Metal or ammonium alginates as Lewis base catalysts for the 1,2-addition of silyl nucleophiles to carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2012.02.012

Several metal (Na⁺, Ca²⁺) or ammonium (n-Bu ₄N⁺) derivatives of alginic acid, an abundant bio-polymer obtained from the cell walls of brown algae, were synthesized. Their potential to act as organocatalysts to catalyze the 1,2-addition of various silyl derivatives to carbonyl compounds was evaluated for the first time. Ammonium alginate 1h is able to promote the reaction in modest to good isolated yields (up to 98%) affording access to a large range of substrates (β-cyano alcohols or ester, β-substituted methylacrylate or acrylonitrile, and cyanohydrin) by using only 5 mol % of catalyst.

Full text of DOI:10.1016/j.tetlet.2012.02.012

Tetrahedron Letters 53 (2012) 1958–1960
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Metal or ammonium alginates as Lewis base catalysts for the 1,2-addition of
silyl nucleophiles to carbonyl compounds
Cécile Verrier a,b, Sylvain Oudeyer a, , Isabelle Dez b, , Vincent Levacher a
⇑
⇑
a Laboratoire de Chimie Organique Bio-organique Réactivité et Analyse (COBRA), CNRS UMR 6014 & FR 3038, Université et INSA de Rouen, Rue Tesnière,
Mont-Saint-Aignan Cedex 76821-F, France
b Laboratoire de chimie moléculaire et thio-organique (LCMT), CNRS UMR 6507, INC3M, FR 3038, ENSICAEN, Université de Caen, 6 boulevard du Maréchal Juin, Caen 14050-F, France
a r t i c l e i n f o
a b s t r a c t
Several metal (Na+, Ca2+) or ammonium (n-Bu4N+) derivatives of alginic acid, an abundant bio-polymer
obtained from the cell walls of brown algae, were synthesized. Their potential to act as organocatalysts
to catalyze the 1,2-addition of various silyl derivatives to carbonyl compounds was evaluated for the first
time. Ammonium alginate 1h is able to promote the reaction in modest to good isolated yields (up to
98%) affording access to a large range of substrates (b-cyano alcohols or ester, b-substituted methylacry-
late or acrylonitrile, and cyanohydrin) by using only 5 mol % of catalyst.
Article history:
Received 21 December 2011
Accepted 3 February 2012
Available online 11 February 2012
Keywords:
Nucleophilic addition
Carbonyl compounds
Lewis bases
Ó 2012 Elsevier Ltd. All rights reserved.
Organocatalysis
Renewable resources
In the actual economical context, the development of catalytic
processes using cheap catalysts and the use of renewable feedstock
or materials have become a challenging area for synthetic chemists.
To this viewpoint, organocatalysis1 can be considered as a method
of choice and has therefore attracted a lot of attention since the
early 2000’s. Moreover, it is well known that the heterogenization
of the catalysts provided advantages as it allows the rapid isolation
of the product and easy recycling of the catalyst. In recent years,
chemists have investigated the use of biopolymers such as polysac-
charides, which are cheap and widely abundant in nature, as cata-
lysts for organic transformations. As such, chitosan, a marine
polysaccharide derived from chitin, was involved in organometallic
chemistry2 or organocatalytic3 processes as catalyst support or as
the catalyst itself. Surprisingly, alginate salts 1, derived from alginic
acid 2 which is another marine polysaccharide extracted from the
cell walls of brown algae, have been less frequently used in catalytic
processes than chitosan. Indeed, although the physical properties of
metal alginates 1 have been extensively studied4 for biological
purposes,5 their use in catalysis remains limited to metal catalyst
support.6 To the best of our knowledge, no application as organo-
catalyst has been reported in the literature to date. Sodium alginate
In 2007, Mukaiyama7 reported a cyanomethylation reaction8 of
carbonyl compounds 3 with (trimethylsilyl)acetonitrile 4a cata-
lyzed by alkali acetates used as Lewis bases. We postulated that
the carboxylate function of the alginate could act as an efficient
heterogeneous Lewis base catalyst for the addition of 4a to car-
bonyl compounds 3. To check our working hypothesis, we chose
the addition of 4a to benzaldehyde 3a as the model reaction and
commercially available sodium alginate 1a was used as catalyst.9
We were pleased to find out that under our heterogeneous condi-
tions, the reaction proceeded to completion within 5 days but in a
modest 35% isolated yield compared to the 66% yield obtained by
using Mukaiyama’s conditions (Scheme 1).
RO2C
RO2C OH
O
RO2C
OH
O
HO
O
O
O
OH
O
OH
O
HO
O
O
O
OH
RO2C
OH
O
OH RO2C
OH
G
M
M
G
G
Figure 1. Polysaccharidic structure of Na alginate 1a (R = Na) or alginic acid 2
(R = H).
1a constitutes of a sequence of two monomers (b-
D mannuronate
(M) and guluronate (G)) randomly arranged in homogeneous
(MM or GG) or heterogeneous blocks (GM) (Fig. 1).
a
-L
OH
Catalyst
O
TMSCH CN
H+
+
H
(10 mol%)
CN
2
Ph
Ph
DMF, rt
3a
4a
5aa
Mukaiyama's conditions: AcONa, 3h: 66% yield
⇑
Corresponding authors. Fax: +33 (0) 235522962 (S.O.).
E-mail addresses: sylvain.oudeyer@univ-rouen.fr, sylvain.oudeyer@insa-rouen.fr
This work: Na-alginate 1a, 5d: 35% yield
(S. Oudeyer).
Scheme 1. Na-alginate 1a catalyzed cyanomethylation of 3a: Preliminary results.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.012

C. Verrier et al. / Tetrahedron Letters 53 (2012) 1958–1960
1959
1) Amberlyst A26 (OH-)
MeOH, 7h30
3) Alginic acid 2
MeOH, 12h
In an effort to optimize the reaction, we then turned our atten-
tion to the macromolecular structure of alginates. Thus, Ca-algi-
nate hydrogel 1b was prepared from 1a and then dried under
two different conditions, namely either by lyophilization or by
supercritical CO2 drying process to furnish Ca-alginates 1c and
1d respectively. Then, cross-linked Na-alginate (glutaraldehyde10
as a cross-linker) was obtained and dried under the same condi-
tions as those described previously to give 1e and 1f. Finally, a
weak gel structure of Na-alginate was prepared by the precipita-
tion of a solution of 1a in acetone: this particular structure named
Na-alginate acetogel 1g was used without drying step. All these
metal alginates were evaluated in the model reaction (Table 1).
Among all the alginates tested, Na alginate acetogel 1g fur-
nishes the best yield with a catalytic amount of catalyst (entry
6). The catalyst can be recovered and reused twice without any loss
of catalytic activity nevertheless a drop of the yield is observed
after 3 cycles (entry 6, 29% vs 44%). One could expect some chiral
induction from alginates which display a chiral backbone. Unfortu-
nately, only racemic products were formed whatever the catalyst
used. It is noteworthy that despite a quantitative transformation
of the starting materials observed in most cases, only poor isolated
yield not exceeding 54% was obtained (even when 3 equivalents of
benzaldehyde where used) probably due to a possible trapping of
the aldehyde within the polymeric matrix. Accordingly, this phe-
nomenon severely hampers the potential use of metal alginates
as heterogeneous Lewis base catalysts.
It is well known that quaternary ammonium salts are an effi-
cient phase transfer catalysts (PTC) able to improve the rate or
the efficiency of a solid/liquid reaction.11 We thus postulated that
the association of the insoluble polymeric alginate matrix with a
soluble organic quaternary ammonium could have a positive effect
in terms of catalytic activity by making the resulting ammonium
alginate more soluble. This higher solubility of the catalyst could
have a positive impact on both the rate and the efficiency of the
reaction. A similar strategy has already been successfully applied
to the alkylation of glycine derivatives catalyzed by polymer sup-
ported chiral quaternary ammonium sulfonates or carboxylates.12
First, we synthesized tetra-n-butylammonium alginate 1h by using
a resin exchange process previously reported by Mukaiyama for
the preparation of chiral ammonium phenoxides13 (Scheme 2).
Ammonium alginate 1h was used as an organocatalyst in our
model reaction (see Table 1) at rt in DMF and we were pleased
to observe the formation of the desired product 5aa in higher yield
R4N+Br-
Alginate-CO2- R4N+
1h
R4N+OH-
2) Filtration
4) Evaporation
, R = nBu
with toluene (x3)
Scheme 2. Preparation of tetra-n- butylammonium alginate 1h.
(ie 77%) than those that could be obtained previously with metal
alginates 1a–g (Table 1). After the optimization of the reaction
parameters, we were able to reach 88% isolated yield by perform-
ing the reaction at rt in toluene. Then, the scope and limitation of
this method was studied using the following general conditions at
room temperature (Table 2).
The general trend regarding the different substrates 3a–o
evaluated reveals that aromatic aldehydes 3a–k furnished higher
Table 2
1,2-addition of 4a to carbonyl compounds 3a–o catalyzed by 1h
1) 1h (5 mol%)
R1
O
rt, toluene, 24h
R2 OH
CN
TMSCH CN
+
2
+
CN
R1
R2
R2
2) HCl 1M, MeOH R1
3a-o
4a
5aa-oa
6ia;ka
(1 equiv) (1.4 equiv)
Entry
3
R1
R2
5: Yield (%)a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
5aa:88
5ba:95
5ca:58
5da:64
5ea:75
5fa:80
5ga:63
5ha:65
5ia:5c
5ja:76
5ka:75d
5la:25
5ma:35
5na:22
5oa:26e
4-NC-C6H4
2-NC-C6H4
4-F3C-C6H4
4-MeO2C-C6H4
4-Cl-C6H4
4-F-C6H4
4-MeO-C6H4
2,4,6-(MeO)3-C6H2
3-Pyridyl
9b
10
11
12
13
14
15
3j
3k
3l
3m
3n
3o
2-Thiophenyl
–(CH2)2–C6H5
–tBu
C6H5
C6H5
(E)-CH@CH-C6H5
a
b
c
Unless otherwise stated, only the addition product 5 was observed.
A maximum 70% conversion was reached.
The compound 6ia was obtained in a 57% yield as a E/Z ratio of 21/79 (deter-
mined by 1H NMR analysis).
d
The compound 6ka was obtained in a 17% yield as a E/Z ratio of 70/30 (deter-
mined by 1H NMR analysis).
e
The 1,4-addition product was isolated in a 12% yield.
Table 1
1,2-addition of 4a–3a catalyzed by metal alginates 1b–g
1) M-alginate 1b-g (X mol%)
OH
O
DMF, rt
CN
+
TMSCH2CN
Ph
Ph
H
2) HCl 1M, MeOH
3a
(1 equiv)
4a
5aa
(1.4 equiv)
Entry
1
Alginate (Metal)
Form
X (mol %)
Time
Conva (%)
5aa Yield (%)
1c (Ca)
Freeze-dried
100
10
10
100
100
100
100
10
3d
3d
3d
2d
6d
4d
2d
2d
100
100
93
13
100
—
38
26
10
—
51
—
22
2
3
4
5
6
1d (Ca)
1b (Ca)
1eb (Na)
1fb (Na)
1g (Na)
SC–CO2 dried
Hydrogel
Freeze dried
SC–CO2 dried
Acetogel
100
100
44
29c
54d (27)e
Measured by GC and/or 1H NMR analyses.
Alginate was cross-linked with glutaraldehyde.
Yield obtained after 3 cycles.
10% Vol. of acetone in DMF was used.
Reaction performed with 3 equiv of PhCHO.
a
b
c
d
e

1960
C. Verrier et al. / Tetrahedron Letters 53 (2012) 1958–1960
Table 3
5 mol % of catalyst) for the formation of various addition products
5 or addition-elimination products 6 and 7 in modest to good
yields. These promising results show the great potential of such
natural-occurring catalysts to be a plausible alternative to usual
synthetic catalysts. Further investigations on the use of alginate
derivatives as chiral organocatalysts or support of chiral organocat-
alysts are under way in our laboratory.
1,2-addition of various silyl derivatives 4b–e to aromatic aldehydes 3 catalyzed by 1h
1) 1h (5 mol%)
OH
O
CO2Me
7ib
5: Yield (%) 7:Yield (%)
rt, toluene
or
+
TMS-Y
(1.4 equiv)
4b-e
Ar
Ar
Y
2) HCl 1M
Ar
H
MeOH
5
3
Entry 3: Ar
4:Y
1
2
3
4
5
6
7
8
3a:C6H5
4b:CH2CO2Me
5ab:49
—
—
3i:2,4,6-(MeO)3-C6H2 4b:CH2CO2Me
3a:C6H5
3b: 4-NC-C6H4
3h: 4-MeO-C6H4
3p: 2-MeO-C6H4
3a:C6H5
7ib:69a
Acknowledgments
4c:CN
4c:CN
4c:CN
4c:CN
4d:CF3
5ac:98
5bc:78
5hc:61
5pc:96
5ad:42b
—
—
—
—
—
—
This work was supported by the CNRS, University of Caen and
Rouen and INSA of Rouen, ENSICAEN, the région Haute-Normandie
and the région Basse-Normandie. C. V. thanks the INC3 M (FR3038)
for a Grant.
3a:C6H5
4e:2-furanyloxy 5ae:65c
a
b
c
A E/Z ratio of 88/12 was determined by 1H NMR analysis of the crude product.
Reaction performed in DMF.
A anti/syn ratio of 75/25 was determined by the comparison of the chemical
Supplementary data
shift of H-3 with the 1H NMR data reported in the literature.14
Supplementary data (general informations, procedure for the
preparation of alginate materials 1, spectral data for tetra-n-butyl-
ammonium alginate 1h, general procedures and copies of NMR
spectra for compounds 5, 6 and 7) associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2012.02.012.
isolated yields than aliphatic aldehydes 3l–m and ketones 3h–o
(entries 1–11 vs 12–15). It is worth noting that aromatic aldehydes
bearing both electron-withdrawing and -donating groups afforded
the various addition products 5 in good to excellent yields, except
for the more sterically hindered aldehyde 3i (entry 9) for which the
desired product 5ia was obtained in a rather low yield along with
the formation of the acrylonitrile derivative 6ia resulting from an
addition-elimination sequence. Heteroaromatic aldehydes 3j–k
gave the corresponding addition products 5j–k in 76% and 75%
yields respectively (entries 10–11).
The addition of various silyl derivatives 4b–e to aromatic alde-
hydes 3 was also assessed under the conditions reported in Table 3.
When methyl(trimethysilyl)acetate 4b was allowed to react
with 3a, the addition product 5ab was obtained in modest yield
(entry 1). More interestingly, the use of 3i instead of 3a leads
exclusively to the formation of methyl cinnamate derivative 7ib
in a 69% yield (entry 2). The synthesis of cyanohydrins 5ac;bc;
hc;pc was also achieved in good to quantitative yields by using
TMSCN 4c as pro-nucleophile (entries 3–6). The trifluoromethyla-
tion of 3a using the Ruppert-Prakash reagent 4d afforded the cor-
responding addition product 5ad in a modest 42% yield (entry 4).
At last, a vinylogous Mukaiyama aldol reaction was performed by
using 2-trimethylsilyloxyfuran (TMSOF) 4e. The addition product
5ae was obtained in a 65% yield as a 75/25 mixture of anti/syn
diastereomers.
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