Gallium(III) triflate catalyzed diastereoselective mukaiyama aldol reaction by using low catalyst loadings

Article abstract of DOI:10.1002/ejoc.201301100

A mild method for the diastereoselective Mukaiyama aldol reaction is reported. By using a low loading of the gallium(III) triflate catalyst (down to 0.01 mol-%), the transformation proceeds efficiently to afford the corresponding β-hydroxy ketones in yields up to 92a€‰%. To the best of our knowledge, this is the first report of a metal triflate acting as a safe, bench-stable, and slow-releasing source of triflic acid for the Mukaiyama aldol reaction. A diastereoselective Mukaiyama aldol reaction was performed under mild conditions with a low loading of the gallium(III) triflate catalyst (down to 0.01 mol-%). The transformation proceeded efficiently to afford the corresponding β-hydroxy ketones in yields up to 92a€‰%. Copyright

Full text of DOI:10.1002/ejoc.201301100

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301100
Gallium(III) Triflate Catalyzed Diastereoselective Mukaiyama Aldol Reaction
by Using Low Catalyst Loadings
[a]
[a]
[a]
[a]
Baptiste Plancq, Lyse Carole Justafort, Mathieu Lafantaisie, and Thierry Ollevier*
Keywords: Gallium / Aldol reactions / Lewis acids / C–C bond formation / Gallium
A mild method for the diastereoselective Mukaiyama aldol
reaction is reported. By using a low loading of the gallium(III)
triflate catalyst (down to 0.01 mol-%), the transformation pro-
ceeds efficiently to afford the corresponding β-hydroxy
ketones in yields up to 92%. To the best of our knowledge,
this is the first report of a metal triflate acting as a safe,
bench-stable, and slow-releasing source of triflic acid for the
Mukaiyama aldol reaction.
Introduction
Ga(OTf)
for an efficient and diastereoselective Mukaiyama
3
aldol reaction. An asymmetric version of this reaction was
The β-hydroxy carbonyl functionality is an extremely already described by using a high catalyst loading of
[
8]
common feature in many natural products and biologically Ga(OTf)3 (20 mol-%). Considering the importance of
active molecules.[ For the formation of this motif, the catalytic processes nowadays, there was clearly a need to
Mukaiyama aldol reaction is certainly one of the most no- develop new efficient methods with the use of a much lower
table C–C bond-forming reactions, by focusing on the ad- amount of catalyst.
1]
dition of silyl enolates to aldehydes in the presence of Lewis
[
1a,2]
acids.
Initially mediated by stoichiometric amounts of
[
2a,2b]
TiCl4,
the first catalytic version of this reaction was
[
3]
reported by Bergman and Heathcock in 1989. Sub-
sequently, numerous Lewis acid catalysts conjointly used
with chiral ligands have been reported for catalytic asym-
metric Mukaiyama aldol reactions.[ Since the initial stud-
Results and Discussion
4]
Our initial studies began with the model coupling of
ies by Mukaiyama on the TiCl -mediated addition of silyl benzaldehyde (2a) with propiophenone-derived silyl enol
4
enolates to aldehydes, many Lewis acid catalysts have been ether 1 by using a catalytic amount of Ga(OTf) (Table 1).
3
reported to mediate this C–C bond-forming reaction. Some First, we screened various solvents at room temperature
of the Lewis acids used include BF ·OEt , SnCl4, with the use of 1 mol-% catalyst (Table 1, entries 1–6). The
3
2
Sn(OTf) , Yb(OTf) , and silyl triflates. Yet, moisture sensi- use of acetonitrile or dichloromethane as the solvent al-
2
3
tivity of these catalysts and the high cost of some of them lowed the formation of desired β-hydroxy ketone 3a in ex-
often restrain their use. In addition, most of the reported cellent yields but with low diastereoselectivities after a short
reactions involved the use of the Lewis acid in large reaction time (Table 1, entries 1 and 2). Upon conducting
amounts or even in stoichiometric amount.[
2d]
the reaction in diethyl ether or 2-methyltetrahydrofuran,
The identification of new efficient and green catalysts is low yields of aldol product 3a were obtained as a result of
an essential concern nowadays. The pioneering work by partial hydrolysis of silyl enol ether 1 and the formation of
Olah into Friedel–Crafts reactions identified gallium triflate byproducts such as ethers and acetals (Table 1, entries 3 and
as a strong Lewis acid.[ Since then, Ga(OTf) has been 4). In a protic solvent or under aqueous conditions, silyl
5]
[9]
3
used for numerous organic transformations and is now con- enol ether 1 was rapidly hydrolyzed into propiophenone,
sidered a key catalyst for the development of sustainable and only a trace amount of the product was observed
synthetic processes.[ Following our studies involving green (Table 1, entries 5 and 6; DME = 1,2-dimethoxyethane). In-
6]
[7]
Lewis acids derived from main group metals, we want to deed, triflic acid is known to be easily generated from
disclose our results with the use of low loadings of Ga(OTf) in water, and the amount of HOTf released in the
media causes rapid decomposition of the silyl enol
3
[
8,10]
ether.
The high reactivity observed at 22 °C in either
[
a] Département de Chimie, Université Laval,
1
045, avenue de la Médecine, Québec, QC, G1V 0A6, Canada
acetonitrile or dichloromethane meant the reaction tem-
perature could be lowered in these solvents (Table 1, en-
tries 7 and 8), which led to an improvement in the diastereo-
selectivity (Table 1, entry 8).
E-mail: thierry.ollevier@chm.ulaval.ca
http://www.chm.ulaval.ca/tollevier/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301100.
Eur. J. Org. Chem. 2013, 6525–6529
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6525

B. Plancq, L. C. Justafort, M. Lafantaisie, T. Ollevier
SHORT COMMUNICATION
Table 1. Optimization of reaction conditions – solvent and tem-
perature.
Table 3. Catalytic diastereoselective Mukaiyama aldol reaction –
aldehyde scope.
[
a]
[a]
Entry
Solvent
MeCN
Temp.
Time
[h]
syn/anti[b] Yield
[°C]
[%]
1
2
3
4
5
6
7
8
22
22
22
22
22
22
1
1
24
24
0.5
1
56:44
57:43
54:46
40:60
–
90
95
42
30
–
CH
Et
2 2
Cl
2
O
2-MeTHF
EtOH
DME/H
MeCN
CH Cl
2
O (4:1)
–
–
–40
–78
1.5
3
55:45
70:30
90
92
2
2
[
a] Silyl enol ether (1.5 equiv.), benzaldehyde (1 equiv.). [b] Deter-
1
mined by analysis of the crude material by H NMR spectroscopy.
The loading of Ga(OTf) was then examined under the
3
best reaction conditions, that is, by using CH Cl at –78 °C
2
2
(Table 2). Decreasing the loading to 0.2 or 0.1 mol-% did
not greatly affect the reaction time, but good yields were
maintained (Table 2, entries 2 and 3). Moreover, the dia-
stereoselectivity was significantly improved up to 85:15
(Table 2, entry 2). Even with a very low catalyst loading of
0.01 mol-%, a very good yield could be obtained, albeit
with an extended reaction time (Table 2, entry 4).
Table 2. Optimization of reaction conditions – catalyst loading.[a]
Entry
Ga(OTf)
3
loading
Time
[h]
syn/anti[b]
Yield
[%]
[mol-%]
1
2
3
4
1
3
4
4
70:30
85:15
83:17
70:30
92
80
79
90
0.2
0.1
0.01
30
[
a] Silyl enol ether (1.5 equiv.), benzaldehyde (1 equiv.). [b] Deter-
[
–
a] Silyl enol ether (1.5 equiv.), benzaldehyde (1 equiv.), CH
2 2
Cl ,
1
mined by analysis of the crude material by H NMR spectroscopy.
78 °C, 4–192 h. [b] Determined by analysis of the crude material
1
by H NMR spectroscopy. [c] Complex mixture of aldol products
and byproducts. [d] Ga(OTf) (1 mol-%), 0 °C. [e] Ga(OTf)
From a practical point of viewϪmainly in terms of
3
3
shorter reaction timesϪ0.2 mol-% Ga(OTf) was kept as (0.2 mol-%), 0 °C.
3
the optimal catalyst loading, and a wide range of aldehydes
were tested in the Mukaiyama aldol reaction with propio-
phenone-derived silyl enol ether 1 (Table 3). In rare cases, catalyst loading and reaction temperature (Table 3, entry 7).
if reactivity problems were encountered, the temperature However, upon using an aldehyde bearing a strong electron-
and/or the catalyst loading were/was consequently adjusted. donating group, such as 4-methoxybenzaldehyde, a complex
Differently substituted benzaldehydes reacted smoothly mixture of aldol products and byproducts was obtained,
and delivered the products in good yields with good selec- which rendered purification very difficult (Table 3, entry 3).
tivities (Table 3, entries 1–12). For para-substituted benz- Notably, reverse selectivity was observed with ortho-substi-
aldehydes, yields ranging from 76 to 83% were obtained at tuted benzaldehydes (Table 3, entries 8–12). Although sim-
–
8
78 °C, along with good diastereoselectivities (73:27 to ilar chemical yields were obtained (74 to 92%), the anti iso-
5:15; Table 3, entries 1–6). A very good yield of 87% was mers were formed as the major products.
also obtained with less-reactive 4-nitrobenzaldehyde; the
The reaction proceeded smoothly with 2-naphthylcarb-
low diastereoselectivity was probably due to the increased oxaldehyde, and the product was isolated in very good yield
6526
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6525–6529

Diastereoselective Mukaiyama Aldol Reaction
with good diastereoselectivity (Table 3, entry 13). Conju- we cannot rule out that HOTf is the actual catalytic species
gated aldehydes such as cinnamaldehyde (Table 3, entry 14) involved in the process. To discriminate between these two
and acetylenic aldehydes (Table 3, entries 15–17) provided possible reaction pathways, the aldol reaction was carried
the corresponding aldol products in moderate to good out in the presence of 2,6-di(tert-butyl)pyridine (DTBP),
yields, though low diastereoselectivities were recorded in the which is known to inhibit any potential Brønsted acid catal-
[
12]
series of acetylenic aldehydes. Our method was further ex- ysis.
Under our reaction conditions with the use of
tended to heteroaromatic aldehydes, which gave the aldol DTBP [silyl enol ether 1 (1.5 equiv.), benzaldehyde (2a,
products with good diastereoselectivities but in poor chemi- 1.0 equiv.), Ga(OTf)3 (0.2 mol-%), DTBP (0.6 mol-%),
cal yields (Table 3, entries 18 and 19). For aliphatic alde- –78 °C, 4 h], the aldol reaction was completely inhibited
hydes, the corresponding aldol products were obtained with (complete recovery of the starting materials). Additional
good diastereoselectivities but in low yields owing to incom- control experiments were performed with triflic acid. Upon
plete conversion to the products (Table 3, entries 20–22).
using 0.6 mol-% HOTf, only byproducts were formed and
Our reaction conditions were then applied to silyl enol- no trace amount of desired β-hydroxy ketone 3a was ob-
ates 4–9 (Table 4). Acetophenone-derived silyl enol ether re- served. Lowering the catalyst loading of HOTf to 0.2, 0.1,
acted smoothly under the standard conditions to afford the and 0.01 mol-% resulted in the formation of small amounts
corresponding aldol product in high yield (Table 4, entry 1). of aldol product 3a (20–40% yield), along with the same
Low selectivities were obtained with cyclohexanone- and 3- byproducts. Upon using 0.001 mol-% HOTf, no reaction
pentanone-derived silyl enol ethers, but the corresponding occurred. Furthermore, TMSOTf, which could be gener-
β-hydroxy ketones were nevertheless isolated in moderate to ated by the protodesilylation of the silyl enol ether,[ pro-
good yields (Table 4, entries 2 and 3). (O,O)- and (O,S)-Silyl vided the aldol adduct in the same low yield as that pro-
ketene acetals were also suitable substrates for the reaction, vided with HOTf. All these results suggest that a Brønsted
which furnished the corresponding ester and thioester prod- acid is clearly involved in the process. However, the observa-
13]
ucts in good yields (Table 4, entries 4 and 5). Finally, a vin- tion that the yield of the HOTf-catalyzed reaction is lower
ylogous Mukaiyama aldol reaction[
7c,11]
was successfully than that of the Ga(OTf) -catalyzed process suggests that a
3
carried out. It proceeded exclusively through γ-addition, gallium(III) salt is likely to be involved to some extent as a
and the corresponding vinylogous aldol was obtained in Lewis acid as well. Probably, Brønsted acid activation of
[
14]
good yield (Table 4, entry 6).
the Lewis acid occurs.
Moreover, the concentration of
HOTf in the reaction medium seems crucial. We assume
that the slow release of HOTf from the hydrolysis of
Table 4. Catalytic diastereoselective Mukaiyama aldol reaction –
silyl enolate scope.
[
a]
Ga(OTf) is the sine qua non condition for the reaction to
3
proceed in good yields. Even if CH Cl was systematically
2
2
[15]
freshly distilled from CaH , the residual water content
2
slowly hydrolyzed Ga(OTf) into HOTf. Interestingly, if the
3
model reaction was carried out in the presence of 4 Å mo-
[
16]
lecular sieves, the reaction was completely inhibited and
the starting materials were quantitatively recovered. This re-
sult lends further support to the argument that slow hydrol-
ysis of Ga(OTf) is essential to the success of this aldol
3
reaction.
Conclusions
In conclusion, we have developed an efficient process
that allows formation of aldol products under mild condi-
tions with a very low catalyst loading of Ga(OTf) . A wide
3
range of substrates can be used in this diastereoselective
Mukaiyama aldol reaction. To the best of our knowledge,
this is the first example of a metal triflate acting as a safe
and stable slow-releasing source of triflic acid to be re-
ported for the Mukaiyama aldol reaction. HOTf is not
[
a] Silyl enol ether (1.5 equiv.), benzaldehyde (1 equiv.). [b] Deter- bench stable, and special care is needed to handle this
1
mined by analysis of the crude material by H NMR spectroscopy. strong acid. In contrast, Ga(OTf) is a stable white solid
3
[
c] Ga(OTf)
–
–
3
(0.2 mol-%), –78 °C. [d] Ga(OTf)
78 °C. [e] Ga(OTf) (1.0 mol-%), 0 °C. [f] Ga(OTf)
45 °C.
3
(1.0 mol-%),
(0.2 mol-%),
that can be easily weighed. Although only moderate stereo-
selectivities were obtained, Ga(OTf) was demonstrated to
be very efficient to get the Mukaiyama aldol reaction to
3
3
3
Given that Ga(OTf) is known to be easily hydrolyzed, proceed by using only very low catalyst loadings (down to
3
which leads to the release of triflic acid into the medium, 0.01 mol-%). Moreover, both Ga(OTf)3 and HOTf have
Eur. J. Org. Chem. 2013, 6525–6529
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6527

B. Plancq, L. C. Justafort, M. Lafantaisie, T. Ollevier
SHORT COMMUNICATION
never been extensively used as a catalyst for the Mukaiyama anti): δ = 10.9, 15.7, 44.9, 47.0, 67.8 (d, J = 1.7 Hz), 70.8 (d, J =
1.8 Hz), 115.2 (d, J = 21.4 Hz), 115.5 (d, J = 22.0 Hz), 124.4 (d, J
[
17]
aldol reaction,
which renders our methodology inno-
=
=
3.5 Hz), 124.6 (d, J = 3.4 Hz), 128.5 (d, J = 4.4 Hz), 128.6 (d, J
4.3 Hz), 128.7, 128.8, 128.9, 129.0 (d, J = 8.3 Hz), 129.0 (d, J =
vative. Beyond the fact that Ga(OTf) acts as a HOTf surro-
3
gate, it also surpasses it in terms of efficiency and cleanli-
ness of the reaction,[ presumably because of its involve-
ment to some extent as a Lewis acid. Other applications in
synthesis will be reported in due course.
1
1
2
2.9 Hz), 129.1, 129.4 (d, J = 8.3 Hz), 129.6 (d, J = 13.5 Hz), 133.7,
33.9, 135.8, 136.7, 159.4 (d, J = 244.5 Hz), 160.2 (d, J = 245.4 Hz),
18]
+
05.2, 206.0 ppm. HRMS (ESI-TOF): calcd. for C16H15FNaO
2
M + Na]+ 281.0948; found 281.0948.
[
3-(2-Bromophenyl)-3-hydroxy-2-methyl-1-phenylpropan-1-one (3j):
Colorless oil, white solid (m.p. 90–95 °C), yield 242.5 mg (76%).
Reaction time = 5 h. R (hexane/AcOEt = 4:1) = 0.64 (syn), 0.47
anti). IR (neat): ν˜ = 3506, 3485, 2982, 1960, 1819, 1662, 1592,
Experimental Section
f
(
General Information: All reactions were performed in flame-dried
–
1 1
1
3
4
3
468, 1370, 1214, 917, 681 cm . H NMR (400 MHz, CDCl , syn-
j): δ = 1.11 (d, J = 7.3 Hz, 3 H), 3.98 (dq, J = 7.3, 1.4 Hz, 1 H),
.10 (d, J = 1.4 Hz, 1 H), 5.51 (dd, J = 1.4, 1.4 Hz, 1 H), 7.13–7.21
12ϫ75 mm culture tubes under an atmosphere of nitrogen or ar-
gon. Dichloromethane (CH Cl ) was distilled from CaH . Solid al-
2
2
2
dehydes were used as received and liquid aldehydes were distilled
prior to use. Gallium(III) triflate was purchased from Strem Chem-
(
m, 1 H), 7.35–7.42 (m, 1 H), 7.47–7.58 (m, 3 H), 7.59–7.65 (m, 1
1
ical. 1H NMR and C NMR spectra were recorded with a
13
H), 7.67–7.72 (m, 1 H), 8.00–8.07 (m, 2 H) ppm. H NMR
1
(400 MHz, CDCl , anti-3j): δ = 1.31 (d, J = 7.2 Hz, 3 H), 3.96 (br.
400 MHz spectrometer in CDCl
3
. For H NMR (400 MHz), tet-
3
s, 1 H), 4.06 (dq, J = 7.2, 6.0 Hz, 1 H), 5.38 (d, J = 6.0 Hz, 1 H),
ramethylsilane served as an internal standard (δ = 0 ppm) and data
are reported as follows: chemical shift, multiplicity (s = singlet, d
7
7
.04–7.11 (m, 1 H), 7.23–7.30 (m, 1 H), 7.37–7.44 (m, 2 H), 7.46–
.56 (m, 3 H), 7.81–7.87 (m, 2 H) ppm. C NMR (100 MHz,
1
3
=
doublet, t = triplet, q = quartet, m = multiplet, br. = broad),
13
3
CDCl , syn + anti): δ = 10.6, 16.1, 43.1, 45.8, 72.0, 75.5, 121.5,
coupling constant, and integration. For C NMR (100 MHz),
CDCl was used as internal standard (δ = 77.23 ppm) and spectra
1
1
2
22.6, 127.6, 128.0, 128.5, 128.6, 128.9, 128.9, 129.1, 129.1, 129.3,
3
29.3, 132.9, 132.9, 133.7, 134.1, 135.7, 136.7, 140.3, 141.8, 205.7,
were obtained with complete proton decoupling. IR spectra were
recorded with a FTIR spectrometer with ZnSe ATR accessory.
High-resolution mass spectra (HRMS) were recorded with an ESI
TOF mass spectrometer. Flash column chromatography was per-
formed on silica gel (230–400 mesh), and analytical thin-layer
chromatography was carried out by using 250 μm commercial silica
gel plates. Visualization of the developed chromatogram was per-
formed by UV absorbance and/or aqueous potassium permanga-
nate.
+
06.9 ppm. HRMS (ESI-TOF): calcd. for C16
H15BrNaO
2
[M +
+
Na] 341.0148; found 341.0151.
3-Hydroxy-2-methyl-3-(2-nitrophenyl)-1-phenylpropan-1-one (3k):
Orange oil and yellow crystals (m.p. 94–99 °C), yield 237.2 mg
(
f
83%). Reaction time = 120 h. R (hexane/AcOEt = 4:1) = 0.32
(
1
syn), 0.21 (anti). IR (neat): ν˜ = 3477, 3380, 2978, 2855, 2359, 1682,
519, 1160, 1000, 883, 703, 681 cm . H NMR (400 MHz, CDCl ,
3
–1
1
syn-3k): δ = 1.17 (d, J = 7.3 Hz, 3 H), 4.01 (dq, J = 7.3, 1.8 Hz, 1
H), 4.24 (br. s, 1 H), 5.80 (d, J = 1.8 Hz, 1 H), 7.42–7.53 (m, 3 H),
Typical Procedure for the Gallium Triflate Catalyzed Mukaiyama
Aldol Reaction: A mixture of Ga(OTf)
7.57–7.64 (m, 1 H), 7.65–7.72 (m, 1 H), 7.94–8.07 (m, 4 H) ppm.
3
(0.2–1.0 mol-%) in CH
2
Cl
2
1
(1 mL) was cooled to –78 °C. Aldehyde (1 mmol) and silyl enol
3
H NMR (400 MHz, CDCl , anti-3k): δ = 1.34 (d, J = 7.2 Hz, 3
ether (1.5 mmol) were subsequently added to the mixture. The reac-
tion mixture was stirred at the same temperature until the aldehyde
was completely consumed (monitored by TLC). The reaction was
H), 4.09 (dq, J = 7.2, 5.3 Hz, 1 H), 4.43 (br. s, 1 H), 5.55 (d, J =
5.3 Hz, 1 H), 7.32–7.43 (m, 3 H), 7.50–7.57 (m, 2 H), 7.67–7.71 (m,
1
3
3
1 H), 7.79–7.89 (m, 3 H) ppm. C NMR (100 MHz, CDCl , syn
quenched with saturated aqueous NaHCO
mixture was extracted with diethyl ether (3ϫ 10 mL), and the com-
bined organic layer was dried with MgSO . The solvents were evap-
3
(5 mL). The resulting
+ anti): δ = 11.2, 16.6, 44.3, 45.6, 68.9, 72.5, 124.7, 125.0, 128.5,
128.6, 128.6, 128.9, 129.0, 129.1, 129.2, 129.9, 133.5, 133.6, 134.0,
134.1, 135.6, 136.5, 137.3, 138.2, 147.5, 148.4, 205.7, 206.6 ppm.
4
+
[M + H]+ 286.1074;
orated under reduced pressure (rotary evaporator). The crude prod-
uct was dissolved in THF (1.5 mL) and 1 m HCl (0.75 mL) was
added. The mixture was stirred for 15–30 min and then quenched
and extracted as mentioned above. The product was purified by
chromatography on silica gel (hexane/ethyl acetate). The syn/anti
ratio was determined by 1H NMR spectroscopy. The diastereo-
isomers of products 3h–l, 11, and 15 were separated by silica gel
flash column chromatography.
HRMS (ESI-TOF): calcd. for C16
found 286.1075.
H16NO
4
3
1
2
-Hydroxy-2-methyl-1-phenyl-3-[2-(trifluoromethyl)phenyl]propan-
-one (3l): White solids [m.p. 30–35 (syn), 90–95 °C (anti)], yield
f
86.0 mg (92%). Reaction time = 48.5 h. R (hexane/AcOEt = 4:1)
=
0.53 (syn), 0.39 (anti). IR (neat): ν˜ = 3463, 3420, 2987, 2976,
–
1
1
1975, 1849, 1667, 1597, 992, 867, 772, 684 cm . H NMR
(
400 MHz, CDCl , syn-3l): δ = 1.20 (d, J = 7.3 Hz, 3 H), 3.74 (dq,
3
3
-(2-Fluorophenyl)-3-hydroxy-2-methyl-1-phenylpropan-1-one (3h):
Colorless oil, yield 211.8 mg (82%). Reaction time = 8 h. R (hex-
ane/AcOEt = 4:1) = 0.51 (syn), 0.41 (anti). IR (neat): ν˜ = 3488,
J = 7.3, 1.2 Hz, 1 H), 4.13 (d, J = 1.2 Hz, 1 H), 5.67 (dd, J = 1.2,
f
1.2 Hz, 1 H), 7.39–7.45 (m, 1 H), 7.46–7.53 (m, 2 H), 7.58–7.65
1
(m, 2 H), 7.65–7.71 (m, 1 H), 7.89–7.98 (m, 3 H) ppm. H NMR
–
1
3
3
446, 2972, 1917, 1674, 1595, 1455, 1219, 1001, 969, 828, 659 cm . (400 MHz, CDCl , anti-3l): δ = 1.08 (d, J = 7.3 Hz, 3 H), 3.60 (d,
1
H NMR (400 MHz, CDCl
3
, syn-3h): δ = 1.15 (d, J = 7.3 Hz, 3
J = 5.6 Hz, 1 H), 3.97 (dq, J = 7.3, 6.0 Hz, 1 H), 5.53 (dd, J = 6.0,
H), 3.84 (dq, J = 7.3, 2.0 Hz, 1 H), 3.89 (br. s, 1 H), 5.54 (d, J =
5.6 Hz, 1 H), 7.34–7.41 (m, 1 H), 7.41–7.48 (m, 2 H), 7.52–7.59 (m,
2
1
.0 Hz, 1 H), 7.00–7.08 (m, 1 H), 7.14–7.22 (m, 1 H), 7.22–7.31 (m, 2 H), 7.63–7.68 (m, 1 H), 7.73–7.79 (m, 1 H), 7.90–7.97 (m, 2
1
3
H), 7.44–7.54 (m, 2 H), 7.56–7.68 (m, 2 H), 7.95–8.04 (m, 2
3
H) ppm. C NMR (100 MHz, CDCl , syn + anti): δ = 10.6, 15.9,
1
H) ppm. H NMR (400 MHz, CDCl
7
1
3
, anti-3h): δ = 1.16 (d, J =
.2 Hz, 3 H), 3.62 (d, J = 6.2 Hz, 1 H), 3.95 (dq, J = 7.2, 7.2 Hz,
H), 5.34 (dd, J = 7.2, 6.2 Hz, 1 H), 6.97–7.06 (m, 1 H), 7.09–7.17
45.0, 47.8, 68.6 (q, J = 1.8 Hz), 71.6 (q, J = 2.2 Hz), 124.6 (q, J =
273.5 Hz), 124.8 (q, J = 274.0 Hz), 125.9 (q, J = 5.9 Hz), 126.2 (q,
J = 5.9 Hz), 126.7 (q, J = 30.0 Hz), 127.8, 128.1 (q, J = 29.9 Hz),
128.1, 128.5, 128.6, 128.8, 128.9, 129.1, 129.3, 132.0, 132.6, 133.7,
3
, syn + 134.1, 135.5, 136.8, 140.1 (q, J = 1.2 Hz), 141.4 (q, J = 1.2 Hz),
(m, 1 H), 7.19–7.28 (m, 1 H), 7.39–7.47 (m, 2 H), 7.47–7.58 (m, 2
13
H), 7.90–7.98 (m, 2 H) ppm. C NMR (100 MHz, CDCl
6528
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6525–6529

Diastereoselective Mukaiyama Aldol Reaction
04.9, 206.8 ppm. HRMS (ESI-TOF): calcd. for C17
+
2
H
16
F
3
O
2
[M
Yamashita, H. Shimizu, S. Kobayashi, J. Am. Chem. Soc. 2000,
122, 5403; h) E. M. Carreira, R. A. Singer, W. Lee, J. Am.
Chem. Soc. 1994, 116, 8837; i) D. A. Evans, J. A. Murry, M. C.
Kozlowski, J. Am. Chem. Soc. 1996, 118, 5814; j) D. A. Evans,
M. C. Kozlowski, C. S. Burgey, D. W. C. MacMillan, J. Am.
Chem. Soc. 1997, 119, 7893; k) D. A. Evans, D. W. C. MacMil-
lan, K. R. Campos, J. Am. Chem. Soc. 1997, 119, 10859; for
asymmetric Mukaiyama aldol reactions under aqueous condi-
tions, see: l) T. Ollevier, B. Plancq, Chem. Commun. 2012, 48,
+
+
H] 309.1097; found 309.1095.
-Hydroxy-2-methyl-1-phenyl-5-(trimethylsilyl)pent-4-yn-1-one (3q):
Colorless oil, yield 188.0 mg (72%). Reaction time = 192 h. R (hex-
ane/AcOEt = 4:1) = 0.45 (syn), 0.40 (anti). IR (neat): ν˜ = 3445,
3
f
–
1
2
960, 2174, 1678, 1596, 1448, 1372, 1249, 967, 838, 706, 686 cm .
1
H NMR (400 MHz, CDCl
7.2 Hz, 3 H), 3.21 (br. s, 1 H), 3.68 (dq, J = 7.2, 4.2 Hz, 1 H),
.82 (d, J = 4.2 Hz, 1 H), 7.43–7.52 (m, 2 H), 7.55–7.62 (m, 1 H),
3
, syn-3q): δ = 0.12 (s, 9 H), 1.41 (d, J
=
2289, and references cited therein.
4
7
=
1
[5] G. A. Olah, O. Farooq, S. M. F. Farnia, J. A. Olah, J. Am.
.91–8.01 (m, 2 H) ppm. H NMR (400 MHz, CDCl
0.13 (s, 9 H), 1.31 (d, J = 7.2 Hz, 3 H), 3.12 (br. s, 1 H), 3.77
dq, J = 7.5, 7.2 Hz, 1 H), 4.70 (d, J = 7.5 Hz, 1 H), 7.43–7.52
3
, anti-3q): δ
Chem. Soc. 1988, 110, 2560.
[
[
6] G. K. S. Prakash, T. Mathew, G. A. Olah, Acc. Chem. Res.
012, 45, 565.
(
(
(
6
1
2
1
3
m, 2 H), 7.55–7.62 (m, 1 H), 7.91–8.01 (m, 2 H) ppm. C NMR
100 MHz, CDCl , syn + anti): δ = 0.0, 0.0, 12.8, 15.7, 46.5, 47.1,
3.9, 65.3, 90.5, 91.1, 104.5, 105.1, 128.7, 128.8, 128.9, 129.0, 133.7,
33.8, 136.0, 136.6, 203.9, 204.2 ppm. HRMS (ESI-TOF): calcd.
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Bouchard, V. Desyroy, J. Org. Chem. 2008, 73, 331.
3
+
+
for C15
H
21
O
2
Si [M + H] 261.1305; found 261.1303.
[8] a) H.-J. Li, H.-Y. Tian, Y.-J. Chen, D. Wang, C.-J. Li, Chem.
Commun. 2002, 2994; b) H.-J. Li, H.-Y. Tian, Y.-C. Wu, Y.-J.
Chen, L. Liu, D. Wang, C.-J. Li, Adv. Synth. Catal. 2005, 347,
Supporting Information (see footnote on the first page of this arti-
1
13
cle): Copies of the H NMR and C NMR spectra and characteri-
zation data for all compounds.
1247.
[
[
9] K. Ishihara, Y. Hiraiwa, H. Yamamoto, Synlett 2001, 1851.
10] a) C. F. Baes Jr., R. E. Mesmer, The Hydrolysis of Cations,
Wiley, New York, 1976; b) S. Kobayashi, S. Nagayama, T. Bu-
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Acknowledgments
This work was financially supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the Centre in
Green Chemistry and Catalysis (CGCC), the Canada Foundation
for Innovation (CFI), and Université Laval. L. C. J. is grateful to
the Organization of American States (OAS) for an M.Sc. scholar-
ship. M. L. thanks NSERC and the Fonds Québécois de Recherche
Nature et Technologies (FQRNT) for M.Sc. scholarships.
[
11] G. Casiraghi, L. Battistini, C. Curti, G. Rassu, F. Zanardi,
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[12] For use of this base to differentiate between Lewis acid and
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[
1] a) I. Shiina, Modern Aldol Reactions (Ed.: R. Mahrwald),
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[
2 2
2] a) T. Mukaiyama, K. Narasaka, K. Banno, Chem. Lett. 1973, [16] Freshly distilled CH Cl (1 mL) was stirred over activated 4 Å
1011; b) T. Mukaiyama, K. Banno, K. Narasaka, J. Am. Chem.
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3
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–78 °C, the reagents were successively added.
[17] The use of HOTf is only limited to a few table entries for which
it was used during the optimization processes. For example,
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1988, 61, 1237; b) S. E. Denmark, W. Lee, Chem. Asian J. 2008,
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[
3] G. A. Slough, R. G. Bergman, C. H. Heathcock, J. Am. Chem.
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[
4] For selected examples, see: a) T. Mukaiyama, S. Kobayashi,
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3
[18] If 0.01 mol-% of Ga(OTf) was used, an excellent yield of 3a
1
991, 113, 9365; d) E. J. Corey, C. L. Cywin, T. D. Roper, Tetra-
was obtained (t = 30 h, syn/anti = 70:30, yield 90%), whereas
HOTf only afforded low yields of the aldol product.
Received: July 24, 2013
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Published Online: September 5, 2013
Eur. J. Org. Chem. 2013, 6525–6529
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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