Cerium(IV) oxide as a neutral catalyst for aldehyde-induced decarboxylative coupling of l-proline with triethyl phosphite and nitromethane

Article abstract of DOI:10.1016/j.tetlet.2012.08.012

The application of cerium(IV) oxide (CeO₂) as a neutral and heterogeneous catalyst for aldehyde-induced decarboxylative coupling of l-proline with triethyl phosphite and nitromethane is described. In addition, a [3+2] cycloaddition reaction of the in situ generated 1,3-dipolar intermediate with benzaldehyde in the absence of a nucleophile is also reported. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.012

Tetrahedron Letters 53 (2012) 5515–5518
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Cerium(IV) oxide as a neutral catalyst for aldehyde-induced decarboxylative
coupling of L-proline with triethyl phosphite and nitromethane
⇑
⇑
Habib Firouzabadi , Nasser Iranpoor , Arash Ghaderi, Maryam Ghavami
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The application of cerium(IV) oxide (CeO2) as a neutral and heterogeneous catalyst for aldehyde-induced
Received 16 June 2012
Revised 20 July 2012
Accepted 2 August 2012
Available online 9 August 2012
decarboxylative coupling of L-proline with triethyl phosphite and nitromethane is described. In addition,
a [3+2] cycloaddition reaction of the in situ generated 1,3-dipolar intermediate with benzaldehyde in the
absence of a nucleophile is also reported.
Ó 2012 Published by Elsevier Ltd.
Keywords:
CeO2
Three-component reaction
Proline
Cycloaddition
Decarboxylative coupling
L
-Proline and its derivatives frequently occur in many biologi-
phosphonation of sp3 C–H adjacent to nitrogen has also been
reported.9 Following these reports, the aldehyde-induced intermo-
cally active natural products.1 In recent years, numerous reports
have appeared in the literature applying this
a-amino acid as an
lecular decarboxylative coupling of a-amino acids and phosphites
organocatalyst2 or substrate.3 The merit of proline in organic
synthesis is currently so vast that it is thought to be the ‘simplest
enzyme’.4 Due to the important features of proline, many investi-
gators have focused their attention and efforts to bring about the
facile production of structurally diverse proline compounds bear-
ing various functional groups.1 Despite the attempts made in this
regard, the introduction of a convenient and simple method for
the preparation of proline derivatives would be of great impor-
tance and interest. Several interesting approaches for the intercon-
version of the carboxyl group of proline into other groups have
been reported. The tandem decarboxylation-nucleophilic addition
method is one of the simplest strategies for synthesizing proline
derivatives. Li et al. have described the reaction of N-protected pro-
line with terminal acetylenes using CuBr/tert-butyl peroxide sys-
tem in the presence of N,N,N0,N0-tetramethylethylenediamine as
the ligand.5 The same group has also reported the iron-catalyzed
decarboxylative coupling of proline derivatives with naphthol
and indole derivatives.6 Li7 and Seidel8 independently reported
the three-component coupling reaction between proline, aldehyde,
and various nucleophiles (terminal acetylenes, b-naphthols, in-
doles, and nitro alkanes) producing the target molecules in moder-
ate to good yields. An efficient copper-catalyzed aerobic
or secondary phosphine oxides was developed in the presence
of CuI/N,N-diisopropylethylamine (DIPEA) in toluene (20 h at
130 °C).10 Using a similar three-component approach, the Strecker
reaction has also been reported for this type of process under
microwave irradiation at 200 °C.11 Nitro-Mannich type reaction
was also reported catalyzed by copper bromide in the presence
of TBHP using nitromethane as a coupling partner.12
Attention has also been paid to the use of cerium(IV) oxide
(CeO2) as the catalyst in diesel particulate matter combustion,13
the one-pot selective syntheses of N-alkyl amides from nitriles,
amines, and water,14 one-pot syntheses of organic carbamates
from amines, CO2, and alcohols,15 the syntheses of
a-aminophos-
phonates by ultrasonication,16 and for Ullmann-type coupling
reactions.17
In this report, we describe the use of CeO2 as a useful promoter
for the three-component reaction of proline, aldehyde, and a suit-
able nucleophile.
Initially, a survey on the reaction parameters, including the
catalyst and base was conducted in air at 130 °C in o-xylene using
triethyl phosphite (1.5 mmol), L-proline (1.2 mmol), and benzalde-
hyde (1 mmol) as a model reaction (Table 1). The effects of catalysts
and bases were screened first. The reaction in o-xylene in the ab-
sence of a catalyst and base gave the desired product in only 51%
yield (Table 1, entry 1). Addition of nPr3N or NaOH to the reaction
mixture gave a slightly better conversion to the desired product
(Table 1, entries 2 and 3). The use of CeO2 as the promoter enhanced
⇑
Corresponding authors. Tel.: +98 711 228 4822; fax: +98 711 228 0926.
E-mail addresses: firouzabadi@chem.susc.ac.ir (H. Firouzabadi), iranpoor@
chem.susc.ac.ir (N. Iranpoor).
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.08.012

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H. Firouzabadi et al. / Tetrahedron Letters 53 (2012) 5515–5518
Table 1
Three-component reaction of benzaldehyde, proline, and triethyl phosphite using different catalytic systems
O
P
EtO
O
COOH
N
OEt
catalyst, base
H
NH
P(OEt)3
o-xylene, 130 oC, 16 h
Entry
Catalyst
Base
Conversiona (%)
1
2
3
4
5
—
—
—
—
51
60
56
83
60
71
100
66
nPr3N
NaOH
—
CeO2
CeO2
CeO2
CeO2
CeCl3ꢀ7H2O
nPr3N
NaOH
—
6
7b
8
—
a
Conversion determined by GC.
b
L-Proline (2 equiv) was used, reaction time: 2 h.
Table 2
Different conditions for the three-component reaction of p-nitrobenzaldehyde, L-proline, and nitromethane
NO2
CHO
CeO2, solvent
N
CH3NO2
+
+
COOH
temperature (oC)
N
H
O2N
O2N
Entry
Solvent
Temp (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
Toluene
Toluene
Toluene
H2O
70
100
130
70
3
1
75
82
88
—
35 min
12
12
PEG 400
70
Mixture
the conversion noticeably (Table 1, entry 4). Increasing the amount
of -proline (2 equiv) led the reaction to completion within 2 h in
In the presence of CeO2, a one-pot reaction between p-nitro-
benzaldehyde, -proline, and nitromethane occurred. Our studies
L
L
the presence of CeO2 (Table 1, entry 7). Consequently, the optimized
reaction conditions (Table 1, entry 7) were chosen for subsequent
investigations. We also studied the catalytic effect of CeCl3.7H2O,
however, it was not as effective as CeO2 (Table 1, entry 8).
A proposed reaction pathway is depicted in Scheme 1. After
condensation of proline with benzaldehyde, the iminium cation I
is produced which is converted into intermediate II.18 Elimination
of CO2 from II generates the structures III and IV. Due to the greater
stability of azomethine ylide III,7 it reacts with triethyl phosphite
to produce the observed product.
showed that toluene was the best solvent for this reaction (Table 2).
The reaction in other solvents such as water and PEG 400 did not
proceed. The reaction at different temperatures 70, 100, and
130 °C proceeded smoothly to give the desired product in 75%,
82%, and 88% isolated yields within 3 h, one hour, and 35 min,
respectively (Table 2, entries 1–3).
Employing the optimized conditions, a range of aromatic alde-
hydes reacted with L-proline and triethyl phosphite (Scheme 2).
However, the reactions failed using primary amino acids and
ketones.
O
OH
CHO
O
o-xylene, CeO2
N
N
+
COOH
N
O
130 oC
-H2O
H
I
II
-CO2
O
O
Et
P
P
EtO
N
N
P(OEt)3
N
N
H2O
OEt
OEt
EtO
IV
III
Scheme 1. Proposed pathway for the reaction of benzaldehyde with L-proline and triethyl phosphite.

H. Firouzabadi et al. / Tetrahedron Letters 53 (2012) 5515–5518
5517
O
P
OEt
CHO
CeO2, o-xylene
OEt
N
R
P(OEt)3
+
+
COOH
N
130 o
-CO2, -EtOH
C
H
R
O
P
O
O
P
OEt
OEt
OEt
OEt
P
OEt
N
N
N
OEt
O2N
Me
2 h, 80%
50 min, 87%
O
2.5 h, 80%
O
O
OEt
P
OEt
P
OEt
N
P
OEt
N
N
OEt
OEt
Cl
Cl
1.5 h, 79%
O
24 h, 0%
1.75 h, 75%
OEt
P
OEt
HN
NO2
24 h, 0%
Scheme 2.
CeO2
toluene, 70 o
CHO
C
N
N
+
COOH
N
O2N
4 h
H
O2N
O2N
O
O2N
5.61 ppm
5.28 ppm
H
O
H
N
H
N
N
H
O
O
H
4.62 ppm
+
H
O2N
NO2
O2N
O2N
NO2
NO2
4.49 ppm
5.34 ppm
3.78 ppm
7.94 Hz
64%
6.09 Hz
20%
Scheme 3. [3+2] Cycloaddition of p-nitrobenzaldehyde with the in situ generated 1,3-dipolar intermediate and the 1H NMR spectral data for the two isolated diastereomers.
In the absence of a nucleophile, CeO2 catalyzed the [3+2]
cycloaddition reaction of the aldehyde with the in situ generated
1,3-dipolar intermediate to give the corresponding product in 84%
overall isolated yield for the two diastereomers within 4 h (Scheme3).

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H. Firouzabadi et al. / Tetrahedron Letters 53 (2012) 5515–5518
Comparison of the 1H NMR spectra of the two isolated diastere-
Acknowledgment
oisomers with authentic samples confirmed the structures of the
isolated compounds.19
The authors are thankful to the Shiraz University Research
Council for support.
A full investigation of the catalytic activity of CeO2 using differ-
ent nucleophiles for decarboxylative couplings of
underway in our laboratories.
In summary, the catalytic activity of CeO2 for the aldehyde-
induced decarboxylative coupling of triethyl phosphite and nitro-
L-proline is
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
012.
methane with L-proline is presented. In the presence of CeO2, a
[3+2] cycloaddition reaction of the in situ generated 1,3-dipolar
intermediate with the aldehyde in the absence of a nucleophile
produces two diastereoisomers of 1-oxapyrrolizidine which were
isolated and characterized.
References and notes
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To a solution of benzaldehyde (1 mmol, 0.11 mL) and
L
-proline
(2 mmol, 0.23 g) in o-xylene (3 mL) were added triethyl phosphite
(1.2 mmol, 0.14 mL) and CeO2 (0.2 mmol, 0.034 g). The mixture
was heated at 130 °C and the progress of the reaction was moni-
tored by GC. After completion of the reaction, silica gel (1 g) was
added to the reaction mixture and the desired product was sepa-
rated and purified by column chromatography on silica gel using
hexane/ethyl acetate as eluents.
Typical procedure for the three-component reaction of p-
nitrobenzaldehyde,
L-proline, and nitromethane
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To a solution of p-nitrobenzaldehyde (1 mmol, 0.151 g) and
L
-
proline (2 mmol, 0.23 g) in toluene (3 mL) were added nitrometh-
ane (1.5 mmol, 0.08 mL) and CeO2 (0.2 mmol, 0.034 g). The mixture
was heated at 70 °C and the progress of the reaction was moni-
tored by TLC. After completion of the reaction, silica gel (1 g) was
added to the reaction mixture and the desired product was
separated and purified by column chromatography on silica gel
using hexane/ethyl acetate as eluents.