalyst and organic solvent. The selectivity of amidation, versus the formation of imine as by-product, has been related to the molar ratio electrogenerated NHC/aldehyde. The results, obtained using ionic liquids and electrochemical procedures, have been compared with those obtained using organic solvents and classical procedures.

Full text of DOI:10.1016/j.electacta.2012.11.061

Electrochimica Acta 89 (2013) 692–699
Contents lists available at SciVerse ScienceDirect
Electrochimica Acta
journal homepage: www.elsevier.com/locate/electacta
Internal redox amidation of ␣,␤-unsaturated aldehydes in ionic liquids.
The electrochemical route
Marta Ferocia,∗, Isabella Chiarottoa, Achille Inesib,∗
a Dept. SBAI, Sapienza University of Rome, via Castro Laurenziano, 7, I-00161 Rome, Italy
b Via Antelao, 9, I-00141 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, N-heterocyclic carbene (NHC) activated synthesis of amides has been performed via electrol-
ysis, carried out under galvanostatic control, of an ionic liquid (Bmim-BF4) followed by addition to the
catholyte of an ␣,␤-unsaturated aldehyde and amine. Amides have been isolated, in good to elevated
yields, in the absence of any base, co-catalyst and organic solvent. The selectivity of amidation, versus
the formation of imine as by-product, has been related to the molar ratio electrogenerated NHC/aldehyde.
The results, obtained using ionic liquids and electrochemical procedures, have been compared with those
obtained using organic solvents and classical procedures.
Received 14 September 2012
Received in revised form
14 November 2012
Accepted 15 November 2012
Available online 27 November 2012
Keywords:
Amides
© 2012 Elsevier Ltd. All rights reserved.
N-Heterocyclic carbenes
␣,␤-Unsaturated aldehydes
Room temperature ionic liquids
Organic electrosynthesis
1. Introduction
Carbodiimide, HOBt- or HOAt-based uronium, phosphonium
and immonium salts, chloroformate, pyridinium compounds, are
The noticeable presence, as a peculiar mark, of amide func-
tionality in biological systems (e.g. the chemical bonds that link
aminoacids together to give proteins) and the significant role
played in many pharmaceutically active molecules and in versatile
polymers, have spurred a continuous investigation targeted to set
up efficient procedures of synthesis. Hence, a plethora of strategies
for the amide bond formation have been reported [1–6].
To overcome the ammonium salt formation, the direct amida-
tion of carboxylic acids must be carried out at high temperature
(T > 180 ◦C, Scheme 1) [7].
However, these procedures are incompatible with the presence
in the substrates of other sensitive functional groups. Therefore,
at present, the most used strategies of synthesis of amides rely on
the activation, with coupling reagents, of a carboxylic acid (which
is electron deficient) towards the nucleophilic attack of an amine
(which is electron rich). The activation consists of the replacement
of the hydroxyl group of the carboxylic acid with a leaving group,
as the acid would otherwise simply form a salt with the amine
(Scheme 2).
frequently utilized as coupling agents [2]. Despite the general effi-
ciency of these procedures, different authors have emphasized
some serious limits: stoichiometric use of the reagents, low prod-
uct/waste ratio, poor atom economy, hard product isolation [8].
To overcome some of these drawbacks, enzymatic methods [9],
as well as the use of non metal catalysts (organocatalysts and boron
reagents) [10] have been reported. However, high isolation costs
and limited substrate range must be taken into account.
At present, increasing attention is devoted to developing pro-
cedures of amide bond synthesis employing metal catalysts [8].
Generally, metal-catalyzed protocols allow the amide bond forma-
tion starting from substrates other than carboxylic acids (oximes,
aldehydes, nitriles, alcohols, esters, etc.).
Protocols for the direct amide formation from carboxylic acids
and amines have been lately set up using zirconium (IV) as catalyst
(toluene as solvent, T = 110 ◦C [11], THF as solvent, T = 70 ◦C [12]) or
AlMe3 as coupling reagent (toluene as solvent, rt) [13].
Despite the numerous procedures, the state of the art of amide
bond formation is not quite satisfactory, as emphasized by the
American Chemical Society Green Chemistry; the motion “amide
formation avoiding poor atom economy reagents” has been voted
as the top challenge for organic chemistry in 2007 [14].
Therefore, the amide bond synthesis requires a careful rethink-
ing. The new generation of emerging procedures has been
extensively discussed in recent reviews [15,16].
∗
Corresponding authors. Tel.: +39 06 49766563; fax: +39 06 49766749.
E-mail addresses: marta.feroci@uniroma1.it (M. Feroci),
isabella.chiarotto@uniroma1.it (I. Chiarotto), achille.inesi@uniroma1.it (A. Inesi).
0013-4686/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.electacta.2012.11.061

M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
693
O
O
O
180°C
+
R
OH
R' NH2
R
O
R' NH3
+
H2O
R
NH R'
Scheme 1. Synthesis of amides fom carboxylic acids.
O
Bu
N
O
O
couplingagent
R' NH2
R
LG
R
OH
R
NH R'
X
H
N
LG:leaving group
Me
Scheme 2. Synthesis of amides starting from carboxylic acids and coupling agents.
RTIL 1a-d
X = a: BF4 ; b: PF6 ; c: MeSO4 ; d: I
In the last decade, N-heterocyclic carbenes (NHCs, generally
obtained in situ from azolium salts and suitable bases) have been
frequently utilized as legants in organometallic catalysts [17,18]
and as versatile organocatalysts [19,20] in a very broad range of
organic reactions. The possible NHC-catalyzed oxidative amidation
of aldehydes has been investigated by different authors [21–23].
These syntheses have been carried out in CH2Cl2 solutions contain-
ing, in addition to aldehyde and amine, the precatalyst (an azolium
salt), the base (NEt3), the oxidant (NCS), and the additive (BtOH)
[21].
In addition to the concept of atom economy, the redox econ-
omy (the internal exchange of oxidation states between adjacent
functional groups, targeted at avoiding the utilization of stoichio-
metric redox reactants) has been recently stormed into organic
synthesis. According to the redox economy requirement, a fur-
ther intriguing NHC-catalyzed synthesis (from ␣functionalized
aldehydes, in the absence of any external redox agent) of esters
[24–28] and amides [29–31] has been investigated. A hard draw-
back in this procedure of synthesis of amides is the presence
of a very competitive reaction, i.e. the reaction between the
aldehyde and the amine yielding an imine. The authors have
overcome this trouble utilizing the so-called promoter or co-
catalyst (1-hydroxy-7-azobenzotriazole, 1-hydroxybenzotriazole,
imidazole, 4-(dimethylamino) pyridine, etc.). According, the pro-
cedures have been carried out in complex systems: solutions of
THF or CH2Cl2 as solvents containing ␣functionalized aldehyde
(␣,␤-unsaturated aldehydes, ␣-chloroaldehydes), amine, precata-
lyst (triazolium salt), base and promoter (Scheme 3).
In the course of our ongoing interest in the set up of green elec-
trochemical methodologies, we have extensively investigated the
possible utilization of the intermediate NHCs, electrogenerated via
cathodic reduction of room temperature ionic liquids (RTILs), as
mediators (bases, organocatalysts, etc.), in alternative procedures
of organic syntheses [32–39]. At present, we are engaged in study-
ing the reactivity of ␣,␤-unsaturated aldehydes and amides, in
previously electrolyzed RTILs 1a-d (as solvents, containing NHCs,
Scheme 4).
Aims of this investigation, carried out by classical voltammetric
measurements and electrolyses in galvanostatic conditions, are: a)
the set up of a simple and efficient green synthesis of amides from
␣,␤-unsaturated aldehydes and amines carried out in electrolyzed
RTILs in the absence of organic solvents, bases and co-catalysts; b)
to inquire into the effective role played by the ionic liquid and by
the derived NHC.
Scheme 4. Room temperature ionic liquids used in this work.
2. Experimental
2.1. Starting material
Ionic liquids 1a-d (IoLiTec) were commercially available and
used as pure compounds (impurities reported: water < 0.02%, chlo-
ride <100 mg/Kg), after being kept at reduced pressure at 70 ◦C
for 24 h. DBU, aldehydes 4a-c and amines 5a-l were commercially
available and used as received.
2.2. Instrumentation
1H and 13C NMR spectra were recorded using a Bruker AC 200
spectrometer using CDCl3 as internal standard.
Voltammetric measurements were performed with an Amel 552
potentiostat equipped with an Amel 566 function generator and an
Amel 563 multipurpose unit in a three-electrode cell; the curves
were displayed on an Amel 863 recorder. A 492/Pt/1 Amel micro-
electrode was employed, using a Pt counter electrode and an Ag
quasi reference electrode (q.r.e.).
Constant current electrolyses were carried out (using an Amel
552 potentiostat equipped with an Amel 771 integrator) in a
glass two-compartment home-made cell. Anolyte (ca. 0.5 ml) and
catholyte (ca. 1.5 ml) were separated through a glass disk (poros-
ity 4). The electrode apparent surface areas were 1.0 cm2 for the
cathodic Pt flat spiral (99.9%) and 0.8 cm2 for the anodic Pt flat spiral
(99.9%). The current density was 20 mA/cm2.
2.3. Typical electrochemical procedure and workup
Electrolyses were carried out at 60 ◦C, under nitrogen atmo-
sphere, using BMIM-BF4 as anolyte and catholyte. After the
consumption of 1.4 Faradays per mol of aldehyde (or a differ-
ent amount, as reported in Table 1), the current was switched off
and aldehyde (0.5 mmol) was added to the catholyte under stir-
ring; when the dissolution was complete, amine (1.0 mmol, or the
amount reported in Table 1) was added. The mixture was kept
at 60 ◦C for 2 h. The catholyte was extracted with diethyl ether,
the solvent was removed under vacuum and the residue was ana-
lyzed by 1H-NMR and purified by flash-chromatography (using
thiazolium salt 5%
O
O
base 20%
+
R' NH2
+ H2O
N R'
Ph
Ph
H
promoter (co-catalyst) 1.1eq.
solvent (THF)
H
Scheme 3. Synthesis of amides from aldehydes by internal redox reaction.

694
M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
1H), 7.13-7.33 (m, 10H); 13C NMR (50 MHz, CDCl3) ␦ 31.1, 31.8, 33.2,
38.6, 39.2, 126.0, 126.3, 128.4, 128.5, 141.0, 141.4, 172.1.
Table 1
Reactivity of cinnamaldehyde 4a versus benzylamine 5a in pre-electrolyzed ionic
liquid 1. Effect of the number of Faradays per mol of 4a (Q) and of the 5a/4a molar
ratio (␳) on the yields of amide 6aa and imine 7aa (Scheme 5).a
2.5.5. N-Butyl-3-phenylpropanamide 6ad. [43]
c
Entry
RTIL
Qb
␳
6aa
7aa
Rf (30% ethyl acetate in n-hexane) 0.31; 1H NMR (200 MHz,
CDCl3) ␦ 0.89 (t, J = 6.8 Hz, 3H), 1.17-1.48 (m, 4H), 2.46 (t, J = 7.6 Hz,
2H), 2.97 (t, J = 7.6 Hz, 2H), 3.21 (q, J = 6.8 Hz, 2H), 5.4 (bs, 1H), 7.18-
7.32 (m, 5H); 13C NMR (50 MHz, CDCl3) ␦ 13.7, 20.0, 31.6, 31.8, 38.6,
39.2, 126.2, 128.3, 128.5, 140.9, 172.0.
(yield, %)d
(yield, %)d
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
-
2.0
2.0
2.0
2.0
2.0
3.0
1.0
1.0
1.0
2.0
2.0
2.0
-
95
84
35
21
tr
12
31
95
95
23
95
18
0.3
0.7
1.0
1.4
1.4
1.4
0.7
0.7
1.4
1.4
1.4
15
42
57
88
63
49
tr
tr
58
tr
2.5.6. N-(Cyclohexylmethyl)-3-phenylpropanamide 6ae. [44]
Rf (30% ethyl acetate in n-hexane) 0.26; 1H NMR (200 MHz,
CDCl3) ␦ 0.74-0.91 (m, 2H), 1.13-1.43 (m, 4H), 1.55-1.72 (m, 5H),
2.45 (t, J = 7.6 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 3.05 (t, J = 6.4 Hz, 2H),
5.3 (bs, 1H), 7.19-7.33 (m, 5H); 13C NMR (50 MHz, CDCl3) ␦ 25.8,
26.4, 30.7, 31.8, 37.8, 38.6, 45.7, 126.2, 128.4, 128.5, 140.9, 172.0.
8e
9f
10
11
12
61
a
10.0 mmol of RTIL were subjected to electrolysis (see experimental) and, after
the consumption of a prefixed number of Faradays per mol (Q), cinnamaldehyde 4a
(0.5 mmol) and, 5 minutes later, benzylamine 5a in a prefixed molar ratio (␳) were
added to the catholyte.
2.5.7. N-Cyclohexyl-3-phenylpropanamide 6af. [31]
Rf (30% ethyl acetate in n-hexane) 0.23; 1H NMR (200 MHz,
CDCl3) ␦ 0.93-1.45 (m, 6H), 1.56-1.88 (m, 4H), 2.44 (t, J = 7.6 Hz,
2H), 2.97 (t, J = 7.6 Hz, 2H), 3,67-3.84 (m, 1H), 5.1 (bs, 1H), 7.19-7.33
(m, 5H); 13C NMR (50 MHz, CDCl3) ␦ 24.8, 25.5, 31.9, 33.1, 38.7, 48.1,
126.2, 128.4, 128.5, 140.9, 171.1.
b
Number of Faradays per mol of 4a supplied to the electrodes.
Molar ratio 5a/4a added to the catholyte.
Isolated yields with respect to starting 4a.
4a and 5a were added simultaneously to the catholyte.
c
d
e
f
Amine 5a was added before 4a to the catholyte.
2.5.8. N-Cyclopentyl-3-phenylpropanamide 6ag. [45]
Rf (30% ethyl acetate in n-hexane) 0.27; 1H NMR (200 MHz,
CDCl3) ␦ 1.23-1.31 (m, 2H), 1.56-1.64 (m, 4H), 1.86-1.98 (m, 2H),
2.44 (t, J = 7.6 Hz, 2H), 2.97 (t, J = 7.6 Hz, 2H), 4.11-4.23 (m, 1H), 5.2
(bs, 1H), 7.19-7.33 (m, 5H); 13C NMR (50 MHz, CDCl3) ␦ 23.6, 31.9,
33.0, 38.7, 51.1, 126.2, 128.4, 128.5, 140.9, 171.6.
n-hexane/ethyl acetate from 7/3 to 1/1 as eluent), affording the cor-
responding pure amide. All amides are known compounds and gave
spectral data in accordance with the ones reported in the literature.
2.4. Recycle of catholyte
2.5.9. N-Cycloheptyl-3-phenylpropanamide 6ah. [45]
Rf (30% ethyl acetate in n-hexane) 0.33; 1H NMR (200 MHz,
CDCl3) ␦ 1.21-1.89 (m, 12H), 2.43 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz,
2H), 3.86-4.01 (m, 1H), 5.3 (bs, 1H), 7.18-7.33 (m, 5H); 13C NMR
(50 MHz, CDCl3) ␦ 24.0, 28.0, 31.9, 35.1, 38.8, 50.3, 126.2, 128.4,
128.5, 140.9, 170.8.
After ethereal extraction of the cathodic Bmim-BF4 and isolation
of amide 6aa, the catholyte was kept under vacuum under stirring
at 60 ◦C for 1 h, then the catholyte was used in a new electrolysis for
the synthesis of 6aa. The same ionic liquid was used three times,
obtaining (after 1.4 F/mol of 4a each time) 6aa in 88, 66, 49% yields,
respectively.
2.5.10. 3-Phenyl-1-(piperidin-1-yl)propan-1-one 6ai. [31]
Rf (30% ethyl acetate in n-hexane) 0.43; 1H NMR (200 MHz,
CDCl3) ␦ 1.44-1.65 (m, 6H), 2.58-2.67 (m, 2H), 2.94-3.02 (m, 2H),
3.34 (app. t, J = 5.3 Hz, 2H), 3.57 (app. t, J = 5.3 Hz, 2H), 7.17-7.34 (m,
5H); 13C NMR (50 MHz, CDCl3) ␦ 24.5, 25.6, 26.4, 31.6, 35.2, 42.7,
46.6, 126.1, 128.4, 128.5, 141.5, 170.4.
2.5. Isolated products
2.5.1. N-Benzyl-3-phenylpropanamide 6aa. [31]
Rf (30% ethyl acetate in n-hexane) 0.23; 1H NMR (200 MHz,
CDCl3) ␦ 2.53 (t, J = 7.6 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H), 4.41 (d,
J = 5.6 Hz, 2H), 5.6 (bs, 1H), 7.14-7.33 (m, 10H); 13C NMR (50 MHz,
CDCl3) ␦ 31.7, 38.5, 43.6, 126.3, 127.4, 127.7, 128.4, 128.5, 128.5,
128.6, 138.2, 140.8, 171.9.
2.5.11. 1-Morpholino-3-phenylpropan-1-one 6aj. [Commercial]
Rf (30% ethyl acetate in n-hexane) 0.43; 1H NMR (200 MHz,
CDCl3) ␦ 2.62 (t, J = 7.6 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 3.36 (app.
t, J = 4.6 Hz, 2H), 3.52 (app. t, J = 4.6 Hz, 2H), 3.63 (s, 4H), 7.20-7.34
(m, 5H); 13C NMR (50 MHz, CDCl3) ␦ 31.5, 34.8, 41.9, 46.0, 66.5, 66.9,
126.3, 128.5, 128.5, 141.1, 170.8.
2.5.2. N-benzylcinnamaldehyde imine 7aa. [40]
Rf (20% ethyl acetate in n-hexane) 0.40; 1H NMR (200 MHz,
CDCl3) ␦ 4.73 (d, J = 1.2 Hz, 1.8H), 4.84 (d, J = 1.4 Hz, 0.2H), 6.98-7.01
(m, 2H), 7.29-7.41 (m, 8H), 7.47-7.52 (m, 2H), 8.14-8.18 (m, 1H);
13C NMR (50 MHz, CDCl3) ␦ 65.3, 127.2, 127.3, 128.0, 128.1, 128.5,
128.9, 129.2, 135.8, 139.2, 141.9, 163.4.
2.5.12. N-(2-Hydroxy-2-phenylethyl)-3-phenylpropanamide
6ak. [46]
Rf (30% ethyl acetate in n-hexane) 0.18; 1H NMR (200 MHz,
CDCl3) ␦ 2.49 (t, J = 7.5 Hz, 2H), 2.97 (t, J = 7.5 Hz, 2H), 3.26 (ddd, AB,
ꢀ␯ = 78 Hz, JAB = 14.0 Hz, J = 7.0, 5.0 Hz, 1H), 3.4 (bs, 1H), 3.65 (ddd,
AB, ꢀ␯ = 78 Hz, JAB = 14.0 Hz, J = 7.9, 3.3 Hz, 1H), 4.75 (dd, J = 7.9,
3.3 Hz, 1H), 5.9 (bs, 1H), 7.17-7.38 (m, 10H); 13C NMR (50 MHz,
CDCl3) ␦ 31.7, 38.3, 47.5, 73.6, 125.8, 126.3, 127.8, 128.4, 128.5,
128.6, 138.9, 140.7, 141.7, 173.5.
2.5.3. N-Phenethyl-3-phenylpropanamide 6ab. [41]
Rf (30% ethyl acetate in n-hexane) 0.27; 1H NMR (200 MHz,
CDCl3) ␦ 2.43 (t, J = 7.4 Hz, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.96 (t,
J = 7.4 Hz, 2H), 3.48 (q, J = 6.9 Hz, 2H), 5.4 (bs, 1H), 7.09-7.13 (m, 2H),
7.18-7.35 (m, 7H); 13C NMR (50 MHz, CDCl3) ␦ 31.7, 35.7, 38.5, 40.6,
126.2, 126.5, 128.4, 128.5, 128.6, 128.7, 138.9, 140.9, 172.0.
2.5.4. 3-Phenyl-N-(3-phenylpropyl)propanamide 6ac. [42]
2.5.13. N-(4-Hydroxybutyl)-3-phenylpropanamide 6al. [45]
Rf (1% EtOH in ethyl acetate) 0.26; 1H NMR (200 MHz, CDCl3)
␦ 1.50-1.53 (m, 4H), 1.8 (bs, 1H), 2.46 (t, J = 7.6 Hz, 2H), 2.97 (t,
J = 7.6 Hz, 2H), 3.20-3.30 (m, 2H), 3.60-3.65 (m, 2H), 5.6 (bs, 1H),
Rf (30% ethyl acetate in n-hexane) 0.28; 1H NMR (200 MHz,
CDCl3) ␦ 1.77 (quint, J = 7.4 Hz, 2H), 2.44 (t, J = 7.6 Hz, 2H), 2.58 (t,
J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 3.26 (q, J = 7.6 Hz, 2H), 5.4 (bs,

M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
695
Bu
Bu
N
N
+
e
1
_
2
(1)
(2)
H
+
H2
N
Me
RTIL 1a-d
N
Me
3
2
Bu
N
O
1) + e
H
+
Ph
N
Ph
Ph
N
Ph
N
Me
2) + PhCH=CH-CHO, 4a
3) + PhCH2NH2, 5a
H
6aa
7aa
2
2: cation of RTILs 1a-d
Scheme 5. Generation and reactivity of NHC.
7.20-7.33 (m, 5H); 13C NMR (50 MHz, CDCl3) ␦ 26.2, 29.6, 31.8, 38.5,
39.2, 62.3, 126.2, 128.4, 128.5, 140.9, 172.2.
This change in the voltammetric curves (curve c vs curve b) could
be related to the fast reaction between aldehyde 4a and amine 5a
yielding imine 7aa. To test this hypothesis, immine 7aa was syn-
thesized from 4a and 5a in 1a as solvent (in quantitative yield) and
the cyclic voltammetry of this solution showed a reduction peak at
-1.48 V.
On the contrary, voltammetric curves recorded for solutions of
pre-electrolyzed RTILs (containing NHC 3) do not show the pres-
ence of the specific reduction peak at -1.15 V vs Ag r. e. after the
addition of aldehyde 4a, as well as no reduction peak (at E = - 1.48)
has been observed after the following addition of amine 5a. Accord-
ing, the presence of 4a and of 7aa can be excluded, and the reaction
between 4a and 5a must related to a different route.
Spurred by these initial results, we have evaluated the reactiv-
ity of 4a vs 5a in RTIL 1a (in the absence and in the presence of the
derived NHC 3) according the following procedure: Bmim-BF4 1a
was electrolyzed under galvanostatic conditions (divided cell, N2
atmosphere, at 60 ◦C in order to enhance the medium conductiv-
ity). After the consumption of a prefixed number of Faradays, the
current was switched off and cinnamaldehyde 4a and, 5 minutes
later, benzylamine 5a (in a prefixed molar ratio) were added to the
catholyte. The mixture was stirred at 60 ◦C for 2.0 h. Conventional
workup of this final solution allows to isolate the products and to
assess the yields (Table 1).
2.5.14. Benzyl 3-(4-methoxyphenyl)propanamide 6ba. [47]
Rf (30% ethyl acetate in n-hexane) 0.21; 1H NMR (200 MHz,
CDCl3) ␦ 2.49 (t, J = 7.5 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 3.79 (s, 3H),
4.40 (d, J = 5.6 Hz, 2H), 5.6 (bs, 1H), 6.80-6.84 (m, 2H), 7.10-7.17 (m,
4H), 7.27-7.31 (m, 3H); 13C NMR (50 MHz, CDCl3) ␦ 30.9, 38.8, 43.5,
55.2, 113.9, 114.0, 127.4, 127.7, 128.6, 129.3, 129.3, 132.8, 138.2,
158.1, 171.9.
2.5.15. N-Benzyl-3-(furan-2-yl)propanamide 6ca. [30]
Rf (40% ethyl acetate in n-hexane) 0.47; 1H NMR (200 MHz,
CDCl3) ␦ 2.55 (t, J = 7.4 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 4.42 (d,
J = 5.6 Hz, 2H), 5.8 (bs, 1H), 6.02-6.04 (m, 1H), 6.27-6.29 (m, 1H),
7.20-7.33 (m, 6H); 13C NMR (50 MHz, CDCl3) ␦ 24.1, 35.0, 43.6,
105.6, 110.2, 127.5, 127.7, 128.7, 138.2, 141.2, 154.3, 171.5.
3. Results and discussion
In a preliminary investigation, carried out via voltammetric
analysis, we have tested the different behaviour of cinnamalde-
hyde 4a (in the absence and in the presence of benzylamine 5a) in
Bmim-BF4 1a with respect to the one in electrolyzed Bmim-BF4 1a
(Scheme 5) [48].
We were pleased to find that, in the experimental conditions
selected by us (i.e. electrolyzed RTIL 1a), the amidation of 4a to
The voltammetric curves, recorded at a Pt cathode for RTIL 1a
(␯ = 0.2 Vs−1, 25 ◦C) do not show meaningful values of the reduc-
tion current as regard the potential window from–0.40 V to -1.65 V
(vs Ag pseudo reference electrode; Fig. 1, curve a). Voltammetric
measurements, reported by us in previous papers [32,49,50] prove
that the cathodic reduction of cation Bmim+, in pure BmimBF4, is
effective at a cathodic potential more negative than -2.0 V (vs Ag
r.e.).
On the contrary, voltammetric curve of a solution of 1a, con-
taining aldehyde 4a, displays the presence of an irreversible peak
(Ep = -1.15 V, vs Ag r.e.), marked by a broad pre-peak (Ep = –0.9 V, vs
Ag r.e.) (Fig. 1, curve b). Therefore, the cathodic current recorded in
curve b must be related to the reduction of the carbonyl group of
aldehyde 4a. The value of the peak current of curve b, monitored
versus time, is stable. According, any reaction of aldehyde 4a with
ionic liquid 1a can be ruled out.
The addition of amine 5a (an electroinactive substrate in the
experimental conditions considered by us) to the solution of 1a con-
taining aldehyde 4a, causes the disappearance of the irreversible
peak at -1.15 V, and of the related broad pre-peak at–0.9 V, and the
appearance of a new peak at -1.48 V vs Ag r.e. (Fig. 1, curve c).
Fig. 1. Voltammetric curves, at a Pt cathode (vs Ag, ␯ = 0.2 V s−1, T = 25 ◦C) of Bmim-
BF4 (2 ml, curve a), Bmim-BF4 and 4a (0.5 mmol, curve b), Bmim-BF4 and 4a and 5a
(1.0 mmol, curve c).

696
M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
Bu
N
N
Me
O
O
OH
O
Me
N
Me
N
Me
N
3
(1)
Ph
H
Ph
Ph
Ph
H
Bu
RTIL1a
4a
N
N
N
Bu
Bu
O
O
Me
N
H+
PhCHNH2, 5a
2
Ph
N
Ph
Ph
H
N
6aa
Bu
I
O
(2)
+
Ph
H
Ph
NH2
+ H2O
Ph
N
Ph
RTIL1a
4a
5a
7aa
Scheme 6. Reaction between cinnamaldehyde and NHC or benzylamine.
6aa could be achieved in the absence of any co-catalyst, base and
organic solvent.
This unexpected efficiency could be related to the reaction
of aldehyde 4a and carbene 3, in Bmim-BF4, yielding the sta-
ble cationic adduct I (as reported in previous communications
[32–39]), and to the following nucleophilic attack of the amine 5a to
adduct I. On the contrary, the formation of imine 7aa derives from
the direct reaction between the amine 5a and residual aldehyde 4a
(i.e. “free” aldehyde 4a, not consumed by the formation of adduct
I, Scheme 6).
An increase of the number of Faradays per mole of aldehyde 4a
supplied to the electrodes (i.e. an increase of the number of moles
of carbene 3 per mole of aldehyde 4a) provokes an increase of the
“activated” aldehyde (via formation of the structure I by reaction of
4a with 3) and a decrease of the “free” aldehyde. Consequently, an
increase of the consumed number of Faradays causes an increase
of the yield of amide 6aa and a decrease of imine 7aa. According to
a stoichiometric consumption of Faradays, 4a has been efficiently
activated as adduct I and amide 6aa has been isolated in elevated
yield (88%), while imine 7aa was absent in the reaction mixture.
The catholyte was then reused for two more electrolyses (under
the same conditions) and 6aa was isolated in 66 and 49% yields
respectively.
The number of Faradays per mole of 4a supplied to the electrode
(Q, Table 1, entries 2-5) and the molar ratio 5a/4a (␳, Table entries
5-7) both significantly affect the yields of isolated 6aa and 7aa. An
increase of Q (i.e. of the concentration of 3 in the solution) causes
an increase of the yields of amide 6aa and a consistent decrease of
imine 7aa. In the optimized condition (Q = 1.4 Faraday mol−1 and 3
present in stoichiometric quantity), amide 6aa has been isolated in
elevated yield (88%) and the presence of imine 7aa in the mixture of
the reaction has been ruled out (Table 1, entry 5). On the contrary,
imine 7aa was the only product (in quantitative yields) when the
reaction between 4a and 5a was carried out in Bmim-BF4 in the
absence of electricity (Table 1, entry 1), as reported also by Andrade
and coworkers [51].
When the synthesis was carried out adding 4a and 5a at the
same time to the catholyte (or 5a before 4a), imine 7aa was isolated
in quantitative yields (95%) and the presence of amide 6aa was
excluded (Table 1, entries 8 and 9). This result suggests that the
reaction between 4a and 5a yielding imine 7aa (Scheme 6, reaction
2) is faster than the reaction between 4a, 5a and NHC 3 yielding
amine 6aa (Scheme 6, reaction 1).
In order to acquire further data to clear the limits of this method-
ology, we have studied the reactivity of 4a versus 5a in different
solvents (organic solvents, VOCs) in the presence of NHC 3 gener-
ated according to the classical chemical procedure (deprotonation
of the parent Bmim-BF4 with a suitable base, DBU; Table 2).
Last, the nature of the anion in the starting ionic liquid could
significantly modify the yields of the isolated products (Table 1,
entries 10-12).
In previous communications about the NHC-catalyzed synthesis
of amides via internal redox oxidation of ␣-functionalized alde-
hydes (carried out in organic solvent, using a triazolium salt in the
presence of a base as precatalyst), the fast formation of imines,
leading to an extensive inhibition of the desired catalytic amida-
tion process, has been avoided by adding suitable promoters (the
so-called co-catalysts) [29–31]. In the absence of co-catalysts the
amide was isolated in 5% yield [29]. In the opinion of the authors,
the first step of the overall process involves the reaction between
the aldehyde and the promoter yielding the relative acyl-promoter
species (NHC-catalyzed internal oxidation of the aldehyde). The
second step regards the nucleophilic attack of the amine to the
acyl-promoter species yielding the desired amide.
Table 2
Reactivity of cinnamaldehyde 4a versus benzylamine 5a in the presence of Bmim-
BF4 and DBU. Effect of the solvent on the yields of amide 6aa and imine 7aa (Bmim-
BF4: 1.0 mmol; DBU: 1.0 mmol; 4a: 0.5 mmol; 5a: 1.0 mmol).a
Entry
Solvent
6aa (yield, %)b
7aa (yield, %)b
1
2
3
4
5
6
THF
MeCN
DMF
Toluene
CH2Cl2
Bmim-BF4
18
24
78
42
16
52
12
4
22
12
3
4
a
1.0 mmol Bmim-BF4 and 1.0 mmol DBU were added to 2 ml of solvent, under
Our experimental data, compared with the previous investiga-
tions, suggest that the peculiar system RTIL 1a (as solvent)/3 (as
NHC) is able to promote the formation of 6aa in elevated yield in the
absence of any co-catalyst (provided 3 is present in stoichiometric
amount).
nitrogen atmosphere. Then 0.5 mmol of cinnamaldehyde 4a and, 5 minutes later,
1.0 mmol of benzylamine 5a were added to the mixture, which was kept at 60 ◦
C
(50 ◦C for THF and 30 ◦C for CH2Cl2) for 2 hours. Usual workup gave 6aa and 7aa in
the yields reported.
b
Isolated yields respect to starting 4a.

M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
697
Table 3
Electrochemical synthesis of amides 7 via reaction of aldehydes 4a-c and amines 5a-l in pre-electrolyzed Bmim-BF4.a
Entry
Aldehyde
Amine
Amide 6 (yield, %)
O
O
Ph
NH2
Ph
N
H
Ph
1c
H
Ph
5a
4a
6aa
88
O
O
Ph
Ph
Ph
NH2
N
H
Ph
2
3
4
5
H
Ph
5b
4a
6ab
O
O
NH2
Ph
N
H
6ac
Ph
H
Ph
5c
4a
O
O
NH2
N
Ph
Ph
H
Ph
5d
H
4a
6ad
O
O
NH2
N
H
H
Ph
Ph
Ph
Ph
5e
5f
4a
6ae
O
O
N
Ph
6
7
8
H
NH2
NH2
H
4a
6af
O
O
N
Ph
H
H
5g
4a
6ag
O
O
N
Ph
H
NH2
H
4a
5h
NH
6ah
O
O
N
Ph
9
H
Ph
Ph
5i
4a
6ai
O
NH
O
N
Ph
O
10
H
O
4a
5j
6aj
O
Ph
O
NH2
Ph
N
H
Ph
11d
OH
5k
H
Ph
Ph
OH
4a
6ak
O
O
HO
HO
NH2
N
H
Ph
12d
H
5l
4a
6al

698
M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
Table 3 (Continued )
Entry
Aldehyde
Amine
Amide 6 (yield, %)
O
O
Ph
Ph
NH2
NH2
Ph
Ph
N
H
Ph-p-OCH3
O
13
H
Ph-p-OCH3
O
5a
5a
4b
6ba
O
O
N
H
14
H
4c
6ca
a
Synthesis carried out following the experimental conditions reported in Table 1, entry 5.
Isolated yields respect to starting aldehyde.
b
c
Entry 5 of Table 1, reported here for comparison.
d
No amino ester was isolated, only unreacted amino alcohol.
The results show that the efficiency of the procedure of amida-
[6] J. de, M. Mun˜oz, J. Alcázar, A. de la Hoz, A.S. Díaz-Ortiz, A.A. de Diego, Preparation
of amides mediated by isopropylmagnesium chloride under continuous flow
conditions, Green Chemistry 14 (2012) 1335.
[7] B.S. Jursic, Z. Zdravkovski, A simple preparation of amides from acids and
amines by heating of their mixture, Synthetic Communications 23 (1993) 2761.
[8] C.L. Allen, J.M.J. Williams, Metal-catalysed approaches to amide bond forma-
tion, Chemical Society Reviews 40 (2011) 3405.
[9] M.X. Wang, Enantioselective biotransformations of nitriles in organic synthesis,
Topics in Catalysis 35 (2005) 117.
[10] J.E. Anderson, R. Davis, R.N. Fitzgerald, J.M. Haberman, Selective phenol alkyl-
ation: an improved preparation of efaproxiral, Synthetic Communications 36
(2006) 2129.
[11] C.L. Allen, A.R. Chhatwal, J.M.J. Williams, Direct amide formation from unacti-
vated carboxylic acids and amines, Chemical Communications 48 (2012) 666.
[12] H. Lundberg, F. Tinnis, H. Adolfsson, Direct amide coupling of non-activated
carboxylic acids and amines catalysed by zirconium(IV) chloride, Chemistry- A
European Journal 18 (2012) 3822.
[13] J. Li, K. Subramaniam, D. Smith, J.X. Qiao, J.J. Li, J. Qian-Cutrone, J.F. Kadow, G.D.
Vite, B.-C. Chen, AlMe3-promoted formation of amides from acids and amines,
Organic Letters 14 (2012) 214.
[14] D.J.C. Constable, Key green chemistry research areas—a perspective from phar-
maceutical manufacturers, Green Chemistry 9 (2007) 411.
[15] V.R. Pattabiraman, J.W. Bode, Rethinking amide bond synthesis, Nature 480
(2011) 471.
tion is strongly affected by the nature of the solvent (Table 2) as well
by the procedure adopted (classical or electrochemical, Table 1,
entry 5 versus Table 2, entry 6); it should be kept in mind that
the amount of NHC 3 in the two different methodologies could be
different.
In order to verify the effectiveness and generality of this pro-
cedure, we have extended the investigation to amines 5b-l and
aldehydes 4b-c, carrying out the synthesis under the optimized
condition reported in Table 1 (entry 5). In all cases, the amidation
was obtained in good to elevated yields, irrespective of the nature
of the amine (primary, secondary, linear or cyclic; Table 3, entries
1-10) and of the aldehyde (Table 3, entries 13 and 14), while when
using amino alcohols 5k and 5l the reaction led to a complete selec-
tivity versus the amine moiety (giving the corresponding hydroxy
amide) and no amino ester was obtained (Table 3, entries 11 and
12).
4. Conclusions
[16] K. Scheidt, Amide bonds made in reverse, Nature 465 (2010) 1020.
[17] O. Schuster, L. Yang, H.G. Raubenheimer, M. Albrecht, Beyond conventional N-
heterocyclic carbenes: abnormal, remote, and other classes of NHC ligands with
reduced heteroatom stabilization, Chemical Reviews 109 (2009) 3445.
[18] H. Clavier, S.P. Nolan, Percent buries volume for phosphine and N-heterocyclic
carbene ligands: steric properties in organometallic chemistry, Chemical Com-
munications 46 (2010) 841.
A simple electrochemical methodology (the electrolysis in
galvanostatic conditions of the common and inexpensive ionic liq-
uid Bmim-BF4) provides a medium (RTIL/NHC) able to activate the
amidation of ␣,␤-unsaturated aldehydes via NHC-catalized inter-
nal oxidation.
[19] D. Enders, O. Niemeier, A. Hanseler, Organocatalysts by N-heterocyclic car-
benes, Chemical Reviews 107 (2007) 5606.
Imines could be obtained as by-products, via the direct reaction
of “free” aldehyde with amines. The procedure, carried out in the
absence of any base, promoter and organic solvent, allows to isolate
amides 6 in good to elevated yields.
The amidation of cinnamaldehydes has been related to the
nucleophilic attack of the amine to the intermediate cationic struc-
ture I (derived by the reaction of aldehyde and carbene 3 in the
presence of ionic liquid 1a). According, the formation of I actives
the amidation and therefore decreases the concentration of “free”
aldehydes in the solution and the yield of isolated imine as by-
product.
[20] X. Bugaut, F. Glorius, Organocatalytic umpolung: N-heterocyclic carbenes and
beyond, Chemical Society Reviews 41 (2012) 3511.
[21] S. Kuwano, S. Harada, R. Oriez, K.-I. Yamada, Chemoselective conversion of ␣-
unbranched aldehydes to amides, esters, and carboxylic acids by NHC-catalysis,
Chemical Communications 48 (2012) 145.
[22] S. Iwahana, H. Iida, E. Yashima, Oxidative esterification, thioesterification, and
amidation of aldehydes by a two-component organocatalytic system using a
chiral N-heterocyclic carbene and redox-active riboflavin, Chemistry- A Euro-
pean Journal 17 (2011) 8009.
[23] K. Ekoue-Kovi, C. Wolf, One-pot oxidative esterification and amidation of alde-
hydes, Chemistry- A European Journal 14 (2008) 6302.
[24] A. Chan, K.A. Scheidt, Conversion of ␣,␤-unsaturated aldehydes into saturated
esters: an umpolung reaction catalyzed by nucleophilic carbenes, Organic Let-
ters 7 (2005) 905.
[25] S.S. Sohn, J.W. Bode, Catalytic generation of activated carboxylated from enals:
a product-determining role for the base, Organic Letters 7 (2005) 3873.
[26] K. Zeitler, Stereoselective synthesis of (E)-␣,␤-unsaturated esters via carbene-
catalyzed redox esterification, Organic Letters 8 (2006) 637.
References
[1] C.A.G.N. Montalbetti, V. Falque, Amide bond formation and peptide coupling,
Tetrahedron 61 (2005) 10827.
[27] N.T. Reynolds, J.R. de Alaniz, T. Rovis, Conversion of ␣-haloaldehydes into acy-
lating agents by an internal redox reaction catalyzed by nucleophilic carbenes,
Journal of the American Chemical Society 126 (2004) 9518.
[28] N.T. Reynolds, T. Rovis, Enantioselective protonation of catalytically generated
chiral enolates as an approach to the synthesis of ␣-chloro esters, Journal of
the American Chemical Society 127 (2005) 16406.
[29] H.U. Vora, T. Rovis, Nucleophilic carbene and HOAt relay catalysis in an amide
bond coupling: an orthogonal peptide bond forming reaction, Journal of the
American Chemical Society 129 (2007) 13796.
[30] J.W. Bode, S.S. Sohn, N-heterocyclic carbene-catalyzed redox amidations of
␣-functionalized aldehydes with amines, Journal of the American Chemical
Society 129 (2007) 13798.
[2] E. Valeur, M. Bradley, Amide bond formation: beyond the myth of coupling
reagents, Chemical Society Reviews 38 (2009) 606.
[3] S.K. Verma, R. Ghorpade, A. Pratap, M.P. Kaushik, Solvent free, N,Nꢀ-
carbonyldiimidazole (CDI) mediated amidation, Tetrahedron Letters 53 (2012)
2373.
[4] S.T. Heller, T. Fu, R. Sarpong, Dual Brønsted acid/nucleophilic activation of car-
bonylimidazole derivatives, Organic Letters 14 (2012) 1970.
[5] J. McNulty, R. Vemula, V. Krishnamoorthy, A. Robertson, The phosphate-
carboxylate mixed-anhydride method: a mild, efficient process for ester and
amide bond construction, Tetrahedron 68 (2012) 5415.

M. Feroci et al. / Electrochimica Acta 89 (2013) 692–699
699
[31] P.-C. Chiang, Y. Kim, J.W. Bode, Catalytic amide formation with ␣ꢀ-
hydroxyenones as acylating reagents, Chemical Communications 45 (2009)
4566.
[32] M. Feroci, I. Chiarotto, M. Orsini, G. Sotgiu, A. Inesi, Reactivity of electrogener-
ated N-heterocyclic carbene in room-temperature ionic liquids. Cyclization to
2-azetidinone ring via C3-C4 bond formation, Advanced Synthesis and Catalysis
350 (2008) 1355.
[41] A.J.A. Watson, O.C. Maxwell, J.M.J. Williams, Ruthenium-catalyzed oxidation of
alcohols into amides, Organic Letters 11 (2009) 2667.
[42] I. Shiina, Y. Kawakita, The effective use of substituted benzoic anhydrides for
the synthesis of carboxamides, Tetrahedron 60 (2004) 4729.
[43] D.H.R. Barton, J.A. Ferreira, N-hydroxypyridine-2(1H)-thione derivatives of
carboxylic acids as activated esters. Part I. The synthesis of carboxamides,
Tetrahedron 52 (1996) 9347.
[33] I. Chiarotto, M.M.M. Feeney, M. Feroci, A. Inesi, Electrogenerated N-heterocyclic
carbene. N-Acylation of chiral oxazolidin-2-ones in ionic liquids, Electrochi-
mica Acta 54 (2009) 1638.
[44] Y. Aoki, S. Kobayashi, Development of a reductive alkylation method using p-
Benzyloxybenzylamine (BOBA) resin for the synthesis of N-alkylated amides,
Journal of Combinatorial Chemistry 1 (1999) 371.
[34] I. Chiarotto, M. Feroci, M. Orsini, G. Sotgiu, A. Inesi, Electrogenerated N-
heterocyclic carbene. N-Functionalization of benzoxazolones, Tetrahedron 65
(2009) 3704.
[45] C.L. Allen, S. Davulcu, M.J. Williams, Catalytic acylation of amines with alde-
hydes or aldoximes, Organic Letters 12 (2010) 5096.
[46] M. Murakami, M. Hayashi, N. Tamura, Y. Hoshino, Y. Ito,
A new water-
[35] M. Feroci, M.N. Elinson, L. Rossi, A. Inesi, The double role of ionic liq-
uids in organic electrosynthesis: precursors of N-heterocyclic carbenes and
green solvents. Henry reaction, Electrochemistry Communications 11 (2009)
1523.
[36] M. Feroci, I. Chiarotto, M. Orsini, A. Inesi, Electrogenerated NHC as an organocat-
alyst in the Staudinger reaction, Chemical Communications 46 (2010) 4121.
[37] M. Orsini, I. Chiarotto, M.M.M. Feeney, M. Feroci, G. Sotgiu, A. Inesi, Umpol-
ung of ␣,␤-unsaturated aldehydes by electrogenerated NHCs in ionic liquids:
synthesis of ␥-butyrolactones, Electrochemistry Communications 13 (2011)
738.
compatible dehydrating agent DPTF, Tetrahedron Letters 37 (1996) 7541.
[47] V. Gotor, E. Menendez, Z. Mouloungui, A. Gaset, Synthesis of optically active
amides from ␤-furyl and ␤-phenyl esters by way of enzymatic aminolysis,
Journal of the Chemical Society, Perkin Transactions 1 1 (1993) 2453.
[48] Although this particular NHC has never been isolated, in previous works we
have trapped it by reaction with sulfur, to give the corresponding imidazole-2-
thione (M. Feroci, M., Orsini, A., Inesi, Adv. Synth. Catal. 351 (2009) 2067) and
with aliphatic aldehydes, to yield the corresponding ionic adducts (I. Chiarotto,
M., Feroci, M., Orsini, M. M. M. Feeney, A., Inesi, Advanced Synthesis & Catalysis
352 (2010) 3287).
[38] M. Feroci, Investigation of the role of electrogenerated N-heterocyclic carbene
in the staudinger synthesis in ionic liquid, International Journal of Organic
Chemistry 1 (2011) 191.
[49] M. Feroci, I. Chiarotto, M. Orsini, G. Sotgiu, •A−. Inesi, Carbon dioxide as carbon
source: activation via electrogenerated O2
Acta 56 (2011) 5823.
in ionic liquids, Electrochimica
[39] M. Feroci, I. Chiarotto, M. Orsini, R. Pelagalli, A. Inesi, Umpolung reactions in
ionic liquid catalyzed by electrogenerated N-heterocyclic carbenes. Synthe-
sis of saturated esters from activated ␣,␤-unsaturated aldehydes, Chemical
Communications 48 (2012) 5361.
[40] D.A. Colby, R.G. Bergman, J.A. Ellman, Synthesis of dihydropyridines and
pyridines from imines and alkynes via C−H activation, Journal of the American
Chemical Society 130 (2008) 3645.
[50] M. Orsini, I. Chiarotto, G. Sotgiu, A. Inesi, Polarity reversal induced by electro-
chemically generated thiazol-2-ylidenes: the Stetter reaction, Electrochimica
Acta 55 (2010) 5823.
[51] C.K.Z. Andrade, S.C.S. Takada, L. Magalhães Alves, J.P.A. Petrocchi Rodrigues,
Z. Suarez, R.F. Brandão, V.C.D. Soares, Molecular sieves in ionic liquids as an
efficient and recyclable medium for the synthesis of imines, Synlett (2004)
2135.