Applications of lanthanide trichloride hydrates, prepared from mischmetall, in the Biginelli reaction

Article abstract of DOI:10.1055/s-2007-992387

An inexpensive alloy of light lanthanides, called mischmetall, has been used in the preparation of a mixture of lanthanide trichloride hydrates. The use of this new type of material is described in Biginelli reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992387

LETTER
105
Applications of Lanthanide Trichloride Hydrates, Prepared from
Mischmetall, in the Biginelli Reaction
Use of
L
nC
l
·7H
O
2 inathe Biginel
r
R
eacti
i
3
Laboratoire de Catalyse Moléculaire CNRS, ICMMO, Bât 420, Université Paris-Sud, 91405 Orsay, France
Fax +33(1)69154680; E-mail: flohelion@icmo.u-psud.fr
Received 6 July 2007
These multicomponent reactions (MCRs), unexplored un-
til the 1980s, have attracted considerable attention over
the past decade, since dihydropyrimidin-2(1H)-ones and
their derivatives were found to display a fascinating array
of pharmacological and therapeutic properties.3 DHPMs
have been developed as antiviral, antibacterial or antihy-
pertensive agents, a1a-antagonists, neuropeptide Y (NPY)
antagonists or potent calcium channel blockers. More-
over, recently marine alkaloids have been isolated that
contain a dihydropyrimidinone-5-carboxylate core (the
batzelladine alkaloids), and these alkaloids were found to
be potent HIV gp-120-CD4 inhibitors.4
Abstract: An inexpensive alloy of light lanthanides, called misch-
metall, has been used in the preparation of a mixture of lanthanide
trichloride hydrates. The use of this new type of material is de-
scribed in Biginelli reactions.
Key words: mischmetall, lanthanide trichlorides, Biginelli-type re-
action
We have reported, in a preceding letter,1 a simple method
for the preparation of a mixture of lanthanide trichloride
hydrates directly from mischmetall and hydrochloric acid
(Scheme 1). We used this new reagent in stoichiometric
amounts in the Luche-type reduction to prepare allylic al-
cohols or allyl alkyl ethers. Results showed that misch-
metall trichloride hydrates were as efficient as cerium
trichloride hydrates.
The initial one-pot Biginelli procedure, catalyzed by hy-
drochloric acid in ethanolic solution, suffers from major
drawbacks such as long reaction times and low yields, es-
pecially when aliphatic and substituted aromatic alde-
hydes are used. Recently, growing interest in MCRs and
the elucidation of the mechanism of the Biginelli reaction
have been combined to considerably improve the efficien-
cy of the reaction. Various strategies have been developed
to overcome problems: among these are multistep syn-
thetic strategies,5 improvement of the one-pot procedure
using acidic clay,6 ionic liquids,7 microwave irradiation
under solventless conditions8 or catalysis using Lewis ac-
ids (BiCl3, BF3·OEt2–CuCl/H+, InCl3).9 Lanthanide com-
plexes have also proved to be efficient catalysts in the
Biginelli-type reaction: asymmetric synthesis of dihydro-
pyrimidin-2(1H)-ones has been demonstrated using CeCl3
or Ln(OTf)3 (Ln = La, Sm or Yb)10 with chiral ligands and
original processes such as parallel synthesis using solid-
supported ytterbium(III).11 Cerium(IV) ammonium ni-
trate has also been used as a catalyst.12 In this field, lan-
thanide complexes are very interesting since these mild
Lewis acids are environmentally friendly (LaCl3·7H2O)13
and some of them can easily be recycled [Ln(OTf)3].14
Nevertheless, many of these methods involve expensive
reagents; therefore, we wish to report the direct synthesis
of 3,4-dihydropyrimidin-2(1H)-ones using lanthanide
trichloride heptahydrates derived from mischmetall. This
inexpensive catalyst can be easily prepared in a one-step
procedure from mischmetall and promotes the Biginelli
reaction under mild conditions (Scheme 3).
H2O, r.t., 30 min
+
LnCl3⋅7H2O + 3/2 H2
Ln
3 HCl
95%
Ln = mischmetall (ingots)
Scheme 1 Synthesis of lanthanide trichloride hydrates from
mischmetall ingots
Herein we wish to report the first use of this new material
as a catalyst. We studied the synthesis of 3,4-dihydropyri-
midin-2-(1H)-ones obtained by a one-pot Biginelli-type
reaction and compared the reactivity of this catalyst with
classically-used trichloride hydrates derived from pure
lanthanide metals.
In 1893, Biginelli reported the first synthesis of 3,4-dihy-
dropyrimidin-2-(1H)-ones (DHPMs) via a one-pot reac-
tion involving aromatic aldehydes, urea (or thiourea) and
ethyl acetoacetate in an ethanolic solution under acidic
conditions (Scheme 2).2
Ph
EtO2C
EtO2C
H+
NH
NH2
Ph
+
+
EtOH, reflux
O
H2N
O
O
H
N
O
H
Scheme 2 Typical Biginelli-type reaction
Evaluation of the efficacy of LnCl3·7H2O in a Biginelli-
type reaction is relevant due to a communication by Lu et
al.13 describing a similar study using lanthanum chloride
(50 mol%/aldehyde) as a catalyst.
SYNLETT 2008, No. 1, pp 0105–0107
Advanced online publication: 03.12.2007
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DOI: 10.1055/s-2007-992387; Art ID: D31007ST
© Georg Thieme Verlag Stuttgart · New York

106
M.-I. Lannou et al.
LETTER
Ar
Table 1 Use of LnCl3·7H2O as Catalyst in Biginelli-Type
Reaction15
EtO2C
LnCl3⋅7H2O
EtO2C
NH2
Ar
NH
(cat.)
+
+
Entry Ar
Y
Catalyst
(equiv)
Product Yield
(%)a
HCl (1 drop),
reflux, 5 h
O
H2N
Y
O
H
N
H
Y
Y = O, S
Ln = mischmetall
1
2
Ph
O
O
S
0.5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.5
0.2
0.5
0.5
1
1
2
3
3
4
5
5
6
6
7
7
8
8
9
92
85
83
84
64b
88
82
36b
83
68b
56
80
31
75
56
Scheme 3 Biginelli reaction catalyzed by lanthanide trichloride hy-
drates
Ph
3
Ph
Our results are presented in Table 1. A test reaction was
carried out with benzaldehyde, urea and ethyl acetoace-
tate; the use of 0.2 equivalent (entry 2) instead of 0.5
equivalent of LnCl3·7H2O (entry 1) did not significantly
affect the yield. In both cases, reaction time could be re-
duced to five hours instead of 18 hours under classical
Biginelli conditions. Furthermore, urea could be easily re-
placed by thiourea (entry 3) without significantly decreas-
ing the yields (entries 2 vs. 3 and 4 vs. 6). Therefore, we
chose to lower the catalyst amount to 20 mol% from 50
mol%.13 Two general cases were observed:
4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-BrC6H4
3-BrC6H4
4-ClC6H4
4-ClC6H4
4-HOC6H4
4-HOC6H4
4-O2NC6H4
4-O2NC6H4
furyl
O
O
S
5
6
7
O
O
O
O
O
O
O
O
O
8
9
10
11
12
13
14
15
1) Benzaldehyde or activated aromatic aldehydes pro-
duced DHPMs in good yields (entries 1–6, 9 and 10), even
with low catalyst loading and in the absence of hydrochlo-
ric acid. However, when the reaction was performed with
p-hydroxybenzaldehyde, it was necessary to increase the
amount of catalyst to obtain the DHPM in good yield (en-
tries 11 and 12); this may be due to catalyst coordination
to the free hydroxyl group. When hydrochloric acid was
not added to the reaction, lower yields were always ob-
served (entries 5, 8 and 10).
a Yields of pure products (after recrystallization).
b The reaction was performed without HCl.
Ar
2) When deactivated aromatic aldehydes were used (en-
tries 7, 8, 13 and 14) yields were lower, but remained sat-
isfactory. However, in these cases, the lack of
hydrochloric acid seemed to have a dramatic influence on
the completion of the reaction (entries 7 and 8).
– H2O
Ar
H
H2N
NH2
N
NH2
+
(LnCl3)
O
A
O
O
LnCl3
A comparison of our results with those published by Lu et
al.13 showed that using a mixture of lanthanide trichlo-
rides instead of lanthanum trichloride heptahydrate did
not significantly affect the yields of DHPMs or reaction
times. We demonstrated that the amount of catalyst could
be lowered to 0.2 equivalent without significantly de-
creasing the yield. In all cases, the reaction was about
three times faster than the original Biginelli reaction and
the yields were improved (classical conditions: catalytic
HCl in EtOH, reflux, 18 h).2,13
Ar
N
NH2
Ln3+
B
O
OH
CO2Et
Ar
Ar
EtO2C
The mechanism of the Biginelli reaction has recently been
revised by Kappe.16 Based on this work we suggest the
following mechanism for the LnCl3·7H2O-catalyzed Big-
inelli reaction (Scheme 4).
– H2O
EtO2C
NH
NH
NH2
N
O
O
O
H
C
D
The first step is the acid-catalyzed condensation of alde-
hyde and urea (or thiourea). The formation of N-acyl imi-
ne intermediate A is the rate-limiting step of the reaction.
The intermediate A is complexed by lanthanide chlorides,
giving B, which acts as an electrophile for the nucleo-
philic addition of the ketoester enol. The resulting adduct
C undergoes condensation with the urea-NH2 to give the
cyclized product D.
Scheme 4 Assumed mechanism for LnCl3·7H2O-catalyzed Biginel-
li reaction
Lanthanide trichloride hydrates prepared from mischmet-
all can be used as catalysts for the Biginelli-type cyclo-
condensation. This method not only preserves the
simplicity of the initial one-pot reaction, but also notice-
ably improves the yields of DHPM and reduces reaction
times.
Synlett 2008, No. 1, 105–107 © Thieme Stuttgart · New York

LETTER
Use of LnCl3·7H2O in the Biginelli Reaction
107
(15) Typical Experimental Procedure for Biginelli Reaction:
A mixture of ethyl acetoacetate (638 mL, 5 mmol), urea (451
mg, 7.5 mmol) or thiourea (571 mg, 7.5 mmol), aldehyde (5
mmol), LnCl3·7H2O (Ln = mischmetall, 373 mg, 1 mmol,
0.2 equiv) and 12 M HCl acid (1 drop) in absolute EtOH (10
mL) was placed under magnetic stirring and refluxed in
EtOH for 5 h. The reaction mixture was then cooled to r.t.
and poured onto an ice-water mixture (25 g). The solution
was stirred for 5 min until a solid appeared. The precipitate
was then filtered and the solid was washed with cold H2O
(2 ×), then with an EtOH–H2O mixture (1:1, 2 ×) and finally
dried under vacuum. The crude product was then purified by
recrystallization in absolute EtOH.
This example is the first example of the use of mischmet-
all trichloride hydrates as catalyst in organic synthesis.
This material could be tested in a wide variety of reactions
involving lanthanide salts as catalyst.
Acknowledgment
We thank University of Paris-Sud and CNRS for their financial sup-
port.
References and Notes
Selected Spectral Data for 6-Methyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid Ethyl
Ester (1): colorless crystals; mp 207–209 °C (lit.8 mp 206–
209 °C); yield: 1.954 g, 92% (cat.: 0.5 equiv); yield:1.106 g,
85% (cat.: 0.2 equiv). 1H NMR (250 MHz, CDCl3): d = 1.16
(t, JCH3–CH2 = 7.1 Hz, 3 H, OEt), 2.35 [s, 3 H, C(6)Me], 4.07
(q, JCH2-CH3 = 7.1 Hz, 2 H, OEt), 5.40 [d, J4,3 = 2.9 Hz, 1 H,
C(4)H], 5.65 [br s, 1 H, N(3)H], 7.31 (m, 5 H, Har), 7.97 [br
s, 1 H, N(1)H]. 13C NMR (62.9 MHz, DMSO): d = 15.0,
18.7, 54.9, 60.2, 100.2, 127.2, 128.2, 129.3, 145.8, 149.3,
153.1, 166.3. FTIR (NaCl, nujol): 3233, 3110, 1728, 1704,
1644, 1378, 1309, 1290, 1232, 1220, 1090, 779, 758, 681
cm–1. GC–MS(electrospray): m/z (%) = 543.3 (89) [2 × M +
Na]+, 315.2 (60), 283.1 (100) [M + Na]+. 4-(4-Methoxy-
phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimi-
dine-5-carboxylic Acid Ethyl Ester (4): colorless crystals;
mp 149–151 °C (lit.17 mp 150–152 °C); yield: 1.347 g, 88%.
1H NMR (250 MHz, CDCl3): d = 1.10 (t, JCH3–CH2 = 7.1 Hz,
3 H, OEt), 2.26 [s, 3 H, C(6)Me], 3.71 (s, 3 H, OMe), 4.00
(q, JCH2–CH3 = 7.1 Hz, 2 H, OEt), 5.28 [d, J4,3 = 2.9 Hz, 1 H,
C(4)H)], 5.80 [br s, 1 H, N(3)H], 6.76 [d, J3¢,2¢ = J5¢,6¢ = 8.6
Hz, 2 H, C(3¢)H, C(5¢)H)], 7.16 [d, J2¢,3¢ = J6¢,5¢ = 8.6 Hz, 2 H,
C(2¢)H, C(6¢)H], 8.26 [br s, 1 H, N(1)H]. 13C NMR (62.9
MHz, DMSO): d = 15.0, 18.0, 54.4, 56.0, 60.5, 101.9, 114.8,
128.5, 136.6, 145.7, 159.7, 166.1, 174.9. FTIR (NaCl,
nujol): 3305, 3161, 3097, 1666, 1574, 1510, 1331, 1270,
1120, 1023 cm–1. GC–MS(electrospray): m/z (%) = 636.2
(25) [(2 × M + 1) + Na]+, 635.2 (68) [2 × M + Na]+, 330.1
(18), 329.1 (100) [M + Na]+, 307.1 (35).
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Synlett 2008, No. 1, 105–107 © Thieme Stuttgart · New York

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