Tetrahedral boronates as basic catalysts in the aldol reaction

Article abstract of DOI:10.1515/znb-2015-0029

β-Hydroxyketones are versatile building blocks in organic synthesis, which can be conveniently synthesized from ketones and aldehydes by aldol reactions. Unfortunately, these reactions often suffer from dehydration of the initially formed β-hydroxyketones

Full text of DOI:10.1515/znb-2015-0029

Z. Naturforsch. 2015; 70(8)b: 587–595
Tobias Müller, Kristina Djanashvili, Joop A. Peters, Isabel W.C.E. Arends and Ulf Hanefeld*
Tetrahedral boronates as basic catalysts
in the aldol reaction
DOI 10.1515/znb-2015-0029
Received February 11, 2015; accepted April 2, 2015
NaOH, Na CO , and Ca(OH) were applied in stoichiomet-
2
3
2
ric amounts for this purpose [2–5]. Unfortunately, the base
used for the initial deprotonation of the ketone is often
also active in an undesired consecutive reaction, dehydra-
Abstract: β-Hydroxyketones are versatile building blocks tion of the formed β-hydroxyketone. Suppression of this
in organic synthesis, which can be conveniently synthe- elimination reaction is highly desired as β-hydroxyketones
sized from ketones and aldehydes by aldol reactions. can be used as building blocks for diols, amino alcohols,
Unfortunately, these reactions often suffer from dehydra- and polyketides [6–11].
tion of the initially formed β-hydroxyketones. Previously,
A way to increase the chemo-selectivity towards the
tetrahedral 3,5-difluorophenylborate was shown to be an β-hydroxyketone was introduced by Mukaiyama et al.,
efficient and selective catalyst for this reaction. The pre- applying stoichiometric amounts of silyl enol ether as
sent investigation concerns the catalytic performance of donor in the aldol reaction to form β-hydroxyketone [12–
phenyl borates with different substitution patterns in the 14]. A further improvement was introduced by Mori et al.,
aldol reaction. It appears that the dehydration reaction who applied diarylborinic acid in the Mukaiyama reac-
can be suppressed by selecting substituents and substitu- tion [15]. The advantage is a higher stereoselectivity of the
ent positions with reduced electron withdrawing effects reaction than that obtained before. This can be explained
on the borate function. Optimal suppression of the dehy- by a shorter bond length of the B–O bond as compared to
dration of β-hydroxyketones was obtained for compounds metal oxygen bonds, resulting in a tighter six-membered
corresponding to phenylboronic acids with a pK ꢀ>ꢀ 7. The ring transition state of the addition reaction [16, 17]. The
a
reactions between benzaldehyde and butanone or 3-pen- boron-mediated reaction by Mori with silyl enol ethers
tanone did not show diastereoselectivity, which suggests was performed in water at 30 °C.
that the catalysts merely act as bases rather than as tem-
More recently, activation of the ketone by the highly
plates for the transition state of the aldol reaction. Steri- reactive trimethylsilyl (TMS) chloride was avoided by gen-
cally more demanding ketones were not converted.
erating the boron enolate in situ [18]. However, with this
procedure, high selectivities towards aldols could only be
Keywords: aldol condensation; aldol reaction; boron; obtained when the ketone had an α-hydroxygroup.
catalysis; dehydration.
In a recent communication, we presented a borate salt,
as a basic catalyst for the aldol reaction, which showed
high selectivity towards the aldol product with a wide
range of aldehydes. This catalyst was soluble in organic
solvents, which allowed us to perform the reaction in the
substrate (acetone) as solvent [19]. No further co-solvent
was needed, which is desirable for an environmentally
friendly process. The good solubility of the catalyst was
achieved by attaching electron withdrawing groups to
the aromatic ring. Furthermore, the electron withdrawing
groups stabilized the negatively charged borate function.
Here, we report on an investigation of the influence
of electron withdrawing groups on the performance of
these borate salts as catalysts in the aldol reactions. Fine
tuning of β-hydroxyketone selectivity was obtained in this
way. Additionally, different ketones were investigated to
support the previously proposed mechanism with the cat-
alyst acting as a base rather than as a template.
1
Introduction
The aldol reaction was discovered 150 years ago and
originally was performed with stoichiometric amounts of
sodium to deprotonate the enol in the activation step of
the reaction [1]. Later, other inorganic bases such as LiOH,
*
Corresponding author: Ulf Hanefeld, Gebouw voor Scheikunde,
Afdeling Biotechnologie, Technische Universiteit Delft, Julianalaan
1
36, 2628 BL Delft, The Netherlands, Fax: +31-15-278-1415,
E-mail: u.hanefeld@tudelft.nl
Tobias Müller, Kristina Djanashvili, Joop A. Peters and
Isabel W.C.E. Arends: Gebouw voor Scheikunde, Afdeling
Biotechnologie, Technische Universiteit Delft, Julianalaan 136,
2628 BL Delft, The Netherlands
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88ꢀꢀꢀꢀꢁꢀT. Müller et al.: Tetrahedral boronates as basic catalysts
iPrOH,
a 100
B(OH)2
toluene,
Dean–Stark
trap
B(O-iPr)2
B(O-iPr)3
iPrONa in
iPrOH
8
6
0
0
R2
R1
R2
R1
R2
R1
1
a−f
2 a−f
3 a−f
1
2
1
2
a
b
c
R ,R = 3,5-di-CF3 (pKa = 6.62)
d
e
f
R
R
= 3-F, R = H (pKa = 7.50)
1
2
1
2
40
R ,R = 3,5-di-F (pKa = 7.08)
= 2-F, R = H (pKa = 7.83)
1
2
R1 = 4-F, R = H (pKa = 8.66)
2
R ,R = 2,4-di-F (pKa = 7.12)
20
Scheme 1:ꢀSynthesis of the catalysts. The pK values of the starting
a
boronic acids (1) are given in brackets [22, 23].
0
0
20
40
60
80
100
Time (min)
2
Results and discussion
b 100
The catalysts were prepared in two steps. First, the sub-
stituted phenylboronic acid was esterified with isopro-
panol in toluene using a Dean–Stark trap to remove the
produced water.
80
6
4
2
0
0
0
Then, the desired catalysts were obtained by reacting
the resulting diesters with an equimolar amount of sodium
isopropanolate (see Scheme 1). An attempt to prepare the
2
,6-difluoro and 2,4,6-trifluoro substituted borate salts
failed due to cleavage of the B–C bond during the reaction
with sodium isopropanolate. This is most likely caused
by an increase of steric strain and electrostatic repulsion
during the conversion of the boron atom from planar trigo-
nal to tetrahedral [20, 21].
0
20
40
60
80
100
Time (min)
Fig. 1:ꢀAmount of aldol (6) (in % of initial benzaldehyde 4 concen-
tration) as a function of time during the reaction of 2 mmol of 4 in
0 mmol of acetone at 30 °C in the presence of 10 mol% of 3 (a) and
■
The catalysts were tested in the aldol reaction of ben-
2
zaldehyde (4) and acetone (5) at 30 °C (see Scheme 2). High 20 mol% of 3 (b); 3a ▴, 3b •, 3c , 3d ◂, 3e ▾, and 3f ▸.
conversions were obtained rapidly after mixing the reac-
tants. With 10 mol% of catalyst, a maximum conversion The large difference in reaction rates between the aldol
to the desired β-hydroxyketone (6) was obtained within 10 reaction and the subsequent elimination allows termina-
min. In addition, small amounts of side products (mainly tion of the reaction when the yield of aldol is maximal
7
) were obtained due to elimination and oligomerization (Table 1).
reactions.
The final slopes of the curves in Fig. 1 suggest that the
Figure 1a and b display the course of the reaction as relative rates of the elimination reaction for the various
a function of time (0–90 min) for the reaction using 10 or catalysts increase in the order 3a ꢀ<ꢀ 3b ꢀ<ꢀ 3c ꢀ<ꢀ 3d ꢀ<ꢀ 3e ꢀ<ꢀ
2
0 mol% of catalyst 3, respectively. After fast conversion 3f. This order is the same as that of the pK values of
a
of benzaldehyde (4) to the aldol product 6 during the first the corresponding phenylboronic acids (1) in water (see
few minutes, a relatively slow decrease of the concentra- Scheme 1) [22, 23]. The pK values of the boronic acids are
a
tion of 6 occurs. Analysis of the reaction mixture showed determined by the charge density at the boron atom, and
that this is caused by elimination of water from 6 to give hence it can be concluded that the activities in the elimi-
7
and minor amounts of its oligomerization products. nation reaction with catalysts 3a–f depend on the charge
density of the boron atoms. Those with the highest posi-
tive charge density (the catalysts derived from the boronic
B-catalyst
O
O
OH
O
O
acids with the lowest pK ) show the lowest elimination
a
o
30 C, N2
rates, whereas the rates of the aldol reaction are very high
Ph
H
Ph
− H2O Ph
for all catalysts investigated.
4
5
6
7
The initial rates of the reactions with 10 or 20 mol% of
catalyst were too high to enable accurate kinetics. Neither
Scheme 2:ꢀThe aldol reaction catalyzed by borate salts 3a–f.
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Table 1:ꢀConversion and selectivity for the boron catalyzed aldol
reactions between benzaldehyde (2 mmol) and acetone (20 mmol),
O
Na
a
at 30 °C after 10 min.
B
O
R1
OH
O
Entryꢁ Catalystꢁ
Amount ofꢁ Conversion (%)ꢁ Aldol ꢂ (%)b
catalyst (mol%)
H
O
R2
R3
O
ꢃ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃaꢄ
ꢃbꢄ
ꢃcꢄ
ꢃdꢄ
ꢃeꢄ
ꢃfꢄ
ꢃꢅꢄ
ꢆꢇꢄ
ꢆꢅꢄ
ꢆꢋꢄ
ꢆꢇꢄ
ꢆꢌꢄ
ꢆꢋꢄ
ꢆꢍꢄ
ꢆꢌꢄ
ꢆꢌꢄ
ꢆꢍꢄ
ꢆꢉꢄ
ꢆꢍꢄ
ꢋꢊꢄ
ꢊꢌꢄ
ꢈꢉ
ꢈꢅ
ꢉꢇ
ꢆꢃ
ꢍꢊ
ꢉꢉ
ꢍꢊ
ꢉꢉ
ꢉꢊ
ꢍꢋ
ꢍꢅ
ꢌꢍ
ꢋꢅ
ꢊꢇ
ꢊ
ꢃꢅꢄ
ꢃꢅꢄ
ꢃꢅꢄ
ꢃꢅꢄ
ꢃꢅꢄ
ꢊꢅꢄ
ꢊꢅꢄ
ꢊꢅꢄ
ꢊꢅꢄ
ꢊꢅꢄ
ꢊꢅꢄ
ꢌꢄ
ꢇ
H
O
ꢋ
O
O
Na
Na
R3
ꢌ
B
B
ꢍ
O
O
R1
R1
O
O
ꢉ
ꢃaꢄ
ꢃbꢄ
ꢃcꢄ
ꢃdꢄ
ꢃeꢄ
ꢃfꢄ
ꢈ
R2
R2
ꢆ
3
ꢃꢅ
ꢃꢃ
ꢃꢊ
ꢃꢇ
ꢃꢋ
O
OH
OH
R3
ꢃfꢄ
ꢃfꢄ
Scheme 3:ꢀThe mechanism of aldol reaction catalyzed by the
synthesized borate salts 3a–f.
ꢊꢄ
a
1
As determined by H NMR spectroscopy.
b
The remainder is mainly elimination product 7 in addition to minor
amounts of products derived from sequential oligomerization and
elimination reactions.
negative charge densities. Consequently, these catalysts
will be stronger Brønsted bases leading to enhancement
of the reaction rate of the deprotonation of acetone.
reducing the catalyst concentration (Table 1, entries 13 Accordingly, catalysts 3 corresponding to boronic acids
and 14) nor cooling the reaction mixture enabled evalu- (1) with the lowest pK values show the slowest elimina-
a
ation of accurate kinetics. A comparison of the benzal- tion reactions.
dehyde (4) conversion at various catalyst concentrations
(
To evaluate the regio- and stereoselectivity, catalysts
see Table 1) and that of the final slopes of the aldol con- 3a–c and 3e were also applied in the aldol reactions of
centration as a function of time (Fig. 1) suggest that both benzaldehyde (4) and 3-pentanone (8a) or butanone
the rates of the aldol reaction and the subsequent elimi- (8b) at 30 °C (Scheme 4). In this study 20 mol% of boron
nation reaction are approximately first order in catalyst, catalyst was used, and again very fast conversion of 4
which underlines the importance of the catalyst in the rate was observed during the first few minutes of the reac-
determining step of these reactions.
tion, after which the reaction slowed down dramatically.
The effect of variation of the ratio 4:5 was investigated The maximum amount of β-hydroxyketone was obtained
in reactions with 10 mol% of 3b under the conditions given already after 10 min (Table 2).
in Table 1. An increase of this ratio from 1:5, 1:10 to 1:20 led
For 3-pentanone (8a), the selectivity towards the
to an increase of the aldol reaction rate as reflected in an rac-erythro- and rac-threo-β-hydroxyketones (9a, 10a)
increase of the conversion from 55 % to 95 %, while the was high, and no dehydration was observed. In contrast,
selectivity for aldol 6 remained about 80 %. All phenom- one of the aldols formed from the reaction of butanone
ena observed are consistent with the previously suggested with benzaldehyde, 11 dehydrated to give 12 (Scheme 4).
mechanism (see Scheme 3) [19].
Probably, steric hindrance by the methyl group prevents
Catalyst 3 deprotonates acetone to form the boron- the elimination reaction of 9 and 10. With NaOiPr as the
bound enolate. Then reaction with the aldehyde results in basic catalyst, the behavior was similar. These reactions
β-hydroxyketone (6). The subsequent dehydration is not appeared to be prone to oligomerization of the aldol
catalyzed by any of the catalysts 3 due to their steric bulk. product after 90 min, as observed by GCMS analysis.
This is in contrast to sterically less demanding bases such This oligomerization could be suppressed by decreasing
as NaOiPr [19].
the reaction temperature to 0 °C. However, under those
Increasing the positive charge density on the boron conditions, the reaction stopped after 10 min with ꢀ<ꢀ 30
atoms through the substituents at the phenyl groups of % conversion of benzaldehyde (Table 2, entry 6). At low
the catalysts will make them more electron withdraw- temperatures, the aldol reaction products probably coor-
ing and hence the neighboring O atoms will have higher dinate relatively strongly to the catalyst, thereby blocking
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90ꢀꢀꢀꢀꢁꢀT. Müller et al.: Tetrahedral boronates as basic catalysts
O
OH
O
homogeneous. Additionally, it had earlier been shown
that water does not inhibit the reaction [19].)
Ph
Ph
8a
All reactions with butanone and 3-pentanone showed
no diastereoselectivity, neither with NaOiPr nor with
3a,b,c, and 3e as the catalyst (Table 2, entries 1–6 and
O
9a rac-syn
B-catalyst
Ph
H
OH
O
− H O
2
4
7–11). The ratio of 9 and 10 is about the same in all cases.
Therefore, it is not very likely that catalysts 3 act as a tem-
plate for a six-membered transition state in the reaction
between the enolate of the ketone (5, 8a/b) and benzalde-
hyde (4) [24–26]. Compounds 3 rather are basic catalysts
for the deprotonation of the ketone in this case.
When more rigid cyclohexanone (8c) was employed
instead of 3-pentanone 8a, only traces of the aldol prod-
ucts were observed (Scheme 5). While 3a displayed suffi-
cient activity to catalyze the conversion of acetone, 8a and
1
0a rac-anti
O
OH
O
Ph
8b
O
9
b rac-syn
B-catalyst
Ph
H
OH
O
− H O
2
4
Ph
Ph
8
b, the boron catalyst is too weak as a base to deprotonate
10b rac-anti
the cyclic ketone 8c. This might be due to an increased
ring strain when deprotonating 8c. Also no dehydration
occurred and product 13 was not detected. NaOiPr as a
much stronger base catalyzed the reaction; formation
of an aldol product and subsequent dehydration took
place (Table 3). As expected for NaOiPr, no diastereose-
lectivity was observed, and 9c and 10c were formed in
equal amounts. Due to the higher activation energy for
the deprotonation, this catalyst displayed slightly better
selectivity and only 4 % of elimination product 13c was
detected.
OH
O
O
Ph
1
1
− H2O
12
Scheme 4:ꢀThe boron-catalyzed aldol reaction of benzaldehyde and
-pentanone (8a) or butanone (8b).
3
it for further reaction. (The termination of the reaction
at 0 °C after about 10 min cannot be due to hydrolysis
of the catalyst by water formed during the dehydra-
tion reaction, since that would lead to precipitation of
the catalyst. In all cases the reaction mixture remained
OH
O
O
O
Ph
rac-9c
O
catalyst
Table 2:ꢀConversion and selectivity for the boron catalyzed aldol
reactions between benzaldehyde (2 mmol) and 3-pentanone (8a) or
butanone (8b, 20 mmol) in the presence of 20 mol% of catalyst, at
o
Ph
30 C, N2
Ph
H
−
H2O
OH
O
4
8c
13
3
0 °C after 10 min.a
Ph
rac-10c
Entry ꢁ Catalystꢁ Conversion (%)ꢁ ꢄ (%)ꢁ ꢅꢆ (%)ꢁ ꢅꢅ (%)ꢁ ꢅꢇ (%)
ꢈa
Scheme 5:ꢀThe boron catalyzed aldol reaction of benzaldehyde and
cyclohexanone (8c).
b
–b
–
–
–
–
–
ꢂꢃ
ꢂꢊ
ꢂꢇ
ꢂꢋ
ꢂꢌ
ꢂꢍ
ꢈb
ꢂꢉ
ꢂꢈ
ꢂꢆ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
NaOiPr ꢄ
ꢆꢃꢄ
ꢆꢊꢄ
ꢆꢃꢄ
ꢆꢋꢄ
ꢆꢋꢄ
ꢊꢍꢄ
ꢇꢇꢄ
ꢊꢌꢄ
ꢊꢍꢄ
ꢊꢆꢄ
ꢊꢋꢄ
ꢃꢅꢄ
ꢌꢍꢄ
ꢋꢃꢄ
ꢋꢉꢄ
ꢌꢉꢄ
ꢋꢈꢄ
ꢃꢌꢄ
– ꢄ
ꢃa
ꢃb
ꢃc
ꢃe
ꢄ
ꢄ
ꢄ
ꢄ
ꢄ
–ꢄ
–ꢄ
–ꢄ
–ꢄ
–ꢄ
Table 3:ꢀConversion and selectivity for the boron catalyzed aldol
reaction between benzaldehyde and cyclohexanone (8c) in the
presence of 20 mol% of catalyst, at 30 °C after 10 min.
c
ꢃe
Entryꢁ
Catalystꢁ
Conversion (%)ꢁ
ꢄc + ꢅꢆc (%)ꢁ
ꢅꢃ (%)
ꢄ
ꢄ
ꢄ
NaOiPr ꢄ
ꢃa
ꢃb
ꢆꢇꢄ
ꢆꢊꢄ
ꢉꢌꢄ
ꢆꢉꢄ
ꢆꢌꢄ
ꢃꢅꢄ
ꢃꢇꢄ
ꢃꢊꢄ
ꢉꢄ
ꢃꢍꢄ
ꢃꢉꢄ
ꢃꢊꢄ
ꢈꢄ
ꢊꢌꢄ
ꢇꢊꢄ
ꢇꢍꢄ
ꢊꢃꢄ
ꢊꢊꢄ
ꢋꢃ
ꢉ
ꢄ
ꢄ
ꢄ
ꢄ
ꢃa
ꢄ
ꢄ
NaOiPr ꢄ
ꢉꢊꢄ
∼ꢊꢄ
ꢇꢋ + ꢇꢋ
Traces
ꢄ
ꢄ
ꢋ
–
b
b
–
ꢊ
ꢃa
ꢄ
ꢂꢃꢅ ꢄ ꢃc
ꢂꢃꢃ ꢄ ꢃe
ꢇꢉ
ꢇꢉ
a2 mmol of benzaldehyde in 20 mmol of cyclohexanone with
ꢉꢄ
ꢃꢅꢄ
1
2
0 mol% of NaOiPr; conversion was determined by H NMR
a
1
As determined by H NMR spectroscopy; GC-MS suggested that the
remainder consists of oligomerization products.
spectroscopy.
b
1 mmol of benzaldehyde in 10 mmol of perdeuterated
cyclohexanone with 20 mol% of 3a; the reaction was followed
b
Not observed.
c
1
After 30 min at 0 °C.
in situ by H NMR spectroscopy.
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with literature to assign structures. Thin layer chromato-
graphy (TLC) was performed with silica gel 60 F254
3
Conclusion
(Merck) and analyzed at 254 and 365 nm. If needed, the
Triisopropyl esters of fluoro-substituted phenylboronic
acids are efficient basic catalysts for the aldol reactions of
unhindered starting materials. They are highly stable in
the substrate, which can also function as solvent. Manipu-
lation of the charge density of the borate group through
the fluoro-substituents can be used to optimize the selec-
tivity towards the desired β-hydroxyketone. This effect is
mainly due to suppression of the undesired subsequent
elimination reaction of the β-hydroxyketone. The highest
product was visualized with iodine on the TLC plate. Mass
spectrometry was performed with a Shimadzu QP-2010S
GCMS spectrometer using GCMS solution software for data
processing. Satisfactory elemental analyses or high-reso-
lution mass spectra could not be obtained probably due to
the boron and fluorine content of the compounds. Similar
problems have been reported previously [27–29].
selectivity towards the aldol product was obtained with 4.3 Synthesis of the catalyst
borates corresponding to fluoro-substituted phenylbo-
ronic acids with a pK ꢀ>ꢀ 7. As the catalyst acts as a mild All catalysts were prepared according to the procedure
a
base rather than as template, no diastereoselectivity was described for 2b and 3b.
observed; also more demanding ketones were not con-
verted due to this weak basicity.
4
.3.1 Diisopropyl 3,5-difluorophenylboronate (2b)
3
,5-Difluorophenylboronic acid (4.74 g, 30 mmol) and
4
Experimental section
2-propanol (12 g, 15 mL, 200 mmol) were dissolved in 15 mL
of toluene. The reaction mixture was stirred for 24 h under
reflux under a Dean–Stark trap filled with molecular sieve
4
.1 Materials
3
Å (11 g), 2-propanol (5 mL), and toluene (5 mL). After that
the solvent was evaporated under reduced pressure, and
the product was distilled under reduced pressure. Pure
Experiments were performed with commercially available
chemicals. Dry toluene and dry 2-propanol were used to
synthesize the catalysts. All phenylboronic esters were
synthesized by following the procedure for diisopro-
pyl 3,5-difluorophenylboronate or sodium triisopropoxy
2
b (4.1 g) was obtained as a colorless liquid (16.9 mmol,
5
6 %). B.p. 50 °C/6.5 ꢀ×ꢀ 10– mbar. – H NMR (400 MHz,
2
1
CDCl ): δ ꢀ=ꢀ 1.25 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ 6.5 Hz), 4.58 (sept,
3
3
2
2
(
1
H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.5 Hz), 6.81 (m, 1H, H ), 7.06 (m, 2H,
Ar
3
,5-difluorophenylborate (see below). Molecular sieves
1
1
13
ꢀ×ꢀ H ). – B NMR (128 MHz, CDCl ): δ ꢀ=ꢀ 7.6. C NMR
Ar
3
(
3 Å) were purchased from Metrohm. Silica gel (Fluka,
100 MHz, CDCl ): δ ꢀ=ꢀ 24.6, 66.7, 104.7 (t, J ꢀ=ꢀ 25.2 Hz),
3
particle size 0.06–0.2 nm) was used for the isolation of
the products. For the separation of the products, ethyl
acetate/petroleum ether (gradient) was used as eluent.
Benzaldehyde was freshly distilled. All chemicals were
purchased from Sigma-Aldrich (Schnelldorf, Germany)
unless otherwise stated.
15.1 (m), 138.5 (C–B), 163.0 (dd, J ꢀ=ꢀ 249.7 Hz, J ꢀ=ꢀ 11.2 Hz).
1
2
4
.3.2 Sodium triisopropoxy (3,5-difluorophenyl)borate
3b)
(
The reaction was carried out under a nitrogen atmos-
phere. Sodium (345 mg, 15 mmol) was dissolved in 60 mL
of 2-propanol. The solution was stirred for 1 h under
4
.2 Analytical techniques
1
11
13
H, B, and C NMR spectra were recorded at 400, 128, and reflux and then cooled to 30 °C. Then a solution of 3.63 g
00 MHz, respectively, with a Bruker Avance-400 spectrom- (15 mmol) of diisopropyl 3,5-difluorophenylboronate (2b)
1
1
13
eter, and at 300 ( H) or 75 MHz ( C) with a Varian Inova-300 in 8 mL of 2-propanol was added dropwise over 30 min.
1
1
spectrometer. The chemical shifts in B NMR spectra were The mixture was stirred for 16 h at 30 °C, after which the
referenced to a 0.1 ꢁ boric acid solution in D O at 0 ppm. solvent was removed under vacuum to give 4.78 g of white
2
1
13
1
All other resonances in the H and C spectra were refer- powder (14.8 mmol; yield: 98 %). – H NMR (300 MHz,
enced to the residual solvent peak and are reported in ppm [D ]2-propanol): δ ꢀ=ꢀ 1.11 (d, 18H, 6 ꢀ×ꢀ CH , J ꢀ=ꢀ 6 Hz),
8
3
with respect to TMS. Boron-substituted aromatic carbon 3.9 (sept, 3H, CHOB, J ꢀ=ꢀ 6 Hz), 6.54–7.04 (m, 3H, 3 ꢀ×ꢀ H ).
Ar
1
1
13
nuclei were not observed in some cases due to severe line – B NMR (128 MHz, [D ]2-propanol): δ ꢀ=ꢀ –15.5. – C NMR
broadening. NMR data of aldol products were compared (75 MHz, [D ]2-propanol): δ ꢀ=ꢀ 25.3, 63.6, 99.3 (m), 115.3 (m),
8
8
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92ꢀꢀꢀꢀꢁꢀT. Müller et al.: Tetrahedral boronates as basic catalysts
1
62.6 (dd, J ꢀ=ꢀ 10.3 Hz; J ꢀ=ꢀ 245.8 Hz), 162.9 (dd, J ꢀ=ꢀ 246.5 Hz; 4.4.5 Diisopropyl 3-fluorophenylboronate (2d)
1
J2 ꢀ=ꢀ 10.4 Hz).
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.29 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ 6.1
3
3
Hz), 4.64 (sept, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.1 Hz), 7.06–7.14 (m, 1H,
1
1
4
.4 NMR data of the other phenylboronic
esters
H ), 7.29–7.38 (m, 3H, H ). B NMR (128 MHz, CDCl ): δ ꢀ=ꢀ
Ar Ar 3
1
3
7
.3. – C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 24.7, 66.5; 116.2 (d, J ꢀ=ꢀ
3
2
1.0 Hz), 119.5 (d, J ꢀ=ꢀ 19.1 Hz), 128.4 (d, J ꢀ=ꢀ 3.0 Hz), 129.6 (d,
4
.4.1 Diisopropyl 3,5-bis-(trifluoromethyl)
J ꢀ=ꢀ 7.2 Hz), 136.4 (C–B), 162.7 (d, J ꢀ=ꢀ 244.9 Hz).
phenylboronate (2a)
1
H NMR (400 MHz, CDCl ): δ ꢀ=ꢀ 1.27 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ 4.4.6 Sodium triisopropoxy (3-fluorophenyl)borate (3d)
3
3
6
.1 Hz), 4.59 (sept, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.1 Hz), 7.89 (m, 1H,
1
1
1
H ), 8.00 (m, 2H, 2 ꢀ×ꢀ H ). – B NMR (128 MHz, CDCl ): δ ꢀ=ꢀ H NMR (300 MHz, CD OD): δ ꢀ=ꢀ 1.15 (d, 18H, 6 ꢀ×ꢀ CH , J ꢀ=ꢀ
Ar
Ar
3
3
3
13
7
. 5. C NMR (100 MHz, CDCl ): δ ꢀ=ꢀ 24.70, 67.10, 123.19 (quin, 6.2 Hz), 3.93 (sept, 3H, CHOB, J ꢀ=ꢀ 6.2 Hz), 6.67–6.73 (m, 1H,
3
11
J ꢀ=ꢀ 3.8 Hz), 123.2 (q, J ꢀ=ꢀ 274.0 Hz), 130.90 (q, J ꢀ=ꢀ 33.0 Hz), H ), 7.08–7.19 (m, 2H, H ), 7.27 (d, 1H, H J ꢀ=ꢀ 7.1 Hz). – B
Ar
Ar
Ar,
1
33.0, 137.3 (C–B).
NMR (128 MHz, [D ]2-propanol): δ ꢀ=ꢀ –15.1.
8
1
3
C NMR (75 MHz, CD OD): δ ꢀ=ꢀ 25.3, 64.7; 112.1 (d, J ꢀ=ꢀ
3
2
1.2 Hz), 119.8 (d, J ꢀ=ꢀ 16.2 Hz), 128.6 (d, J ꢀ=ꢀ 7.5 Hz), 129.6 (d,
4
.4.2 Sodium triisopropoxy 3,5-bis-(trifluoromethyl)
phenyl-borate (3a)
J ꢀ=ꢀ 2.3 Hz), 155.9 (C–B), 164.1 (d, J ꢀ=ꢀ 240.7 Hz).
1
H NMR (300 MHz, CD OD): δ ꢀ=ꢀ 1.15 (d, 18H, 6 ꢀ×ꢀ CH , J ꢀ=ꢀ 4.4.7 Diisopropyl 2-fluorophenylboronate (2e)
3
3
6
.2 Hz), 3.92 (sept, 3H, CHOB, J ꢀ=ꢀ 6.2 Hz), 7.56 (s, 1H, H ),
Ar
11
1
8
.03 (s, 2H, 2 ꢀ×ꢀ H ). – B NMR (128 MHz, [D ]2-propanol): H NMR (400 MHz, CDCl ): δ ꢀ=ꢀ 1.22 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ
Ar
8
3
3
13
δ ꢀ=ꢀ –15.51. – C NMR (75 MHz, CD OD): δ ꢀ=ꢀ 25.3, 64.7, 119.3 6.1 Hz), 4.44 (sept, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.1 Hz), 7.01 (t, 1H, HAr,
3
(
1
quin, J ꢀ=ꢀ 3.89 Hz), 124.3, 127.9, 130.0 (q, J ꢀ=ꢀ 117.68 Hz), J ꢀ=ꢀ 7.3 Hz), 7.14 (t, 1H, H J ꢀ=ꢀ 8.5 Hz), 7.35 (m, 2H, 2 ꢀ×ꢀ H ).
A
r
,
A
r
1
1
13
31.54, 134.1.
– B NMR (128 MHz, CDCl ): δ ꢀ=ꢀ 8.3. C NMR (100 MHz,
3
CDCl ): δ ꢀ=ꢀ 24.6, 67.1, 114.9 (d, J ꢀ=ꢀ 24.1 Hz), 121.9 (C–B),
3
1
24.6 (d, J ꢀ=ꢀ 2.8 Hz), 130.8 (d, J ꢀ=ꢀ 8.2 Hz), 133.7 (d, J ꢀ=ꢀ
4
.4.3 Diisopropyl 2,4-difluorophenylboronate (2c)
10.0 Hz), 164.4 (d, J ꢀ=ꢀ 239.7 Hz).
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.22 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ
3
3
6
(
.0 Hz), 4.44 (sep, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.0 Hz), 6.70–6.80 4.4.8 Sodium triisopropoxy (2-fluorophenyl)boronate (3e)
m, 1H, H ), 6.84–6.94 (m, 1H, H ), 7.30–7.42 (m, 1H, H ).
Ar
Ar
Ar
11
13
1
–
B NMR (128 MHz, CDCl ): δ ꢀ=ꢀ 8.0. C NMR (75 MHz, H NMR (400 MHz, [D ]2-propanol): δ ꢀ=ꢀ 1.16 (d, 18H, 6 ꢀ×ꢀ
3 8
CDCl ): δ ꢀ=ꢀ 24.6, 67.2, 103.51 (dd, J ꢀ=ꢀ 12.2 Hz; J ꢀ=ꢀ 28.8 Hz), CH , J ꢀ=ꢀ 6.2 Hz), 3.94 (sept, 3H, CHOB, J ꢀ=ꢀ 6.2 Hz), 6.62–6.78
3
1
2
3
1
11.5 (dd, J ꢀ=ꢀ 20.3, Hz; J ꢀ=ꢀ 3.2 Hz), 134.9 (dd, J ꢀ=ꢀ 7.6 Hz; (m, 1H, H ), 6.88–7.06 (m, 2H, H ); 7.61–7.82 (m, 1H, H ).
1 2 1 Ar Ar Ar
1
1
B NMR (128 MHz, [D ]2-propanol): δ ꢀ=ꢀ –15.7. – 13C
J ꢀ=ꢀ 9.5 Hz), 162.9 (dd, J ꢀ=ꢀ 67.34 Hz; J ꢀ=ꢀ 11. 7 Hz), 166.2 (dd,
2
1
2
8
J ꢀ=ꢀ 11.6 Hz; J ꢀ=ꢀ 11.5 Hz).
NMR (100 MHz, CDCl ): δ ꢀ=ꢀ 25.2, 64.7; 112.0 (d, J ꢀ=ꢀ 28.3 Hz),
1
3
1
2
3
19.77 (d, J ꢀ=ꢀ 21.6 Hz), 128.6 (d, J ꢀ=ꢀ 9.0 Hz), 129.6 (d, J ꢀ=ꢀ
.1 Hz), 155.9, 164.1 (d, J ꢀ=ꢀ 320.9 Hz).
4
.4.4 Sodium triisopropoxy (2,4-difluorophenyl)borate (3c)
1
H NMR (300 MHz, CD OD): δ ꢀ=ꢀ 1.15 (d, 18H, 6 ꢀ×ꢀ CH , 4.4.9 Diisopropyl 4-fluorophenylboronate (2f)
3
3
J ꢀ=ꢀ 6.2 Hz), 3.93 (sept, 3H, CHOB, J ꢀ=ꢀ 6.2 Hz), 6.51–6.59
1
(
m, 1H, H ), 6.65–6.72 (m, 1H, H ), 7.44–7.51 (m, 1H, H ). H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.25 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ
Ar Ar Ar 3 3
11
13
–
B NMR (128 MHz, [D ]2-propanol): δ ꢀ=ꢀ –15.8. – C NMR 6.1 Hz), 4.60 (sept, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.1 Hz), 7.05 (t, 2H,
8
1
1
(
75 MHz, [D ]MeOH): δ ꢀ=ꢀ 25.3, 64.7, 102.5 (dd, J ꢀ=ꢀ 16.9 Hz; HAr, J ꢀ=ꢀ 9.1 Hz), 7.58 (t, 2H, H J ꢀ=ꢀ 7.29. Hz). – B NMR
4
1
A
r
,
1
3
J ꢀ=ꢀ 33.0 Hz), 110.0 (dd, J ꢀ=ꢀ 18.3 Hz; J ꢀ=ꢀ 2.9 Hz), 131.7 (C–B), (128 MHz, CDCl ): δ ꢀ=ꢀ 8.2. C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ
2
1
3
3
1
38.0 (dd, J ꢀ=ꢀ 15.8 Hz; J ꢀ=ꢀ 8.6 Hz), 163.1 (dd, J ꢀ=ꢀ 241.5, Hz; 24.8, 66.4, 114.9 (d, J ꢀ=ꢀ 19.8 Hz), 129.3 (C–B), 135.2 (d, J ꢀ=ꢀ
1 2 1
J ꢀ=ꢀ 13.7 Hz), 165.8 (dd, J ꢀ=ꢀ 238.6 Hz; J ꢀ=ꢀ 10.5 Hz).
7.5 Hz), 163.9 (d, J ꢀ=ꢀ 246.6 Hz).
2
1
2
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.4.10 Sodium triisopropoxy (4-fluorophenyl)borate (3f) quantitative measurements by integration of signals) were
dissolved in butanone or 3-pentanone (20 mmol, 10 eq).
1
H NMR (400 MHz, CD OD): δ ꢀ=ꢀ 1.15 (d, 18H, 6 ꢀ×ꢀ CH , J ꢀ=ꢀ An aliquot of 25 μL was taken from the reaction mixture to
3
3
6
.2 Hz), 3.92 (sept, 3H, CHOB, J ꢀ=ꢀ 6.2 Hz), 7.05 (m, 2H, H
prepare the NMR samples in CDCl . A catalyst (borate salt,
Ar,
3
1
1
J ꢀ=ꢀ 9.0 Hz), 7.46 (dd, 2H, HAr, J1 ꢀ=ꢀ 6.15, J ꢀ=ꢀ 8.5 Hz). – B NMR 0.4 mmol, 20 mol%) was added to the reaction mixture
2
13
1
(
128 MHz, [D ]2-propanol): δ ꢀ=ꢀ –14.9. – C NMR (100 MHz, and the conversion was followed by H NMR spectroscopy
8
MeOD): δ ꢀ=ꢀ 25.3, 64.7, 113.5 (d, J ꢀ=ꢀ 18.4 Hz), 135.5 (d, J ꢀ=ꢀ at 30 °C.
.3 Hz), 162.9 (d, J ꢀ=ꢀ 237.7 Hz).
6
4
.7 General procedure for the aldol reaction
with cyclohexanone)
4
.4.11 Diisopropyl 2,6-difluorophenylboronate
(
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.21 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ
3
3
With sodium isopropoxide:
6
.0 Hz), 4.38 (sept, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.0 Hz), 6.82 (m, 2H,
The aldol reaction was performed in a 10 mL one-necked
flask (dried in the oven overnight, flushed with nitrogen).
Benzaldehyde (212 mg, 2 mmol, 1 eq) and 1,3,5-trimethoxy-
benzene (67 mg, 0.4 mmol, 0.2 eq, internal standard for
quantitative measurements by integration of signals) were
dissolved in cyclohexanone (20 mmol, 10 eq). A 25 μL sample
11
2
ꢀ×ꢀ H ), 7.28 (m, 1H, H ). – B NMR (128 MHz, CDCl ): δ ꢀ=ꢀ
Ar
Ar
3
13
5
.0. – C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 24.6, 67.7, 111.0 (dd,
3
J ꢀ=ꢀ 25.7 Hz; J ꢀ=ꢀ 1.7 Hz), 131.2 (t, J ꢀ=ꢀ 9.8 Hz), 164.5 (dd, J ꢀ=ꢀ
1
2
1
2
43.2 Hz; J ꢀ=ꢀ 14.7 Hz).
1
was taken from the reaction mixture to prepare the H NMR
4
.4.12 Diisopropyl 2,4,6-trifluorophenylboronate
samples in CDCl . NaOiPr (33 mg, 0.4 mmol, 20 mol%) was
3
added to the reaction mixture and the conversion was fol-
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 1.21 (d, 12H, 4 ꢀ×ꢀ CH , J ꢀ=ꢀ
3
3
1
lowed by H NMR spectroscopy at 30 °C. The products were
6
.2 Hz), 4.38 (sept, 2H, 2 ꢀ×ꢀ CHOB, J ꢀ=ꢀ 6.2 Hz), 6.60 (dd, 2H,
compared with literature known compounds [30].
11
H , J ꢀ=ꢀ 6.8 Hz, J ꢀ=ꢀ 9.0 Hz). – B NMR (96 MHz, CDCl ): δ ꢀ=ꢀ
Ar
3
13
7
.0. C NMR (75 MHz, CDCl ): δ ꢀ=ꢀ 24.5, 67.8, 100.0 (ddd,
3
With sodium borate 3a:
J ꢀ=ꢀ 3.2 Hz; J ꢀ=ꢀ 25.1 Hz; J ꢀ=ꢀ 28.6 Hz), 106.6 (C–B), 163.9 (td,
The aldol reaction was performed in a 5 mm ø NMR
J ꢀ=ꢀ 249.6 Hz, J ꢀ=ꢀ 15.7 Hz), 164.7 (ddd, J ꢀ=ꢀ 243.3 Hz; J ꢀ=ꢀ
1
2
1
2
1
tube at 30 °C. The reaction was monitored by H NMR
1
8.0 Hz; J ꢀ=ꢀ 16.9 Hz).
3
spectroscopy. Eighty-five milligrams (0.2 mmol) of sodium
borate (3a), 106 mg (1 mmol) of benzaldehyde, and 68 mg
(
0.4 mmol) of 1,3,5-trimethoxybenzene, which was used as
4
.5 General procedure for the aldol reaction
with acetone)
an internal standard, were dissolved in 1.08 g (10 mmol) of
D ]cyclohexanone.
[
(
10
Aldol reactions were performed in an NMR tube with
1
5
mm diameter at 30 °C. The reaction was monitored by H
4
.8 Isolation of the aldol product 6
NMR spectroscopy. The amount of sodium borate (3a–f)
desired for the particular experiment, 1 mmol of benzalde-
hyde, and 68 mg (0.4 mmol) of 1,3,5-trimethoxy benzene,
which was used as an internal standard, were dissolved in
Borate salt (0.4 mmol 3b) and 2 mmol of benzaldehyde
were dissolved in 1.16 g (20 mmol) of acetone. The reac-
tion mixture was stirred for 20 min at 30 °C. The excess
of acetone was evaporated and the residue was dissolved
in 3 mL of water. The product was extracted with 3 ꢀ×ꢀ 5 mL
of ethyl acetate. The organic layers were combined, dried
6
40 mg (10 mmol) of [D ]acetone.
6
4
.6 General procedure for the aldol reaction with MgSO , and filtered, and the solvent was evaporated.
4
The crude product was purified by column chromatogra-
(with butanone, 3-pentanone)
phy to yield 34 % of 4-hydroxy-4-phenylbutan-2-one (6).
1
The aldol reactions were performed in a 10 mL one-necked – H NMR (400 MHz, CDCl ): δ ꢀ=ꢀ 2.18 (s, 3H, CH ), 2.77–2.92
3
3
flask (dried in the oven overnight, flushed with nitrogen). (m, 2H, CH ), 3.30 (s, 1H, OH), 5.16 (m, 1H, CHCOH), 7.28–
2
1
3
Benzaldehyde (212 mg, 2 mmol, 1 eq) and 1,3,5-trimethoxy- 7.36 (m, 5H, H ). – C NMR (100 MHz, CDCl ): δ ꢀ=ꢀ 30.8,
Ar
3
benzene (100 mg, 0.6 mmol, 0.3 eq, internal standard for 52.1, 69.9, 125.7, 127.7, 128.6, 142.9, 209.1.
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94ꢀꢀꢀꢀꢁꢀT. Müller et al.: Tetrahedral boronates as basic catalysts
4
.9 Isolation of the aldol products 9a
and 10a
with MgSO , and filtered, and the solvent was evaporated
to give 320 mg of the crude product. For purification by
column chromatography, 20 g of silica gel (0.060–0.200
4
Boronate salt (0.2 mmol 3b) and 212 mg (2 mmol) of ben- mm, pore diameter: 6 nm) was used, along with an 8:2
zaldehyde were dissolved in 1.72 g (20 mmol) of 3-pen- petroleum ether:ethyl acetate eluent. From two combined
tanone (8a). The reaction mixture was stirred for 20 min fractions containing the aldol products, the solvents were
at 30 °C. The excess of 3-pentanone was evaporated and evaporated. The residues were two colorless oils, one
the residue was dissolved in 3 mL of water. The product of these being anti-4-hydroxy-3-methyl-4-phenylbutan-
was extracted with 3 ꢀ×ꢀ 5 mL of ethyl acetate. The organic 2-one in a yield of 28.6 mg (0.16 mmol, 8.0 %) and the
layers were combined, dried over MgSO , and filtered, other being a mixture of 1-hydroxy-1-phenylpentan-3-one
4
and the solvent was evaporated to give 489 mg of crude (34.7 mg, 0.20 mmol, 9.7 %) and syn-4-hydroxy-3-methyl-
product, which was purified by column chromatography 4-phenylbutan-2-one (11.6 mg, 0.07 mmol, 3.2 %).
using a column of 10 g silica gel (0.060–0.200 mm, pore
diameter: 6 nm) The column was eluted subsequently
with 9:1 petroleum ether-ethyl acetate 9:1, 8:2, and 7:3. 4.10.1 Syn-4-hydroxy-3-methyl-4-phenylbutan-2-one (9b)
The fractions containing the aldol products were com-
1
bined and the solvents were evaporated to give 50 mg H NMR (400 MHz, CDCl ): δ ꢀ=ꢀ 1.02–1.06 (d, J ꢀ=ꢀ 7.4 Hz, 3H,
3
of colorless oil consisting of a syn-1-hydroxy-2-methyl- CH ), 2.14 (s, 3H, CH ), 2.82 (dd, J ꢀ=ꢀ 3.8 Hz, J ꢀ=ꢀ 7.4 Hz, 1H,
3
3
1
2
1
-phenylpentan-3-one (0.26 mmol, 13 % yield) and anti- CH), 3.08 (s, br, 1H, OH), 5.12 (d, J ꢀ=ꢀ 4.2 Hz, 1H, CHOH),
1
3
1
-hydroxy-2-methyl-1-phenylpentan-3-one (0.52 mmol, 7.30–7.36 (m, 5H, H ). – C NMR (100 MHz, CDCl ): δ ꢀ=ꢀ
Ar
3
2
6 % yield).
10.2, 29.4, 53.2, 73.0, 125.6, 125.9, 128.5, 141.8, 213.5.
4
.9.1 Syn-1-hydroxy-2-methyl-1-phenyl-pentan-3-one (9a) 4.10.2 Anti-4-hydroxy-3-methyl-4-phenylbutan-
2-one (10b)
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 0.97 (t, J ꢀ=ꢀ 7.2 Hz, 3H, CH ),
3
3
1
1
(
.01 (d, J ꢀ=ꢀ 7.3 Hz, 3H, CH ), 2.28–2.52 (m, 2H, CH ), 2.93 H NMR (400 MHz, CDCl ): δ ꢀ=ꢀ 0.93 (d, 3H, CH ), 2.21 (s, 3H,
3
2
3
3
dq, J ꢀ=ꢀ 7.2 Hz, J ꢀ=ꢀ 4.2 Hz, 1H, CHCH ), 5.05 (J ꢀ=ꢀ 4.2 Hz, 1H, CH ), 2.84 (s, br, 1H, OH), 2.92 (dd, 1H, CHCH ), 4.74 (d, 1H,
1
2
3
3
3
13
13
CHOH), 7.27–7.37 (m, 5H, H ). – C NMR (100 MHz, CDCl ): CHOH), 7.31–7.35 (m, 5H, H ). – C NMR (100 MHz, CDCl ):
Ar
3
Ar
3
δ ꢀ=ꢀ 7.61, 10.7, 35.5, 52.4, 73.4, 126.0, 127.5, 128.0, 142.0, 216.4. δ ꢀ=ꢀ 14.1, 30.0, 53.7, 76.5, 126.6, 128.0, 128.5, 141.9, 213.4.
4
.9.2 Anti-1-hydroxy-2-methyl-1-phenyl-pentan-
-one (10a)
4.10.3 1-Hydroxy-1-phenylpentan-3-one (11)
3
1
H NMR (400 MHz, CDCl ): δ ꢀ=ꢀ 1.06 (t, J ꢀ=ꢀ 7.4 Hz, 3H, CH ),
3
3
1
H NMR (300 MHz, CDCl ): δ ꢀ=ꢀ 0.93 (d, J ꢀ=ꢀ 7.2 Hz, 3H, CH ), 2.45 (q, J ꢀ=ꢀ 7.3 Hz, 2H, CH ), 2.82 (dd, J ꢀ=ꢀ 3.7 Hz, J ꢀ=ꢀ 8.7 Hz,
3
3
2
1
2
1
.01 (t, J ꢀ=ꢀ 7.3 Hz, 3H, CH ), 2.28–2.52 (m, 2H, CH ), 2.93 (dq, 2H, CH ), 3.36 (s, br, 1H, OH), 5.16 (dd, J ꢀ=ꢀ 8.8 Hz, J ꢀ=ꢀ 4.0
3
2
2
1
2
1
3
J ꢀ=ꢀ 7.2 Hz, J ꢀ=ꢀ 8.3 Hz, 1H, CHCH ), 4.75 (J ꢀ=ꢀ 8.2 Hz, 1H, Hz, 1H, CHOH), 7.30–7.36 (m, 5H, H ). – C NMR (100 MHz,
1
2
3
Ar
13
CHOH), 7.27–7.37 (m, 5H, H ). – C NMR (100 MHz, CDCl ): CDCl ): δ ꢀ=ꢀ 7.50, 36.8, 50.7, 70.0, 125.9, 128.5, 142.9, 211.9.
Ar
3
3
δ ꢀ=ꢀ 7.55, 14.6, 36.6, 52.8, 76.8, 126.1, 128.4, 128.6, 142.3, 216.2.
Acknowledgments: 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 Sci-
4
.10 Isolation of the aldol products 9b,
1
0b, and 11
Boronate salt (0.2 mmol) and 212 mg (2 mmol) of benza- ence. The authors are thankful to L. Panella (DSM), P.
ldehyde were dissolved in 1.44 g (20 mmol) of butanone Alsters (DSM), J. G. de Vries (DSM), B. Kaptein (DSM),
(
8b). The reaction mixture was stirred for 20 min at 30 °C. and G. Kemperman (MSD) for fruitful discussions. The
Butanone was evaporated and the residue was dissolved authors are also thankful to Wuyuan Zhang (TU Delft –
in 3 mL of water. The product was extracted with 3 ꢀ×ꢀ 5 mL NMR) and Guzman Torrelo Villa (TU Delft – Chemicals)
of ethyl acetate. The organic layers were combined, dried for their support.
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T. Müller et al.: Tetrahedral boronates as basic catalystsꢂꢁꢀꢀꢀꢂ595
[
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