SiO2-supported CeCl3·7H2O-NaI Lewis acid promoter: Investigation into the Garcia Gonzalez reaction in solvent-free conditions

Article abstract of DOI:10.1021/jo070384c

(Chemical Equation Presented) The Knoevenagel condensation of aldose sugars with β-dicarbonyl compounds produces furan derivatives having polyhydroxyalkylated alkyl side chains; this reaction is known as the Garcia Gonzalez reaction. Despite the fact that

Full text of DOI:10.1021/jo070384c

SiO2-Supported CeCl3·7H2O-NaI Lewis Acid Promoter:
Investigation into the Garcia Gonzalez Reaction in Solvent-Free
Conditions
Giuseppe Bartoli,† Jose´ G. Ferna´ndez-Bolan˜os,‡ Giustino Di Antonio,§ Gioia Foglia,§
Sandra Giuli,§ Roberto Gunnella,| Michele Mancinelli,† Enrico Marcantoni,*,§ and
Melissa Paoletti§
Dipartimento di Scienze Chimiche, UniVersita` di Camerino, Via S. Agostino 1, I-62032 Camerino (MC),
Italy, Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna, Viale Risorgimento 4,
I-40136 Bologna, Italy, Departamento de Quimica Organica, Facultad de Quimica, UniVersidad de
SeVilla, Apartado 553, E-41071 SeVilla, Spain, and Dipartimento di Fisica, UniVersita` di Camerino,
Via Madonna delle Carceri, I-62032 Camerino (MC), Italy
enrico.marcantoni@unicam.it
ReceiVed February 26, 2007
The Knoevenagel condensation of aldose sugars with â-dicarbonyl compounds produces furan derivatives
having polyhydroxyalkylated alkyl side chains; this reaction is known as the Garcia Gonzalez reaction.
Despite the fact that these polyhydroxyalkyl furans are interesting scaffolds for synthetic chemists to
utilize in the synthesis of a variety of biologically interesting molecules, the reported approach suffers
from harsh conditions. The development of a general and more efficient protocol is of considerable
importance, and in this manuscript, we wish to explore the role of the NaI in enhancing the activity of
CeCl3·7H2O as a useful water-tolerant Lewis acid promoter for the Garcia Gonzalez reaction. The procedure
proceeds with good yields at 50 °C using our system supported on SiO2 in solvent-free conditions and
represents a simple and convenient methodology for the preparation of densely functionalized molecules.
Furthermore, the first qualitative results obtained on mechanistic investigation on the role of iodide on
this our heterogeneous reaction may be of value for optimization of existing organic transformations and
for the development of new ones.
1. Introduction
(III) commercially available, has recently become an attractive
candidate for use as a Lewis acid in chemistry due to its relative
nontoxicity and ready availability at a low cost. In fact, after
the pioneering works by Luche2 and Imamoto,3 numerous
reactions and methodologies employing cerium(III) derivatives
as key components have been developed.4 In particular, major
attention has focused on the use of inexpensive CeCl3·7H2O,
which exhibits excellent properties; e.g., it is water tolerant,
Trivalent rare earth compounds1 such as Ce(III) salts exhibit
characteristic acid properties, and they activate Lewis base
functionalities to promote useful organic transformations. For
this reason, we have frequently employed cerium(III) com-
pounds as highly efficient reagents or catalysts in modern
organic synthesis. CeCl3, the most common source of cerium-
Dedicated to Prof. Achille Umani-Ronchi on his 70th birthday.
* To whom correspondence should be addressed. Phone: +39 0737 402255.
Fax: +39 0737 402297.
(2) (a) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-
5459. (b) Luche, J.-L.; Gemal, A. L. Tetrahedron Lett. 1981, 22, 4077-
4080. (c) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1979, 101, 5848-
5849. (d) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
(3) (a) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press:
New York, 1994. (b) Imamoto, T. Pure Appl. Chem. 1990, 62, 747-776.
(c) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y.
J. Am. Chem. Soc. 1989, 111, 4392-4398.
† Universita` di Bologna.
‡ Universidad de Sevilla.
§ Scienze Chimiche, Universita` di Camerino.
| Fisica, Universita` di Camerino.
(1) Kobayashi, S. Lanthanide: Chemistry and Use inorganic Synthesis;
Springer-Verlag: Heidelberg, Germany, 1999.
10.1021/jo070384c CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/13/2007
J. Org. Chem. 2007, 72, 6029-6036
6029

Bartoli et al.
nontoxic, easy to handle, and suitable for use without further
purification.5 The fact that this water-tolerant Lewis acid
promoter is optimal with regard to economic and ecological
considerations has allowed its application in important organic
transformations. However, the main limitation is that a sto-
ichiometric amount of CeCl3·7H2O is required, and long reaction
times are observed. Therefore, the development of a catalytic
version of a cerium(III) salt promoted reaction remains as a
major objective of modern organic chemistry. Recent studies
by us and by others have shown that the activity of CeCl3·7H2O
increases dramatically in the presence of an iodide source such
as NaI.6 Further to the methodologies involving the CeCl3·
7H2O-NaI system to facilitate the cleavage of carbon-oxygen
and silicon-oxygen bonds under neutral conditions,7 new
reactions for nitrogen-carbon8 and oxygen-carbon9 bond
formation promoted by the CeCl3·7H2O-NaI system have also
been developed. Differences between the activity of CeCl3·7H2O
and that of the CeCl3·7H2O-NaI combination are especially
apparent in the context of carbon-carbon bond-forming reac-
tions.10 The presence of NaI is crucial in these reactions,
resulting in shorter reaction times, diminished byproduct forma-
tion, and improved yields and purity of the products. A pertinent
example is found in work by Spinelli et al.11 on the 1,4-addition
of Fischer bases to nitroenamines. All of these results have
established that the interaction between CeCl3·7H2O and an
inorganic iodide10c gives a complex which exhibits a stronger
Lewis acid character. CeCl3, being a hard Lewis acid,12 is
suitable to form a weak and labile iodide ion-Lewis acid
complex,13 and then the nucleophilic donor can enhance the
electrophilicity of the lanthanide metal.14 Although there is
FIGURE 1. Useful properties of polyhydroxyalkyl furan moieties.
evidence for the formation of this complex, the nature of the
species obtained by the interaction of CeCl3·7H2O with NaI is
not known. For this, even if only very sensible conjectures about
the role of NaI on the performance of CeCl3·7H2O as Lewis
acid promoter in many organic reactions have been advanced,
our CeCl3·7H2O-NaI combination is very suitable from a
synthetic standpoint.
We have recently become interested in evaluating the CeCl3·
7H2O-NaI catalytic system in the so-called Garcia Gonzalez
reaction:15 the Knoevenagel condensation of a â-dicarbonyl
compound16 with an unprotected carbohydrate to give a poly-
hydroxyalkyl furan (Figure 1). Interestingly, more than 100
furans structurally similar to that of Figure 1 have been recently
isolated from plants and microorganisms,17 albeit in low yield.
Substituted furans are also broadly represented among natural
products and medicinal agents. Furthermore, they are useful
building blocks in heterocyclic chemistry18 and in the synthesis
of carbohydrates.19 The latter compounds, of course, are of
enormous importance in chemical, biological, and medicinal
science,20 as well as being of great value in the preparation of
polyfunctional heterocycles of interest in pharmaceutical and
agrochemical practice.21 There is clearly a need for efficient
(4) For a recent review on this argument, see: (a) Dalpozzo, R.; De Nino,
A.; Bartoli, G.; Sambri, L.; Marcantoni, E. Recent Res. DeV. Org. Chem.
2001, 5, 181-191. (b) Bartoli, G.; Marcantoni, E.; Sambri, L. Seminars in
Organic Synthesis; XXV Summer School “A. Corbella”, Gargnano (BS);
Italian Chemical Society: Rome, 2000; pp 117-138. (c) Liu, H. J.; Shia,
K. S.; Shang, X.; Zhu, B. Y. Tetrahedron 1999, 55, 3803-3830.
(5) Bose. D. S.; Fatima, L.; Mereyala, H. B. J. Org. Chem. 2003, 68,
587-590. (b) Christoffers, J.; Werner, T.; Unger, S.; Frey, W. Eur. J. Org.
Chem. 2003, 425-431. (c) Mun˜oz-Mun˜iz, O.; Quintanar-Andelo, M.;
Juaristi, E. J. Org. Chem. 2003, 68, 1622-1625. (d) Keh, C. C. K.;
Namboodiri, V. V.; Varma, R. S.; Li, C.-J. Tetrahedron Lett. 2002, 43,
4993-4996. (e) Martelli, G.; Morri, S.; Savoia, D. Synlett 2002, 158- (f)
Warren, S.; Clayden, J. Angew. Chem., Int. Ed. 1996, 35, 241-270.
(6) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett. 2003, 2101-2116
and references cited therein.
(7) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Marcantoni,
E.; Melchiorre, P.; Sambri, L. AdV. Synth. Catal. 2006, 348, 905-910. (b)
Li, W.-D. Z.; Peng, Y. Org. Lett. 2005, 7, 3069-3072. (c) Urbaneja, L.
M.; Krause, N. Eur. J. Org. Chem. 2004, 4467-4470. (d) Yadav, J. S.;
Subba Reddy, B. V.; Srinivasa Reddy, K. Synlett 2002, 468-470. (e) Bartoli,
G.; Cupone, G.; Dalpozzo, R.; De Nino, A.; Mariuolo, L.; Marcantoni, E.;
Procopio, A. Synlett 2001, 1897-1900.
(12) The cerium trivalent ion is, undoubtedly, a hard cation in Pearson’s
classification; see: (a) Pletnev, I. V.; Zernov, V. V. Anal. Chim. Acta. 2002,
455, 131-142. (b) Pearson, R. G. J. Chem. Educ. 1987, 64, 561-567. (c)
Parr, R. G.; Pearson, R. G. J. Am. Chem. Soc. 1983, 105, 7512-7516. (d)
Pearson, R. G. Science 1966, 151, 172-177.
(13) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Cappa, A.; Marcantoni,
E.; Sambri, L.; Torregiani, E. J. Org. Chem. 1999, 64, 5696-5699.
(14) (a) Denmark, S. E.; Wynn, T.; Bentner, G. L. J. Am. Chem. Soc.
2002, 124, 13405-13407. (b) Denmark, S. E.; Wynn, T. J. Am. Chem.
Soc. 2001, 123, 6199-6200.
(15) (a) Kozikowski, A. P.; Liu, G. Q.; Sprinter, J. P. Tetrahedron Lett.
1987, 28, 2277-2280. (b) Garcia Gonzalez, F.; Gomez Sanchez, A. AdV.
Carbohydr. Chem. 1965, 20, 303-355. (c) Garcia Gonzalez, F. AdV.
Carbohydr. Chem. 1956, 11, 97-143.
(16) Although the base-catalyzed Knoevenagel condensation of a R-hy-
droxy aldehydes with a 1,3-dione can be a method to obtain a furan
derivative, the presence of strong bases several side reactions have been
observed such as polymerization, self-condensation, and Michael addition
on the adduct.
(17) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265-295.
(18) (a) Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006,
71, 8591-8601. (b) Hankaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3,
401-404. (c) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu,
T.; Swaminathan, S.; Xi, N. Synlett 1998, 105-114. (d) Yang, Z.-C.; Jiang,
X.-B.; Wang, Z.-M.; Zhou, W.-S. J. Chem. Soc., Perkin Trans. 1 1997,
317-321. (e) Kunz, U.; Ru¨ck, K. Angew. Chem., Int. Ed. 1993, 32, 336-
358. (f) Hanessian, S. Total Synthesis of Natural Products: the ‘Chiron’
Approach; Pergamon: Oxford, 1983.
(8) (a) Yadav, J. S.; Subba Reddy, B. V.; Srinivas, M.; Padmavani, B.
Tetrahedron 2004, 60, 3261-3266. (b) Sabitha, G.; Kumar Reddy, G. S.
K.; Bhaskar Reddy, K.; Mallikarjuna Reddy, N.; Yadav, S. AdV. Synth.
Catal. 2004, 346, 921-923.
(9) (a) Yeh, M.-C. P.; Yeh, W.-J.; Tu, L.-H.; Wu, J.-R. Tetrahedron
2006, 62, 7466-7470. (b) Yadav, J. S.; Reddy, B. V. S.; Bhaskar, Reddy,
K.; Satyanarayana, M. Tetrahedron Lett. 2002, 43, 7009-7012.
(10) (a) Bartoli, G.; Beleggia, R.; Giuli, S.; Giuliani, A.; Marcantoni,
E.; Massaccesi, M.; Paletti, M. Tetrahedron Lett. 2006, 47, 6501-6504.
(b) Bartoli, G.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.; Melchiorre,
P.; Lanari, S.; Sambri, L. AdV. Synth. Catal. 2005, 347, 1673-1680. (c)
Bartoli, G.; Bosco, M.; Giuliani, A.; Marcantoni, E.; Palmieri, A.; Petrini,
M.; Sambri, L. J. Org. Chem. 2004, 69, 1290-1297. (d) Bartoli, G.; Bosco,
M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L. Synthesis 2004,
895-900. (e) Bartoli, G.; Bosco, M.; Bellocci, M. C.; Marcantoni, E.;
Sambri, L.; Torregiani, E. Eur. J. Org. Chem. 1999, 617-620.
(11) Attanasi, O. A.; Favi, G.; Filippone, P.; Forzato, C.; Giorni, G.;
Moranti, S.; Nitti, P.; Pitocco, G.; Rizzato, E.; Spinelli, D.; Valentin, E.
Tetrahedron 2006, 62, 6420-6434.
(19) (a) Guo, H.; O’Doherty, G. A. Org. Lett. 2006, 8, 1609-1612. (b)
Moreno-Vargas, A. J.; Jime´nez-Barbero, J.; Robina, I. J. Org. Chem. 2003,
68, 4138-4150. (c) Ulgar, V.; Lo`pez, O.; Maya, I.; Fernandez-Bolanos, J.
G.; Bols, M. Tetrahedron 2003, 59, 2801-2809. (d) Moreno-Vargas, A.
J.; Fernandez-Bolanos, J. G.; Fuentes, J.; Robina, I. Tetrahedron Lett. 2001,
42, 1283-1285. (e) Moreno-Vargas, A. J.; Fernandez-Bolanos, J. G.;
Fuentes, J.; Robina, I. Tetrahedron: Asymmetry 2001, 12, 3257-3266. (f)
Zamojski, A. Prep. Carbohydr. Chem. 1997, 615-636. (g) Vogel, P. Bull.
Soc. Chim. Belg. 1990, 99, 395-439. (h) Sanchez Ballesteros, J.; McPhee,
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1576-1624.
6030 J. Org. Chem., Vol. 72, No. 16, 2007

SiO2-Supported CeCl3·7H2O-NaI Lewis Acid Promoter
TABLE 1. Reaction between D-Glucose (1a) and 2,4-Pentandione
(2a) under Different Experimental Conditionsa
SCHEME 1. Garcia Gonzalez Reaction for the Preparation
of Furan Derivatives
CeCl3‚7H2O
(equiv)
NaI
(equiv)
T
(°C)
yieldb
(%)
entry
conditions/time (h)
1
2
3
4
5
6
7
8
0.25
0.25
1.0
1.2
1.0
1.0
1.0
0.30
H2O/7
H2O/7
60
80
60
60
60
60
rt
20
8
H2O/15
H2O/15
CH3CN/25
CH3CN/25
SiO2/25
SiO2/22
25
31
18.5
54
60
95
0.30
0.3
0.3
synthetic avenues to furans.22 In this paper, we describe the
application of our CeCl3·7H2O-NaI system to the condensation
of â-dicarbonyl compounds with unprotected carbohydrates
under solvent-free conditions.23
50
a All reactions were carried out by stirring mixtures of 1a (10 mmol),
1,3-dione 2a (13 mmol), and catalyst for the selected reaction times. b All
yields of product isolated by column chromatography.
2. Results and Discussion
acetoacetate and CeCl3·7H2O (25%) provokes the total epimer-
ization29 at C-1′, in contradiction with Misra’s results.
We decided to explore the role of the NaI in enhancing the
activity of CeCl3·7H2O, and we discovered important advances
in the Garcia Gonzalez reaction. Our initial efforts focused on
achieving the optimum conditions for increasing the yields of
3 with D-glucose (1a) as a model aldohexose, in the presence
of cerium trichloride as the Lewis acid. The results are
summarized in Table 1. By screening the various conditions,
we have observed that the use of acetonitrile as solvent in this
reaction gives a poor yield (18.5%) in a slow reaction (25 h)
(Table 1, entry 5), probably owing to incomplete solution of
carbohydrate 1a. With catalytic amounts of NaI the correspond-
ing product 5aa is realized in moderate yield (Table 1, entry
6). About the same yield of the corresponding polyhydroxyalkyl
furan is obtained under solvent-free conditions and in the
presence of an inorganic support such as silica gel (SiO2) (Table
1, entry 7). The reaction proceeds with good yield at 50 °C
using the CeCl3·7H2O-NaI system supported on SiO2 in
solvent-free conditions. After further attempts to increase the
yield by changing relative amounts of the reactants, we have
found that a mixture of D-glucose (1.0 mmol), 2,4-pentandione
(2a, 1.30 mmol),30 CeCl3·7H2O (0.3 mmol), and NaI (0.3 mmol)
mechanically stirred at an external temperature of 50 °C for 22
h gave an excellent yield (95%) of product 5aa (Table 1, entry
8).
Since the initial Garcia Gonzalez reaction (Scheme 1) using
ZnCl2 in alcohol24 gives polyhydroxyalkylfuran in very low yield
(about 30%), major attention has been focused on the application
of various Lewis acid catalysts. Since trifluoromethanesulfonate
salts promote acid-catalyzed reactions under mild conditions,25
the Knoevenagel condensation of hexoses with 1,3-dione
compounds has been recently carried out under aqueous
conditions in the presence of Yb(OTf)3 or Sc(OTf)3.26 In any
case, the reaction produces the polyhydroalkyl furans 3 taken
with relative further cyclized tetrahydrofuranylfuran derivatives
4, which could with difficulty be separated by chromatography.
Misra et al. have found that unprotected aldose sugars react
with 1,3-diones and â-keto esters in the presence of CeCl3·7H2O
in aqueous mixtures at 90 °C to produce furan derivatives in
good yields.27 Under the Misra conditions, pentose sugars
produce furan derivatives having polyhydroxylated alkyl side
chains. However, when an aldohexose 1 is treated with a
â-dicarbonyl compound a single isolable product is obtained,
but this is a hydroxytetrahydrofuranylfuran 4. Under these harsh
conditions, in fact, after the formation of 3, it further rearranges
to form a double cyclic derivative, which is a less important
synthetic scaffold than polyhydroxyalkyl furans.19b,28 It has also
been reported that the condensation of an aldose with benzyl
(21) Joule, J. A.; Mills, K. Heterocycles Chemistry; Blackwell Science:
Oxford, 2000.
(22) Barma, D. K.; Kundu, A.; Baati, R.; Mioskowski, C.; Falek, J. R.
Org. Lett. 2002, 4, 1387-1389.
(23) In our methodology of the Lewis acid promoter solvent-free reaction,
the term “solvent-free” refers solely to the reaction itself. The preparation
of initial adsorbate and purification of products invariably involve the use
of solvent.
(24) Sanchez Ballesteros, J.; Ayala Montoro, L. Bul. Soc. Quim. Peru
1981, 47, 84-95.
The first clear result is that the use of SiO2 support facilitates
the workup of the reaction mixture31 with better yields of
product, even though the reaction has also been observed in its
absence. Furthermore, the use of inorganic support allows the
reaction to proceed without solvent to adopt the best experi-
mental conditions to reduce the large amounts of organic
(25) (a) Frost, C. G.; Haitely, J. P.; Griffin, D. Synlett 2002, 1928-
1930. (b) Loh, T. P.; Tan, K. T.; Hu, Q.-Y. Angew. Chem., Int. Ed. 2001,
40, 2920-2922. (c) Xie, W.; Bloomfield, K. M.; Jin, Y.; Dolney, N. Y.;
Wang, P. G. Synlett 1999, 498-500. (d) Yu, L.-B.; Chen, D.; Li, J.; Ramirez,
J.; Wang, P. G. J. Org. Chem. 1997, 62, 903-907. (e) Kobayashi, S. Synlett
1994, 689-701.
(29) Molina, L.; Moreno-Vargas, A. J.; Carmona, A. T.; Robina, I. Synlett
2006, 1327-1330.
(30) We have observed that the excess of 1,3-dicarbonyl compound is
advantageous to add in order to avoid decreased yield.
(31) In recent years, solid support catalysts have attracted much interest
in chemistry because of advantages they possess over homogeneous catalysts
including recyclability, more simple product isolation, and reduction of
environmental pollution and have been successfully used in organic
transformations. For recent reviews, see: (a) Leadbeater, N. E.; Marco, M.
Chem. ReV. 2002, 102, 3217-3217. (b) McNamara, C. A.; Dixon, M. J.;
Bradley, M. Chem. ReV. 2002, 102, 3275-3300. (c) Benerjee, A. K.; Laya
Mimo`, M. S.; Vera Vegas, W. J. Russ. Chem. ReV. 2001, 70, 971-990.
(26) Rodrigues, F.; Canac, Y.; Lubineau, A. Chem. Commun. 2000,
2049-2050.
(27) Misra, A. K.; Agnihotri, G. Carbohydr. Res. 2004, 339, 1381-
1387.
(28) Saaby, S.; Bayo`n, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem.
2002, 67, 4352-4361.
J. Org. Chem, Vol. 72, No. 16, 2007 6031

Bartoli et al.
FIGURE 2. Amount of SiO2 influences the efficiency of the reaction.
solvents needed.32 Although SiO2 was originally introduced as
only a support, kinetic studies have revealed that it not only
acts as a carrier to increase the surface area as intended but
also enhances the rate constant33 for the Garcia Gonzalez
reaction. It is known that the silanol groups on the silica surface
might affect the activity of the immobilized catalyst,34,35 and in
fact, the CeCl3·7H2O-NaI system supported on SiO2 gives a
better yield of the adduct than in an unsupported system. This
is possibly due to the interaction between the cerium(III) site
of the catalyst with the silanol groups of the uncapped silica
surface changing the environment of the catalyst active site.
The CeCl3·7H2O-NaI system is also more well-dispersed
throughout the porous support and better separated from each
other.36 This shows that SiO2 functions as an activator for CeCl3·
7H2O-NaI Lewis acid system as well as support. Whereas its
high performance as a support has been well documented, the
fact that SiO2 works as a good activator for our CeCl3·7H2O-
NaI system has often been overlooked. We have argued that
the function of SiO2 as an activator stems from a very probable
electronic interaction between a catalytically active cerium(III)
species and hydroxyl or even oxide groups at surface of SiO2.
Then, the treatment of CeCl3·7H2O-NaI system with SiO2 might
lead to the formation of a supported cerium(III) salt in which
the cerium atom is grafted to the surface via one covalent bond
(≡SIO-Ce)37 and mass balance analysis is in progress in our
laboratories to investigate this possibility. Consequently, this
interaction may reduce the LUMO energy of cerium(III)/SiO2,
and this one is lower in energy than the LUMO of cerium(III).
Given that the strength of a Lewis acid is related to the energy
of its LUMO in such as way that the lower the LUMO energy,
the easier its interaction with a base molecule, we believe that
the Lewis acidity of cerium(III) salt is considerably increased
by incorporation of the lanthanide in the framework of SiO2.
In its absence, the reaction of Garcia Gonzalez affords low yields
of adduct 5aa with longer reaction times, which do not improve
the conversion, because the competitive decomposition of dicar-
bonyl compound begins to be important. Even the amount of
SiO2 is decisive for completion of this type of Garcia Gonzalez
reaction (Figure 2). The results indicate that 0.5 g/mmol of
carbohydrate is the most appropriate ratio, and the use of an
excessive amount of silica gel (more than 0.5 g/mmol) causes
a significantly lower yield of furan derivative 5aa. Analogously,
a decrease in the amount of SiO2 leads to the partial recovery
of the starting material even when the reaction time is prolonged.
The fact that our methodology is clean and the adduct 5aa
has been obtained in high yield without formation of any side
products normally observed under the influence of strong acids
does not exclude the existence in the solid promoter of a
distribution of sites that may contain simultaneously Bro¨nsted
and Lewis sites.38 In fact, according to Spencer’s study,39
investigations aimed at confirming the effective catalyst do not
preclude the existence of a Bro¨nsted acid-catalyzed pathway in
our procedure. The presence of the weak base 2,6-di-tert-butyl-
4-methylpyridine, which only binds to protons and is unable to
coordinate to metal cerium, due to the bulky tert-butyl groups,40
significantly retards the Garcia Gonzalez reaction. Certainly,
the catalytic activity of the CeCl3·7H2O-NaI Lewis acid is in-
dispensable for promoting new bond-forming reactions and is
related to its ability to form acid-base adducts with either the
nucleophile or the electrophile reagent enhancing its reactivity.
(32) The CeCl3‚7H2O-NaI system dispersed on chromatography silica
gel (Baker analyzed reagent with particle size distribution 30-60 µm) was
prepared by simply mixing both reagents in acetonitrile followed by
complete removal of the solvent; see: Bartoli, G.; Bartolacci, M.; Bosco,
M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J.
Org. Chem. 2003, 68, 4594-4597.
(33) Silica gel is recognized as a powerful activator of lanthanide
diketonate complexes; see: Ciufolini, M. A.; Deaton, M. V.; Zhu, S.; Chen,
M. Tetrahedron 1997, 53, 16299-16312.
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Basset, J.-M. Angew. Chem., Int. Ed. 2003, 42, 156-158.
(35) For selected reviews on silica-supported catalysts, see: (a) Fau, Q.-
H.; Li, Y.-M.; Chan, A. S. C. Chem. ReV. 2002, 102, 3385-3466. (b) De
Vos, D. E.; Dams, M.; Sets, B. F.; Jacobs, P. A. Chem. ReV. 2002, 102,
3615-3640.
(36) Huh, S.; Chen, H.; Wiench, J. W.; Pruski, M.; Lin, V. S.-Y. Angew.
Chem., Int. Ed. 2005, 44, 1826-1830.
(37) Zapilko, C.; Widenmeyer, M.; Nagl, I.; Estler, F.; Anwander, R.;
Randschl-Sieber, G.; Groeger, O.; Engelhardt, G. J. Am. Chem. Soc. 2006,
128, 16266-16276.
(38) (a) Boronat, M.; Corma, A.; Renz, M.; Viruela, P. M. Chem. Eur.
J. 2006, 12, 7067-7077. (b) Corma, A.; Garcia, H. Chem. ReV. 2003, 103,
4307-4366. (c) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116,
1561-1562.
(39) Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10,
484-493.
(40) For the use of 2,6-di-tert-butyl-4-methylpyridine, see: (a) Barrett,
A. G. M.; Braddock, D. C.; Henschke, J. P.; Walker, E. R. J. Chem. Soc.,
Perkin Trans. 1 1999, 873-878. (b) Hollis, T. K.; Bosnich, B. J. Am. Chem.
Soc. 1995, 117, 4570-4581.
6032 J. Org. Chem., Vol. 72, No. 16, 2007

SiO2-Supported CeCl3·7H2O-NaI Lewis Acid Promoter
Extending this procedure to reactions of a variety of aldohex-
oses with different â-dicarbonyl compounds, good to excellent
yields of the corresponding polyhydroxyalkyl furan derivatives
have been realized (Table 2, entries 1-10). The success of the
reaction is independent of the type of hexoses used with the
results that are comparable to those of pentoses reported in the
literature.28 Workup is very easy, the hydroxyl groups did not
require prior protection,41 and the avoidance of harsh conditions
for deprotection permits compatibility with a wide range of
functional groups. However, the column chromatography cannot
be avoided because we always observe the formation of traces
of unwanted hydroxytetrahydrofuranyl furan (type 4) as byprod-
uct. The reaction works well with 1,3-dione and â-keto esters,
and by screening a range of 1,3-dicarbonyl compounds in the
reaction with D-glucose, we have observed that with R-benzoil
carbonyl compound the Garcia Gonzalez adduct is obtained in
very modest yield (Table 2, entry 6). In fact, for steric and
electronic reasons the formation of the product 5ag is not
observed at 50 °C after 36 h, so we have increased the
temperature of the reaction to 75 °C obtaining a very low yield
(25%). Under these conditions, a competitive decomposition
of dicarbonyl compound begins to be important. To avoid the
necessity of using too elevated temperatures, we attempted to
favor the homogenization of the reagents by adding the
carbohydrate and the dicarbonyl compound to the CeCl3·7H2O-
NaI mixture in acetonitrile, allowing it to stir for 0.5 h, and
then removing the solvent. In this way, we have succeeded in
getting an increase of the yield to 40%, and this indicates a
limitation of the methodology. Furthermore, while ethyl â-keto
esters (Table 2, entries 2, 4, 7, and 9) work well as substrates,
in the case of the tert-butyl analogue (Table 2, entry 5), a
significantly different result occurs during the course of the
reaction. We have, in fact, purified the desired product in
moderate yield. By analysis of the reaction mixture, besides
the presence of polyhydroxyalkyl furan 5ae and traces of double-
cyclized byproduct, we observe the formation of a â-C-
glycosidic ketone 8 that accounted for 36% of the reaction. This
result prompted us to propose the mechanism in Scheme 2.
Initially, the tert-butyl â-keto ester 2e adds to the aldehyde
moiety of the D-glucose, and the CeCl3·7H2O-NaI system in
this case acts as a Lewis acid promoter of a Knoevenagel
condensation.10a Under the reaction conditions, deprotection of
tert-butyl ester 5 is promoted by our system7a,42 for providing
keto acid derivative 6. Then, a decarboxylation occurs spontane-
ously during the reaction, and finally, an intramolecular Michael
reaction promoted by our CeCl3·7H2O-NaI system43 would give
the â-C-glycoside target.44 Given that these â-C-glycosides are
useful building blocks for the synthesis of various type of natural
products and as potential enzyme inhibitors, the possibility to
obtain â-C-glycosidic ketones with better yields in one step
directly from the unprotected sugar is currently under investiga-
tion in our laboratories.
With this new finding of important advances in the Garcia
Gonzalez reaction promoted by the CeCl3·7H2O-NaI system,
we decided to explore the mechanistic role of NaI in enhancing
the Lewis acid activity of cerium trichloride. In contrast to
Bro¨nsted acidity, it is very difficult to define and quantify Lewis
acidity.37 The trivalent cerium shows a strong affinity toward
hard bases.6 The formation of an adduct implies that an electron
density transfer from the donor to the Lewis acid acceptor occurs
which is directly proportional to the energy difference and
degree of overlap between the occupied orbitals of the base and
the empty orbitals of the acid. In this process of Lewis acid
activity, modification of electronic levels of the metal by
adsorption of a molecule on the metal center should be taken
into account. Consequently, the Lewis acid activity of CeCl3·
7H2O depends not only on the properties of the isolated acid
site but also on the changes caused by its interaction with an
iodide source additive, such as NaI. The central question
concerning the mechanism is whether our optimized Garcia
Gonzalez reaction occurs through a heterogeneous or homoge-
neous promoting pathway. In a heterogeneous manner, the
reaction takes place predominantly on the cerium salt surface
and not in the solution phase; therefore, the reaction would occur
inside the pores of the silica gel. This mechanism would lead
to a complete recovery of our system because leading into the
solution phase would not occur. Under homogeneous conditions
with a heterogeneous promoter, the reaction takes place in the
solution phase with cerium species that are leaded from the solid.
In order to determine if the CeCl3·7H2O-NaI system is acting
in a heterogeneous or homogeneous form, we have performed
this interesting experiment. We have stopped the reaction of
D-glucose (1.0 equiv) with â-dicarbonyl compound 2a (1.3
equiv) in the presence of CeCl3·7H2O (0.3 equiv), NaI (0.3
equiv) supported on SiO2 after the formation of approximately
50% of the product 5aa. Then, after filtration of the heteroge-
neous materials using acetonitrile as solvent, we have allowed
the reaction to continue in the filtrate under the same reaction
conditions (Table 1, entry 6). We later found that the reaction
is completely stopped. This observation led us to conclude that
the reaction takes place via a heterogeneous pathway because no
active-promoting cerium species have been present in solution.
Having established what appeared to be the promoting
pathway of the solid CeCl3·7H2O-NaI system, we switched our
attention to the water of crystallization in the cerium(III) salt.
It seemed appropriate to investigate if the amount of water
present in the reaction mixture might vary the yield of Garcia
Gonzalez adduct.45 Therefore, we carried out a systematic study
on the influence of the amount of water on the reaction rate by
drying CeCl3·7H2O46 before using it supported on dry silica gel47
and then adding water in known amounts to the reaction mixture
(Scheme 3). We analyzed the conversion of 1a in polyhydroxy-
alkyl furan 5aa in the presence of increasing amounts of added
water.
With <1 equiv of water, decreased activity was observed,
and the rate dropped dramatically. On the other hand, with 4
equiv of water, essentially identical results were obtained as
(41) O-Benzyl protection is a standard strategy in syntheses of carbo-
hydrate derivatives; see: Haines, A. H. AdV. Carbohydr. Chem. Biochem.
1976, 33, 11-109.
(42) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2001, 66, 4430-4432. (b) Bartoli, G.;
Bellucci, M. C.; Bosco, M.; Massaccesi, M.; Marcantoni; E.; Petrini, M.;
Sambri, L. J. Org. Chem. 2000, 65, 4553-4559.
(43) (a) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.;
Massaccesi, M.; Torregiani, E. J. Org. Chem. 2005, 70, 169-174. (b)
Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri, L.; Torregiani,
E. J. Org. Chem. 2001, 66, 9052-9055.
(44) Howard, S.; Withers, S. G. J. Am. Chem. Soc. 1998, 120, 10326-
10331.
(45) In some reactions promoted by the CeCl3‚7H2O-NaI system, the
presence of water in the reaction mixture is essential; for instance, see:
Bartoli, G.; Giovannini, R.; Giuliani, A.; Marcantoni, E.; Massaccesi, M.;
Melchiorre, P.; Sambri, L. Eur. J. Org. Chem. 2006, 1476-1482 and
references cited therein.
(46) Imamoto, T.; Takeda, N. Org. Synth. 1998, 76, 228-238.
(47) Hoffmann, F.; Cornelius, M.; Morell, J.; Fro¨ba, M. Angew. Chem.,
Int. Ed. 2006, 45, 3216-3251.
J. Org. Chem, Vol. 72, No. 16, 2007 6033

Bartoli et al.
TABLE 2. Reaction of Aldohexoses (3) with â-Dicarbonyl Compounds (2) Promoted by CeCl3·7H2O-NaI System on SiO2 Under Solvent-Free
Conditions
a All products were identified by their IR, NMR, MS, and elemental analysis. b All yields refer to pure isolated compounds. c No selectivity was obtained,
and a mixture other the furan trisubstitute regioisomer was isolated. d Formation of the corresponding â-C-glycosidic ketone has been observed in 36%
yield.
6034 J. Org. Chem., Vol. 72, No. 16, 2007

SiO2-Supported CeCl3·7H2O-NaI Lewis Acid Promoter
SCHEME 2. Proposed Mechanism for Formation of â-C-Glycosidic Ketone of Type 8
SCHEME 3. Yield Effect of Water on the Garcia Gonzalez
Reaction Promoted by CeCl3·7H2O-NaI-SiO2
find explanation in its coordination, which simplifies the
disaggregation of the crystal lattice of cerium salt and might
lead to a notable increase in the Lewis acidity of the cerium
available at the particle surface.53
The results have established that the choice of hydrated
cerium(III) salt plays a crucial role in the ability of the CeCl3·
7H2O-NaI system supported on SiO2 to promote the Garcia
Gonzalez reaction. We have attempted a similar reaction in the
presence of silica gel and NaI without using CeCl3·7H2O. The
reaction was not successful, and the starting materials remained
intact. We have also noted that in the absence of NaI the
procedure with CeCl3·7H2O on SiO2 does not afford the adduct
5 in the typical reaction conditions. Undoubtedly, the presence
of NaI is also essential for allowing the efficient preparation of
polyhydroxyalkyl furan derivatives 5 by reaction of aldohexoses
with â-dicarbonyl compounds. These findings suggest that the
CeCl3·7H2O-NaI combination leads to a more powerful Lewis
acid. We therefore set about identifying the nature of the Lewis
acid generated from a 1:1 mixture of CeCl3·7H2O and NaI by
NMR spectroscopy. For this we tried to study the complexation
of substrate 1a with CeCl3·7H2O and with a CeCl3·7H2O-NaI
combination. Unfortunately, no identifiable species could be
discerned from the 1H NMR and 13C NMR, due, very probably,
to the presence of paramagnetic Ce(III) species.54
with the cerium salt heptahydrate. The same reaction rate was
obtained with 7 and 10 equiv of water. It is worth noting that
not only does our Lewis acid perform best in the presence of
water,48 but also its promoting activity is amplified by the water.
This effect is taken as a proof-of-principle that substrate
interaction cerium(III) Lewis acid species and water are not
mutually exclusive.49 To obtain further evidence for this effect,
we have carried out the reaction by adding D2O instead of
H2O,50 given that D2O has a higher viscosity that makes mixing
more difficult and reduces the hydrophobic effect.51 The first
results indicate a decrease in the reaction rate, but this isotopic
effect can be only speculative because the transformation is
performed on SiO2, which naturally contains a lot of water as
well as Si-OH functions. Therefore, the D2O could become a
trace amount highly diluted with H2O; other kinetic experiments
in support of this are in progress. However, the remarkable
observed ability of water to generate more active species52 can
The acceleration effect caused by addition of NaI to CeCl3·
7H2O might be rationalized by an halogen exchange reaction55
that leads to more strong Lewis acid (eq 1). But hydrated CeI3
CeCI3 + n NaI n)1-38 CeCI(3-n)In + n NaCI
(1)
(48) Catalysis in water depends on the ability of the catalysts to tolerate
water on one hand and to remain active on the other hand; see: (a)
Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209-217. (b)
Bosnich, B. Aldrichim. Acta 1998, 31, 76-83.
(49) This hydrophobic amplification concept is marvelously rationalized
in: Narayau, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275-3279.
(50) Kleiner, C. M.; Schreiner, P. R. Chem. Commun. 2006, 4315-4317.
(51) (a) Graziano, G. J. Chem. Phys. 2004, 121, 1878-1882. (b)
Graziano, G. Chem. Phys. Lett. 2004, 396, 226-231.
(52) For the coordination chemistry of lanthanide halide, see: Evans,
W. J.; Feldman, J. D.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 4581-
4584.
(53) Glinski, J.; Keller, B.; Legendziewicz, J.; Samela, S. J. Mol. Struct.
2001, 59-66.
(54) (a) Alessandrini, S.; Bartoli, G.; Bellucci, M. C.; Dalpozzo, R.;
Malavolta, M.; Marcantoni, E.; Sambri, L. J. Org. Chem. 1999, 64, 1986-
1992. (b) Hubert-Pfalzgraf, L. G.; Machado, L. Polyhedron 1996, 15, 545-
549. (c) Stecher, H. A.; Sen, A.; Rheingold, A. L. Inorg. Chem. 1989, 28,
3280-3282.
J. Org. Chem, Vol. 72, No. 16, 2007 6035

Bartoli et al.
alone shows an activity only slightly superior to that of CeCl3·
7H2O and significatively lower than that the CeCl3·7H2O-NaI
system.56 Moreover, the system CeCl3·7H2O-3NaI is less
efficient than a 1:1 combination, so that the iodide ion is not
active as a promoter whereas cerium is. Certainly, this 1:1
combination of CeCl3·7H2O and NaI might give CeCl2I·7H2O,
which might be a more powerful Lewis acid than CeCl3·7H2O
parent. All of the efforts into structural characterization of this
complex CeCl3-nIn have been unsuccessful. For understanding
the mechanistic role of NaI we have analyzed the interaction
between CeCl3·7H2O with NaI on SiO2 by X-ray photoelectron
spectroscopy. This provides a valuable technique to quantify
the chemical surroundings of the probed atom by means of the
analysis of the chemical shift in the core level binding energies.58
Fundamental reasons for this are the inherent element specificity
of the element specific core level binding energies. Another
reason is the sensitivity both to the amount of the element
present and its localization at the surface, the latter characteristic
caused by the short mean free path of low energy (30-1000
eV) photoelectrons in the solids. Insulating rare-earth trihalides
like CeCl3 are wide gap in the trivalent state.59 Such systems
show interesting double peak structures in the 3d core-level
spectra with the two peaks showing dramatic changes depending
on the halide element. This is a final state because in the two
different screenings a shoulder at lower binding energy is
observed.60 We have started from a belief that CeCl3 is a rare-
earth trihalide whose initial state is f1 (Ce ) [Xe]4f15d16s2), as
no promotion of f electron is required for a trivalent bonding
with chlorine. Nevertheless, in the final state the charge-transfer
energy defined as the energy required to take an electron from
the ligand p level to the unoccupied 4f level (about 9.7 eV)61
(f2V) is less than the value of the 4f-core hole Coulomb attraction
(12.2 eV). This led to an f2V satellite (where V is the hole in the
valence) at about 3.4 eV lower binding energy. The intensity
and energy of this satellite are sensitive to the degree of
hybridization of the f states with the conduction states.62 Even
if the XPS spectra63 were unable to determine the coordination
environment of the Ce(III) ion because we do not observe a
variation within few percent in the intensity of the f2 satellite,
the results suggest that there is no direct interaction between
the cerium(III) site and the iodide ion. The activity of the CeCl3·
7H2O-NaI system is mainly exerted in the heterogeneous phase,
and above all, we believe that a chloro-bridged oligomeric
structure64 of CeCl3·7H2O is easily broken by donor species such
as the iodide ion. The resulting monomeric CeCl3·7H2O-NaI
complex is a more active Lewis acid promoter.
3. Conclusion
In conclusion, our procedure represents another example of
how the CeCl3·7H2O-NaI system promotes new bond-forming
reactions in solvent-free conditions, such as the popularly known
Garcia Gonzalez reaction, which provide a simple and conve-
nient methodology for the synthesis of densely functionalized
molecules. At the end of these investigations it is clear that
incorporation of NaI in the most common starting material for
cerium complexes as such as CeCl3·7H2O results in remarkable
improvements of key Lewis acid activity. Moreover, the study
provides the first experimental evidence that the origin of the
enhanced activity of the CeCl3·7H2O-NaI system is not due to
a halogen exchange reaction, as it has been observed with other
metal ions.65 Further work is in progress in our laboratories to
study other nucleophiles that may enhance the electrophilicity
of Lewis acidic promoter by disaggregation of oligomeric
structures. Moreover, we are currently expanding our procedure
to cover other synthetically useful organic chemistry processes
which are Lewis acid catalyzed because the use of catalytic
promoters to minimize waste has become a demanding challenge
for chemists when atom economy and green chemistry are
considered.
4. Experimental Section66
General Procedure for the Garcia Gonzalez Reaction (5aa).
Silica gel (0.5 g) was added to a mixture of CeCl3·7H2O (0.113 g,
0.3 mmol) and NaI (13.4 mg, 0.3 mmol) in acetonitrile (7 mL),
and the mixture was stirred overnight at room temperature.
D-Glucose (1a) (0.18 g, 1.0 mmol) was added, and the reaction
mixture was then stirred at room temperature for 1 h. The
acetonitrile was removed by rotary evaporation and to the resulting
powder was added 2,4-pentandione (2a) (0.17 mL, 1.3 mmol). Then,
the mixture was mechanically stirred at an external temperature of
50 °C until the disappearance of the starting aldehexose (22 h,
checked by TLC analysis). After addition of methanol (15 mL),
the mixture was passed through a short pad of Celite and the filtrate
was concentrated under reduced pressure. The crude was purified
by flash chromatography on a silica gel column (eluent, dichlo-
romethane-ethyl acetate, 90:10) to give 0.26 g (95% yield) of the
corresponding Garcia Gonzalez adduct 5aa.
Acknowledgment. We are grateful to Dr. Francesco D’Amico
performing XPS measurements and are also grateful to Dr.
Gianni Rafaiani for NMR experiments. This work was carried
out under the framework of the National Projects supported by
the MIUR (PRIN 2004 and 2006), Rome, by Azioni integrated
Italia-Spagna 2007, MIUR, Rome, and by the University of
Camerino. We thank Pfizer Ascoli Piceno Plant and Teuco
Guzzini Montelupone for funding doctoral fellowships to M.P.
and G.F., respectively. Mr. Franco Lupidi is also gratefully
acknowledged for technical assistance with elemental analysis.
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Ha, T. H.; Kim, D.-W. Tetrahedron Lett. 1994, 35, 1235-1239. (c) Jun,
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(58) Egelhoff, W. E., Jr. Surf. Sci. Rep. 1986, 6, 253-415.
(59) Evans, J. W.; Shreeve, J. L.; Ziller, J. W.; Doedens, R. J. Inorg.
Chem. 1995, 34, 576-585.
Supporting Information Available: Complete experimental
procedures and data on new compounds, copies of NMR on
structures determined, and XPS measurements. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO070384C
(60) Visser, R.; Dorenbos, P.; Andriessen, J.; van Eijk, C. W. E. J. Phys.
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Supporting Information.
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(62) Gunnarsson, O.; Schonhammer, K. Phys. ReV. B 1983, 28, 4315-
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(63) XPS spectra and the relative discussion appear in the Supporting
Information.
6036 J. Org. Chem., Vol. 72, No. 16, 2007