The CeCl3·7H2O-NaI system as promoter in the synthesis of functionalized trisubstituted alkenes via Knoevenagel condensation

Article abstract of DOI:10.1016/j.tetlet.2006.07.031

The arylidene malonates with two different geminal carboxylate functions, a suitable class of substrates of several synthetic and pharmacological studies, are easily available through Knoevenagel condensation of ethyl tert-butyl malonate and different aro

Full text of DOI:10.1016/j.tetlet.2006.07.031

Tetrahedron Letters 47 (2006) 6501–6504
The CeCl3Æ7H2O–NaI system as promoter in
the synthesis of functionalized trisubstituted alkenes
via Knoevenagel condensation
Giuseppe Bartoli,a Romina Beleggia,b Sandra Giuli,c Arianna Giuliani,c,ꢀ
Enrico Marcantoni,c,* Massimo Massaccesic and Melissa Paolettic
a
`
Dipartimento di Chimica Organica ‘A. Mangini’, Universita di Bologna, viale Risorgimento 4, I-40136 Bologna, Italy
b
`
Dipartimento di Scienze degli Alimenti, Universita di Foggia, via Napoli 25, I-71100 Foggia, Italy
`
Dipartimento di Scienze chimiche, Universita di Camerino, via S. Agostino 1, I-62032 Camerino, MC, Italy
c
Received 31 May 2006; revised 6 July 2006; accepted 10 July 2006
Available online 28 July 2006
Abstract—The arylidene malonates with two different geminal carboxylate functions, a suitable class of substrates of several
synthetic and pharmacological studies, are easily available through Knoevenagel condensation of ethyl tert-butyl malonate and
different aromatic aldehydes. The results have increased the potentialities of CeCl3Æ7H2O–NaI system as a type of water-tolerant
green Lewis acid promoter for carbon–carbon bond forming procedures.
Ó 2006 Elsevier Ltd. All rights reserved.
O
The development of promoted organic reactions using
air-stable and water tolerant lanthanide salts as Lewis
acid catalyst is one of the important and challenging
subjects in organic synthesis chemistry.1 In the last
years, cerium trichloride heptahydrate (CeCl3Æ7H2O)
has attracted considerable attention because of its
diverse applications as a promoter in organic synthesis.2
In line with our group’s interests in exploring new and
potentially more concise procedures for carbon–carbon
bond forming promoted by Lewis acids, we have
increased the potentialities of the combination of
CeCl3Æ7H2O with NaI.3
EWG1
EWG2
2
EWG1
EWG2
cat.
R1
+
R1
H
1
3
Scheme 1.
tion provides a new method for the synthesis of different
multifunctional molecules (3) in a single operation. The
corresponding alkylidene malonates appear as a suitable
class of building blocks useful for the synthesis of natu-
ral and non-natural bioactive compounds.6 In particu-
lar, the trisubstituted alkenes7 derived from our
procedure by Knoevenagel condensation with ethyl
tert-butyl malonate (ETBM) could serve as excellent
precursors to esters or acids 2-hydroxymethyl-3-aryl-2-
propenoic, useful building blocks for the preparation
of various biologically active molecules.8
In these years, we have observed that the CeCl3Æ7H2O–
NaI system promotes the addition of CH-acidic com-
pounds to different electrophiles.4 In connection with
our efforts on the synthesis of trisubstituted alkenes,5
we have herein observed that our combination can be
utilized as a green, mild, and efficient method for the
Knoevenagel condensation (Scheme 1) of malonate
derivatives (2) with aldehydes (1). The sequential reac-
It is noteworthy that our procedure has not only
increased the potentialities of CeCl3Æ7H2O–NaI system,
but it has also permitted to overcome the major restric-
tion to the broad application of the Knoevenagel reac-
tion, that is, the inability to arrest the coupling of
aldehydes with 1,3-diesters at the monoaddition stage
since these intermediates are highly Michael acceptors
*
Corresponding author. Tel.: +39 0737 442255; fax: +39 0737
402297; e-mail: enrico.marcantoni@unicam.it
ꢀ
`
´
Present address: Laboratoire de Synthese Organique Selective et
´
Chemie Organometallique (SOSCO), Boulevard de l’Hautil 13, 95092
Cergy Pontoise, France.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.031

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G. Bartoli et al. / Tetrahedron Letters 47 (2006) 6501–6504
in their own right.9 Further, from a close analysis of the
literature methods for Knoevenagel condensation, we
did not find any general procedure for the synthesis of
arylidene-substituted unsymmetrical malonic acid deriv-
atives,10 versatile synthetic intermediates owing to the
various possible transformations of the different carb-
oxylic functionalities.6b However, when a monoester of
malonic acid is used in the Knoevenagel condensation
with carbonyl compounds, the decarboxylation occurs
spontaneously during the reaction.11
to be fairly stereoselective affording E-isomers in high
yields.10,18 In all cases, the olefinic proton signal for both
diastereomers were clearly distinguishable in their 1H
NMR spectra. The olefin proton signal for E-isomer
was downfield relative to the proton for the Z-isomer.
This is in agreement with the principle that hydrogen
cis-standing to the ester group shows a downfield shift.19
Though the E-selectivity has generally been observed in
all the cases, a satisfactory explanation is still not avail-
able at the present stage.
In a preliminary experiment, the Knoevenagel reaction of
benzaldehyde (4a) and ETBM (5) was explored to deter-
mine the optimal conditions (Scheme 2). We examined
the influence of the reactants ratio and of the relative
combination of the two promoter components on the
reaction. We found that the best choice was a 1:1.2 ratio
between 4a and 5 in a ca. 0.1 M solution in acetonitrile12
containing 1.35 equiv of CeCl3Æ7H2O and 1.35 equiv of
NaI. The use of a higher excess of cerium(III) chloride
(3.0 equiv) led to similar results, but lower amounts
(e.g., 0.65 equiv) gave lower chemical yields.
With aromatic aldehydes, this Knoevenagel reaction
proceeds smoothly to give the desired arylidenemalonate
derivatives. However, the electronic nature of the aryl
substituents in the aldehydes has an effect on the rate
of the reaction. It was found that electron-withdrawing
substituted aromatic aldehydes favored this reaction
(Table 1, entries 2 and 3), while the aromatic aldehydes
bearing electron-rich group on the aromatic ring gave
the corresponding trisubstituted alkenes after longer
reaction time (Table 1, entries 4 and 5). The Knoevena-
gel reaction promoted by CeCl3Æ7H2O–NaI system with
electron-poor heteroaromatic aldehydes afforded the
corresponding alkene in moderate diastereoselectivity,
but with high yield (Table 1, entry 6). An alternative
synthesis of the trisubstituted alkene 7 was tried by
Knoevenagel condensation of cheaper ethyl hydrogen
malonate,20 but our procedure gave very low yield of
adduct (GC–MS < 5%), and many side products are
formed. It is worthy to note that our procedure suc-
ceeded even in the presence of the coordinating hetero-
cyclic nitrogen on this substrate, which could in
principle affect the activity of a Lewis acid. In order to
further investigate the scope of the methodology, we at-
tempted the Knoevenagel reaction of the aliphatic alde-
hydes with ETBM (5). Unlike aryl aldehydes, adduct 6
was not observed and GC–MS analysis of the reaction
mixture showed malonic acid half ester as the main
product. Most probably, in our conditions, the alkylide-
nepropanedioic half esters are not stable and retro-aldol
reaction takes place, and the starting aldehyde was
recovered.
The reaction temperature is also important. In fact, the
first step of addition to the aldehyde moiety should be
carried out at room temperature, but the dehydration
and tert-butyl cleavage required a higher temperature
to proceed to completion. When the process was carried
out at room temperature, arylidenemalonate 6a was
observed in very low yield although formation of the ini-
tial adduct was observed.13 Thus, after a first addition
reaction at room temperature, the second step was
conducted at reflux.14 Under these conditions, selective
deprotection of tert-butyl ester15 was observed and
unsymmetrical malonic acid derivative 7a was obtained
in good yield. This procedure proved to be general and
could be applied to a range of aldehydes (see Table 1),
and good results were in fact obtained with aromatic
aldehydes.16 NMR spectroscopy clearly showed malon-
ate mono acid 7 as a unique product isolated without the
presence of decarboxylation product. It should be noted
that in the case of malonic acid addition to aromatic
aldehydes our procedure gives, contrary to the results
proposed by Weaver et al.,17 no evidence of a,b-unsatu-
rated malonic acids.
The mechanism of the reaction is not clear. Certainly,
the acceleration effect caused by the addition of metal
iodide (NaI) to CeCl3 has already been observed by
our group.21 This effect might be rationalized by a halo-
gen exchange reaction that leads to a more reactive spe-
cies, but previous experimental evidences prove that
CeI3 shows a very poor activity as Lewis acid in various
transformations.22,23 A more plausible process is the dis-
aggregation of the crystal lattice of CeCl3 by NaI or
which might lead to a notable increase in the Lewis acid-
ity of the cerium available at the particle surface.
Except for the reaction of nicotinaldehyde (Table 1,
entry 6), the reactions of other aldehydes were found
CO2Et
CO2But
6a-f
O
CO2Et
CO2But
5
CeCl3.7H2O
NaI
Ar
+
Ar
H
CH3CN, r.t.
4a-f
Reflux
In conclusion, this letter clearly demonstrates the power
and economic interest of a CeCl3Æ7H2O–NaI promoted
reaction in the field of synthetic organic chemistry. In
fact, the procedure effects Knoevenagel reaction of aro-
matic aldehydes and malonate derivative efficiently.24
The sequential reaction provides a new method for
arylidenemalonate formation in a single operation.
Extension of the present methodology to the synthesis
CO2Et
Ar
COOH
7a-f
Scheme 2.

G. Bartoli et al. / Tetrahedron Letters 47 (2006) 6501–6504
6503
Table 1. Knoevenagel condensation of aromatic aldehydes 4 with ETBM (5) in the presence of CeCl3Æ7H2O–NaI in acetonitrile
Entry
Aldehydea
Time/h
Conditions
Productb
Yieldc (%)
E:Zd
CHO
CO2Et
COOH
54
2.5
rt
Reflux
1
80
77:23
90:10
93:07
7a
4a
CHO
CO2Et
COOH
40
1.5
rt
Reflux
95
97
2
3
F3C
F3C
4b
4c
7b
7c
CO2Et
COOH
CHO
CHO
37
0.5
rt
Reflux
O2N
O2N
CO2Et
COOH
62
3.5
rt
Reflux
90
85
91
75:25
80:20
60:40
4
5
6
H3C
H3CO
N
H3C
4d
7d
CHO
CO2Et
COOH
64
4.0
rt
Reflux
H3CO
7e
CO2Et
COOH
4e
CHO
42
1.5
rt
Reflux
N
7f
4f
a All starting materials were commercially available.
b All products were identified by their IR, NMR, and GC–MS spectra.
c Yield of products isolated after workup.
d E:Z ratios determined by NMR.
2. (a) Li, W.-D. Z.; Peng, Y. Org. Lett. 2005, 7, 3069–3072;
(b) Dalpozzo, R.; De Nino, A.; Bartoli, G.; Sambri, L.;
Marcantoni, E. Recent Res. Dev. Org. Chem. 2001, 5, 181–
191; (c) Imamoto, T. Lanthanides in Organic Synthesis;
Academic Press: New York, 1994.
of other trisubstituted alkenes, as well as studies dealing
with the transformation of electron-withdrawing func-
tionalities is currently under investigation and will be
reported in due course.
3. Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Marcantoni, E.; Melchiorre, P.; Sambri, L. Adv. Synth.
Catal. 2006, 348, 905–910, and references cited therein.
4. Bartoli, G.; Bosco, M.; Bellucci, M. C.; Marcantoni, E.;
Sambri, L.; Torregiani, E. Eur. J. Org. Chem. 1999, 617–
620.
5. (a) Bartoli, G.; Marcantoni, E.; Sambri, L.; Tamburini,
M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2046–2048; (b)
Bartoli, G.; Marcantoni, E.; Petrini, M.; Sambri, L.
Tetrahedron Lett. 1994, 35, 8453–8456.
6. (a) Fillion, E.; Fishlock, D. J. Am. Chem. Soc. 2005, 127,
13144–13145; (b) Yadav, J. S.; Kumar Gupta, M.; Kumar
Pandey, S.; Reddy, B. V. S.; Sarma, A. V. S. Tetrahedron
Lett. 2005, 46, 2761–2763; (c) Toshima, K.; Arita, T.;
Kato, K.; Tanaka, D.; Matsumura, S. Tetrahedron Lett.
2001, 45, 8873–8876; (d) Andersen, R. J.; Coleman, J. E.;
Piers, E.; Wallace, D. J. Tetrahedron Lett. 1997, 38, 317–
320.
Acknowledgments
Work was carried out in the framework of the National
Project ‘Studio degli Aspetti Teorici ed Applicativi degli
Aggregati di Molecole Target su Siti Catalitici Stereo-
selettivi’ supported by the MIUR, Rome, and by the
University of Camerino. M.P. gratefully acknowledges
the Pfizer Ascoli Piceno Plant for a postgraduate
fellowship.
References and notes
1. Kobayashi, S. Lanthanides: Chemistry and Uses in Organic
Synthesis; Springer: Berlin, 1999.

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G. Bartoli et al. / Tetrahedron Letters 47 (2006) 6501–6504
7. (a) Li, J.; Wang, X.; Zhang, Y. Tetrahedron Lett. 2005, 46,
120.8, 125.6, 127.2, 129.8, 131.2, 134.0, 134.7, 143.8, 165.3,
167.2. Anal. Calcd for C13H11F3O4 (288.23): C, 54.17; H,
3.84: Found: C, 54.13; H, 3.80. Compound 7d: FTIR
(neat): 2968, 1732, 1626 cmÀ1; (E) 1H NMR (CDCl3,
200 MHz): d 10.91 (bs, 1H), 7.91 (s, 1H), 7.55–7.20 (m,
4H), 4.36 (q, 2H, J = 7.14 Hz), 2.40 (s, 3H), 1.38 (t, 3H,
J = 7.12 Hz); 13C NMR (CDCl3, 50 MHz): d 18.9, 27.0,
63.0, 119.7, 128.0, 128.6, 132.3, 140.5, 144.6, 160.7, 163.2;
(Z) 1H NMR (CDCl3, 200 MHz) d 10.30 (bs, 1H), 7.85 (s,
1H), 7.55–7.20 (m, 4H), 4.26 (q, 2H, J = 7.02 Hz), 2.40 (s,
3H), 1.29 (t, 3H, J = 7.08 Hz); 13C NMR (CDCl3, 50
MHz): d 19.2, 27.0, 62.7, 120.5, 128.0, 128.6, 132.3, 140.5,
144.5, 165.0, 166.2. Anal. Calcd for C13H14O4 (234.25): C,
66.65; H, 6.02: Found: C, 66.62; H, 5.98. Compound 7e:
FTIR (neat): 2982, 1731, 1634 cmÀ1; (E) 1H NMR
(CDCl3, 200 MHz): d 11.03 (bs, 1H), 8.02 (s, 1H), 7.57–
7.32 (m, 4H), 4.52 (q, 2H, J = 7.32 Hz), 3.86 (s, 3H), 1.29
(t, 3H, J = 7.10 Hz); 13C NMR (CDCl3, 50 MHz): d 18.6,
54.6, 60.3, 117.1, 119.7, 120.9, 129.7, 142.1, 159.3, 160.8,
5233–5237; A number of diverse approaches to trisubsti-
tuted alkenes can be chosen, and useful protocols of cross-
coupling reactions palladium complexes promoted have
been shown by Negishi ((b) Zeng, X.; Qian, M.; Hu, Q.;
Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259–2263);
However, these procedures suffer from toxicity and air and
moisture sensibility, even if recently Molander reported
cross-coupling reactions of more stable derivatives than
common organometallic compounds (Molander, G. A.;
Yokoyama, Y. J. Org. Chem. 2006, 71, 2493–2498).
8. Besavaiah, D.; Sharada, D. S.; Veerendhar, A. Tetrahedron
Lett. 2004, 45, 3081–3083, and references cited therein.
9. (a) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M.
Tetrahedron Lett. 2002, 43, 1127–1130; (b) Tiezte, L. F.;
Beifuss, U. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; p
341; (c) Jones, G. Org. React. 1967, 15, 204–272.
10. Nigmatov, A. G.; Serebryakov, E. P. Bull. Acad. Sci.
USSR Div. Chem. Sci. (Engl. Trans.) 1991, 40, 961–970.
11. Tanaka, M.; Oota, O.; Miramatsu, H.; Fujiwara, K. Bull.
Chem. Soc. Jpn. 1988, 61, 2473–2477.
12. The use of other solvents (ether, THF, dichloromethane,
nitromethane, DMF, toluene) led to lower yields. The best
result (38% yield) was observed in nitromethane.
1
162.0; (Z) H NMR (CDCl3, 200 MHz) d 10.64 (bs, 1H),
7.96 (s, 1H), 7.56–7.32 (m, 4H), 4.50 (q, 2H, J = 7.10 Hz),
4.00 (s, 3H), 1.21 (t, 3H, J = 7.03 Hz); 13C NMR (CDCl3,
50 MHz): d 19.0, 55.3, 60.9, 116.9, 119.1, 120.8, 130.0,
143.0, 160.8, 164.9, 167.2; MS (EI) m/z: 206, 161, 134, 77,
65, 51. Anal. Calcd for C13H14O5 (250.25): C, 62.39; H,
5.64: Found: C, 62.37; H, 5.58. Compound 7f: FTIR
(neat): 2975, 1730, 1625 cmÀ1; (E) 1H NMR (CDCl3,
200 MHz): d 10.00 (bs, 1H), 8.20–8.13 (m, 1H), 8.08–8.01
(m, 1H), 7.86–7.80 (m, 2H), 7.69 (s, 1H), 7.60–7.48 (m,
4H), 4.49 (q, 2H, J = 6.99 Hz), 1.32 (t, 3H, J = 7.02 Hz);
13C NMR (CDCl3, 50 MHz): d 19.2, 59.4, 115.8, 123.9,
126.4, 126.9, 143.0, 143.5, 145.4, 163.7, 164.7; (Z) 1H
NMR (CDCl3, 200 MHz) d 10.23 (bs, 1H), 8.20–8.13 (m,
1H), 8.10–8.01 (m, 1H), 7.80–7.74 (m, 2H), 7.69 (s, 1H),
7.43–7.28 (m, 4H), 4.52 (q, 2H, J = 6.14 Hz), 1.29 (t, 3H,
J = 7.10 Hz); 13C NMR (CDCl3, 50 MHz): d 18.7, 61.8,
116.4, 123.5, 124.9, 129.5, 142.8, 144.0, 145.0, 165.9, 167.5;
MS (EI) m/z: 177, 150, 92, 78, 53, 45. Anal. Calcd for
C11H11NO4 (221.21): C, 59.72; H, 5.01; N, 6.33: Found: C,
59.70; H, 4.96; N, 6.34.
13. The major product identified by GC–MS was 1-(tert-
butyl)-3-ethyl-2-[hydroxy(phenyl)methyl]malonate.
14. Bartoli, G.; Bellucci, M. C.; Petrini, M.; Marcantoni, E.;
Sambri, L.; Torregiani, E. Org. Lett. 2000, 2, 1791–1793.
15. Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.;
Sambri, L.; Torregiani, E. J. Org. Chem. 2001, 66, 4430–
4432.
16. A typical procedure for preparation of 7 is as follows:
to a stirred suspension of aldehyde 4 (0.5 mmol) and
cerium(III) chloride heptahydrate (0.25 g, 0.675 mmol) in
acetonitrile (5 mL) was added sodium iodide (0.1 g,
0.675 mmol), followed by ETBM 5 (0.11 g, 0.6 mmol)
and the resulting mixture was stirred at room temperature
until complete consumption of aldehyde 4 (Table 1). Then
the reaction mixture was refluxed until no intermediate 6
remains as monitored by GC. The reaction progress was
monitored by withdrawing aliquots which were analyzed
by GC, and the products were identified by GC–MS. After
cooling, the reaction mixture was diluted with dichloro-
methane and treated with 0.5 N HCl (10 mL). The organic
layer was separated, and the aqueous layer was extracted
with dichloromethane. The combined organic layers were
evaporated, the residue was dissolved in 10% NaHCO3
solution (15 mL), and the bicarbonate layer was washed
with ether. Bicarbonate solution was then made acidic to
pH 3 and extracted with dichloromethane. The organic
layer was washed with water and brine, dried over
anhydrous Na2SO4, and evaporated to give arylidenemal-
onate 7 as an oil, which was spectroscopically pure.
Spectral data of products not reported in the literature are
listed as follows: compound 7b: FTIR (neat): 2978, 1723,
17. Tan, C. Y. K.; Weaver, D. F. Tetrahedron 2002, 58, 7449–
7461.
18. Yamashita, K.; Tanaka, T.; Hayashi, M. Tetrahedron
2005, 61, 7981–7985.
19. (a) Hong, W. P.; Lee, K.-J. Synthesis 2005, 33–38; (b)
Mahender, G.; Chowdhury, N.; Banerjee, J. Synthesis
2005, 1000–1002; (c) Schirmeister, T.; Otto, H. H. J. Org.
Chem. 1993, 58, 4819–4822; (d) Jung, M. E.; Buszek, K. R.
J. Am. Chem. Soc. 1988, 110, 3965–3969; (e) Srinivason,
A.; Richards, K. D.; Olsen, R. K. Tetrahedron Lett. 1976,
12, 891–894.
20. Corey, E. J.; Fraenkel, G. J. Am. Chem. Soc. 1953, 75,
1168–1172.
21. Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003,
2101–2116.
22. Marotta, E.; Foresti, E.; Marcelli, T.; Peri, F.; Righi, P.;
Scardovi, N.; Rosini, G. Org. Lett. 2002, 4, 4451–4453.
23. Bartoli, G.; Bosco, M.; Giuliani, A.; Marcantoni, E.;
Palmieri, A.; Petrini, M.; Sambri, L. J. Org. Chem. 2004,
69, 1290–1297.
24. It is known that Knoevenagel condensation catalyzed by
Lewis acids does not show formation of the Michael
addition, see: Prajapati, D.; Sandu, J. S. Chem. Lett. 1992,
1945–1946.
1
1633 cmÀ1; (E) H NMR (CDCl3, 200 MHz): d 10.85 (bs,
1H), 7.93 (s, 1H), 7.67–7.55 (m, 4H), 4.30 (q, 2H,
J = 6.96 Hz), 1.28 (t, 3H, J = 7.00 Hz); 13C NMR (CDCl3,
50 MHz): d 18.7, 62.8, 113.1, 120.3, 121.0, 125.2, 127.6,
131.0, 131.4, 134.7, 160.8, 163.9; (Z) 1H NMR (CDCl3,
200 MHz) d 10.85 (bs, 1H), 7.87 (s, 1H), 7.67–7.55 (m,
4H), 4.30 (q, 2H, J = 7.02 Hz), 1.25 (t, 3H, J = 7.03 Hz);
13C NMR (CDCl3, 50 MHz): d 19.2, 61.3, 112.9, 120.0,