Aldol reactions mediated by a tetrahedral boronate

Article abstract of DOI:10.1039/c2cc37047f

The base is a key factor in aldol reactions in organic media, determining the selectivity. Here, we describe a tetrahedral phenylboronate salt as a mild non-nucleophilic base that is able to catalyse the aldol reaction and significantly decrease the formation of undesired elimination products. This journal is

Full text of DOI:10.1039/c2cc37047f

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Aldol reactions mediated by a tetrahedral boronate†
Tobias Muller, Kristina Djanashvili, Isabel W. C. E. Arends, Joop A. Peters and
¨
Ulf Hanefeld*
Cite this: Chem. Commun.,
2013, 49, 361
Received 28th September 2012,
Accepted 15th November 2012
DOI: 10.1039/c2cc37047f
www.rsc.org/chemcomm
The base is a key factor in aldol reactions in organic media, determining
the selectivity. Here, we describe a tetrahedral phenylboronate salt as a
mild non-nucleophilic base that is able to catalyse the aldol reaction and
significantly decrease the formation of undesired elimination products.
The aldol addition is an important C–C bond forming reaction.1 A
key step in the mechanism is nucleophilic attack of a deprotonated
ketone (enolate) on an aldehyde to form a b-hydroxyketone. Various
inorganic bases, including LiOH, NaOH, Na2CO3 and Ca(OH)2, have
been applied for the initial deprotonation of the ketone.2–5 However,
the base catalyst is often also active in the elimination reaction, the
dehydration of the b-hydroxyketone. Suppression of the aldol elim-
ination is of great interest, as b-hydroxyketones are versatile building
blocks in, for instance, the synthesis of diols, amino alcohols,
lactones and polyketides.6–10
Fig. 1 Molecular structures of the boron-based catalysts discussed.
Boronates are known to mediate aldol reactions by acting both as
an activator and as a template for the reactants, the ketone and the
aldehyde.11–14 An interesting modification is the addition of a highly
reactive trimethyl silyl enol ether to aldehydes in water with sodium
dodecyl sulfate as a surfactant and diarylborinic acid 1 as the catalyst
(Fig. 1).15 More recently, it was shown that the activation of the
ketone as silyl enol ether is unnecessary when salt 2 as the catalyst is
applied (Fig. 1). In this system, which is limited to aqueous solu-
tions, intramolecular interaction of the neighbouring nitrogen and
boron atoms stabilizes the tetrahedral boronate. Side reactions, such
as dehydration, remain a problem; particularly when the reaction is
Scheme 1 The aldol reaction with a series of aldehydes and acetone.
favoured by stabilization of the elimination product as a result of 3,5-difluorophenylboronic acid by reaction with the appropriate
mesomerism. amount of isopropanol and sodium isopropoxide (see Scheme S1,
Here, we report the results of an investigation on the feasibility of ESI†) and were isolated as stable solids with a purity greater than
the application of phenylboronate 4 as a catalyst in aldol reactions in 99%. Both new compounds show good solubility and thermal
organic media (Scheme 1). For comparison, the corresponding stability in organic solvents; they did not show any dissociation as
boronic acid 3 and the classic base sodium isopropoxide were demonstrated by their characteristic 11B NMR chemical shifts for
included in this study. Compounds 3 and 4 were synthesized from trigonal and tetragonal B-atoms, respectively (Fig. S1C and S2C, ESI;†
related to H3BO3 (0.1 M) at 0 ppm). The high stability of these
B-compounds may be ascribed to the electron-withdrawing fluoro-
substituents in the aromatic ring. These substituents also contribute
to the high solubility of these complexes in organic solvents, which
Biokatalyse & Organische Chemie, Gebouw voor Scheikunde, Afdeling
Biotechnologie, Technische Universiteit Delft, Julianalaan 136, 2628BL Delft,
The Netherlands. E-mail: u.hanefeld@tudelft.nl; Fax: +31 15 2781415
allows us to perform the aldol reaction with one of the reactants
acting as solvent. In the present investigation, acetone was used as
† Electronic supplementary information (ESI) available: Material and methods;
NMR and Raman spectroscopy data. See DOI: 10.1039/c2cc37047f
c
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Table 1 The aldol reactions of 2 mmol of 5a and 20 mmol of 6 (see Scheme 1) for
20 min at 30 1C. Conversions and yields are determined by 1H NMR
the solvent and the reactions were monitored by NMR and GC-MS.
To rule out the possible deactivation of the catalyst (4) by water, the
reaction was performed in the presence of equimolar amounts of
it (relative to 4). Neither product formation nor selectivity was
influenced by water.
In the presence of NaOiPr as the catalyst and at 30 1C, benzalde-
hyde (5a) and an excess of acetone (6) reacted very fast to give aldol 7,
which was subsequently dehydrated to a,b-unsaturated ketone 8
with a lower reaction rate (Fig. 2B). The rates of both the aldol
reaction and the elimination reaction appeared to be strongly
dependent on the concentration of the catalyst (Table 1, entries
1–4). In addition to the elimination side product, higher molecular
weight side product 9 resulting from dimerization was observed as
well. Decreasing the temperature to 5 1C did not improve the
Entry 4 (mol%) NaOiPr (mol%) Conv.a (%) Yield 7 (%) Yield 8 (%)
1
2
3
4
5
6
7
8
—
—
—
—
20
10
5
20
10
5
>99
>99
97
13
96
90
39
>99
18
23
40
13
76
80
35
11
57
55
40
o1
8
10
4
2
—
—
—
10
10
45
a
Dimerization side-product, PhCQC(CQO)CQCPh (9) was detected by
GC-MS.
A series of aldehydes was tested in the aldol reaction in the
selectivity towards the desired aldol product (Fig. 2B). Decreasing presence of catalyst 4 (Scheme 1 and Table 2). The reactions
temperature and catalyst concentration at the same time did not proceeded within a few minutes with high conversions. Aromatic
inhibit the elimination reaction either (Fig. S3, ESI†).
aldehydes and furfural, a bio-based platform chemical, all gave rise
Trigonal B-compound 3 (up to 20 mol%) was completely inactive to both aldol adduct 7 and the corresponding dehydration product 8
in the aldol reaction of 5a and 6, which suggests that a base is with a high selectivity towards 7, compared to the results obtained
essential for the reaction to proceed. By contrast, application of with the reported boron catalysts 1 and 2.15,16 The highest selectivity
tetragonal boronate 4 resulted in high conversion to the aldol within was obtained with aliphatic aldehyde 5e: 66% of the b-hydroxy-
a few minutes (Table 1, entries 5–7); the reaction rate towards the ketone 7e and less than 1% of the dehydration product 8e were
aldol was about the same as that with NaOiPr as the catalyst, but formed (Table 2, entry 5). For the aromatic aldehydes conversion,
now the subsequent elimination reaction was much slower. With 20 selectivity to the b-hydroxyketone seems to be related to the nature of
mol% 4, only 8% elimination product was obtained. By decreasing substituents and the bond delocalization. Similar lower yields and
the reaction temperature to 5 1C, similar results were obtained selectivities for 5b and c were observed earlier.15,16
(Fig. 2A). Combining 10 mol% 4 and 10 mol% of NaOiPr resulted in
We suggest a reaction mechanism as depicted schematically in
full conversion of the benzaldehyde. The aldol product was formed Scheme 2. Under the reaction conditions applied, the dissociation of
which was dehydrated by NaOiPr to the condensation product and compound 4 towards ÀOiPr and corresponding 3 is negligible in
some higher molecular weight products resulting from dimerization acetone. This is confirmed by its 11B NMR spectrum, which shows
(Table 1, entry 8).
exclusively a resonance for tetrahedral boron at around À15.49 ppm
(Fig. S4, ESI;† as a standard 0.1 M boric acid solution in D2O at
0 ppm was used). No resonance related to compound 3 was
observed. Since the reaction rate of the aldol reaction, in the
presence of 2 mol% NaOiPr, is much lower than with 20 mol% 4,
it is likely that undissociated 4 rather than isopropoxide is the actual
catalyst in this system (Table 1, entries 4 and 5). After deprotonation
of acetone by 4, the resulting enolate exchanges with iPrOH. The
resulting tetrahedral boron-enolate 10 reacts with the aldehyde to
form the aldol product. In the presence of iPrOH the aldol product 7
is released and the tetrahedral boronate 4 returns into the
catalytic cycle.
The occurrence of an intermediate tetrahedral boronate
with both aldehyde and acetone coordinated to the B-atom, as
Table 2 The aldol reactions of 2 mmol of 5 and 20 mmol of 6 (Scheme 1),
catalysed by 20 mol% of 4 at 30 1C. Conversions and yields are determined by
1H NMR
Entry
R
t (min)
Conv.a (%)
Yield 7 (%)
Yield 8 (%)
1
2
3
4
5
6
a
b
c
d
e
f
20
20
10
5
30
15
96
80
88
95
95
99
76
38
47
52
66
40
8
24
41
o5
o1
21
Fig. 2 Reaction between benzaldehyde and acetone, catalysed by 20 mol% of
boronate salt 4 (A) and sodium 2-propanolate (B), monitored by 1H NMR at 30 1C
(solid data points) and 5 1C (empty data points). The aldol and the elimination
product formation is presented by squares and triangles, respectively.
a
Dimerization side-product, PhCQC(CQO)CQCPh (9), was detected
by GC-MS.
c
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reaction in the aldol formation compared to that when isopropoxide
is applied as the base catalyst.
In conclusion, we present tetrahedral sodium triisopropyl
3,5-difluorophenylboronate (4) as a base, which can catalyse the
aldol reaction. It is soluble in organic media, allowing the use
of a substrate, acetone, as solvent. The reaction proceeds
rapidly, with high conversion and good selectivity towards
b-hydroxyketone. The tetrahedral boronate acts as a base,
suitable to form boron-enolate with acetone, but is not able
to dehydrate the formed aldol.
This research has been performed within the framework of the
CatchBio program. The authors gratefully acknowledge the support
of the Smart Mix Program of the Dutch Ministry of Economic
Affairs and the Dutch Ministry of Education, Culture and Science.
The authors are thankful to L. Panella (DSM), P. Alsters (DSM), J. G.
de Vries (DSM), B. Kaptein (DSM), G. Kemperman (MSD) for fruitful
discussions, and S.A. Kulkarni (TU Delft, P&E/IRS) for the Raman
measurements.
Notes and references
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Scheme 2 Proposed mechanism for the aldol reaction catalysed by tetrahedral
boronate salt 4, including the elimination reaction in the presence of a strong
nucleophilic base, NaOiPr.
suggested by Evans et al. for other B-activated aldol reactions,11 is
unlikely in the present case. 11B NMR spectra of a sample of 4 and
benzaldehyde showed a single resonance at À16 ppm, thus no
coordination of benzaldehyde to 4 (Fig. S5, ESI;† related to 0.1 M
boric acid solution in D2O at 0 ppm). This also rules out the
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In contrast, acetone coordinates to tetrahedral boronate 4, which
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(Fig. S6, ESI†). The latter spectra demonstrate the appearance of an
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and acetone (solid line) compared to the spectra of 4 measured in its
solid form (dashed line). Furthermore, the 11B NMR spectra (inset)
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the only observable resonance was at 8 ppm (related to H3BO3
(0.1 M) at 0 ppm) corresponding to the trigonal boronic acid ester 3.
This is in agreement with its catalytic inertness in the aldol reaction.
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c
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