An environmentally friendly Mukaiyama aldol reaction catalyzed by a strong Bronsted acid in solvent-free conditions

Article abstract of DOI:10.1039/c0ob00837k

o-Benzenedisulfonimide, a new strong bench-stable Bronsted acid, has been shown to efficiently catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under mild solvent-free reaction conditions.

Full text of DOI:10.1039/c0ob00837k

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PAPER
An environmentally friendly Mukaiyama aldol reaction catalyzed by a strong
Brønsted acid in solvent-free conditions†
Margherita Barbero,* Stefano Bazzi, Silvano Cadamuro, Stefano Dughera, Claudio Magistris,
Alessandra Smarra and Paolo Venturello
Received 6th October 2010, Accepted 16th December 2010
DOI: 10.1039/c0ob00837k
o-Benzenedisulfonimide, a new strong bench-stable Brønsted acid, has been shown to efficiently
catalyze the Mukaiyama aldol reaction of aldehydes or dimethyl acetals with silyl enol ethers under
mild solvent-free reaction conditions.
The same authors have also developed the synthesis of N,N-
bis(perfluoroalkanesulfonyl) squaric acid diamides and applied
them as catalysts in two Mukaiyama reactions and in a carbonyl-
ene reaction.3c,d
Introduction
The Mukaiyama aldol reaction1 is one of the most powerful
carbon-carbon bond-forming reactions. The interest in the syn-
thetic developments of this reaction is high, because of the
widespread presence of the aldol motif in natural products.
The reaction occurs between silyl enol ethers or ketene silyl
acetals and carbonyl compounds to afford b-hydroxy ketones
or b-trimethylsilyloxy esters, respectively. The advantages of the
Mukaiyama reaction over the direct cross-aldol reaction are its
milder reaction conditions, nonreversibility, high product yields
and lower amounts of dehydration side-products. The aforemen-
tioned enol equivalents are stable enough to be easily prepared
and stored, but a catalyst is needed to obtain the aldol reaction.
Normally Lewis acid or Lewis base catalysts are used in catalytic
loadings to activate the electrophilic carbonyl substrate or the
nucleophilic silyl enol equivalent, respectively, so a huge number
of examples has been reported in the literature.2 By contrast, in
the last decade very few Brønsted acids have been used as catalysts
in this reaction.
Extraordinarily bulky tris(trimethylsilyl)silyl (TTMSS) enol
ethers of acetaldehyde and propanal have been successfully
reacted with a variety of aliphatic aldehydes in the presence of
bis(trifluoromethanesulfonyl)imide (triflimide, HNTf2)3b as the
catalyst (0.05 mol %). Identical results were obtained by using
TTMSSNTf2. This finding was explained with the silyl triflimide
as the likely true self-repairing catalyst.
A chiral 3,3¢-disubstituted 1,1¢-binaphthyl-2,2¢-disulfonimide
has been reported as the catalyst (2–5 mol %) in an asymmetric
application of the Mukaiyama reaction.4 Ketene silyl acetals were
used as enol equivalents in the reaction with aromatic, a,b-
unsaturated and aliphatic aldehydes with high enantioselectivity. A
Lewis acid mechanism, supported by NMR studies, was proposed.
This involved an intermediate N-silyl disulfonimide as the actual
catalyst.
Rawal and coworkers have reported the catalytic use
of a,a,a¢,a¢-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)
family diols (20 mol %) in both diastereoselective and enan-
tioselective Mukaiyama aldol reactions5a,b and in vinylogous
Mukaiyama aldol reactions.5c The hydrogen bond between the
chiral diols and the carbonyl substrates (aromatic aldehydes or
b-ketoesters) generates highly ordered transition states. These are
responsible for the high enantioselectivity observed in the reaction
products when using hetero-atom substituted ketene acetals.
Several bis-sulfonamides have also been reported to activate,
through hydrogen bonding, the carbonyl group of aromatic
aldehydes in the Mukaiyama reaction with silyl ketene acetals.6
Brønsted acid assisted chiral Lewis acid catalysts, namely chiral
acyloxyboranes derived from tartaric acid, have also been reported
to efficiently catalyze the Mukaiyama aldol reaction of aldehydes
with trimethylsilyl enol ethers7a–b or ketene silyl acetals.7c The high
and enantioselective reactivity of these catalysts was attributed
to the intramolecular hydrogen bonding of a terminal carboxylic
group.
N,N-Bis(trifluoromethanesulfonyl) squaramide has recently
been reported as a strong bench-stable Brønsted acid and ap-
plied in catalytic amounts (1 mol %) to Mukaiyama aldol and
Mukaiyama-Michael reactions between trimethylsilyl enol ethers
and aromatic aldehydes (or electron-deficient ketones) and a,b-
unsaturated ketones, respectively.3a The reaction mechanism was
investigated, since it is known that the Mukaiyama aldol reaction
may be promoted by either a true Brønsted acid catalyst or a
Lewis acid catalyst which corresponds to the in situ silylated
Brønsted acid.3b On the basis of the observed results, a real
Brønsted acid catalysis is however preferred by the authors.
Dipartimento di Chimica Generale
e Chimica Organica, Univer-
sita` degli Studi di Torino, Via Pietro Giuria, 7, 10125, Torino,
Italy. E-mail: margherita.barbero@unito.it; Fax: +390116707642;
Tel: +390116707645
† Electronic supplementary information (ESI) available: General proce-
dures, 1H and 13C NMR spectra of products 6a–e, 9a–i, 10, 12, 13a, 14a–c.
See DOI: 10.1039/c0ob00837k
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Finally, catalytic amounts of benzoic acid improved a boron
enolate-mediated diastereoselective Mukaiyama aldol reaction
between silyl enol ethers and aromatic aldehydes, in the presence
of aryl borinic acids as boron source and a surfactant in water. The
role of the weak Brønsted acid was presumed to be the acceleration
of the Si–B exchange step through the protonation of the hydroxyl
group of the borinic acid.8
the dimethyl acetals of aromatic or aliphatic aldehydes. These,
activated by a Lewis acid catalyst, gave oxocarbenium ions which
are a class of electrophiles that is known to undergo Mukaiyama-
type addition.
Results and discussion
We have recently described the usefulness of a new strong
Brønsted acid, namely o-benzenedisulfonimide (1) (Fig. 1), in
organic synthesis.9 Compared to Lewis acid metal catalyzed
reactions, this compound has proved to be a more efficient and
recyclable organocatalyst in many acid-catalyzed organic reactions
in environmentally friendly conditions.9d,f–h,j
Initially, in order to optimize the reaction conditions, the
model reaction of 1-trimethylsilyloxycyclohex-1-ene (2) or 1-
trimethylsilyloxystyrene (3) and 4-chlorobenzaldehyde (4a; Ar =
4-ClC6H4) catalyzed by 1 was studied under different reactant
ratios and conditions (Scheme 1). The intermediate trimethylsilyl
derivatives 5a and 8a were not isolated and so were immediately
hydrolyzed to the aldol products 6a and 9a.
The most representative results, obtained from trimethylsilyl
enol ethers 2 (entries 1–5) and 3 (entries 6–9), are reported in
Table 1 and can be summarized as follows. The optimal reactant
ratios between the enol equivalents and aldehyde 4a were 2 : 1 and
1.3 : 1, respectively. Polar or slightly polar solvents were tested, but
the best results were obtained in solvent-free reaction conditions.
The effect of the catalytic amount of 1 was also studied. In
the presence of solvents, larger quantities of catalyst were used,
without producing significant product yields. In the optimized
reaction conditions, i.e. without any solvent, 1 was used in 1 mol
% starting from 2 and 2 mol % from 3. All the reactions were
carried out at rt and reached completion in short times. When 2
Fig. 1 o-Benzenedisulfonimide (1).
Herein we wish to report that 1 can catalyze the Mukaiyama
aldol reaction between silyl enol ethers 2 (or 3) and carbonyl com-
pounds 4 in mild and solvent-free reaction conditions in very low
amounts. Reaction conditions were also extended to acetals 13. In
an interesting variation of the Mukaiyama aldol reaction, dimethyl
acetals were used as highly electrophilic aldehyde surrogates.10a
Enol silanes were formed in situ10b and one-pot reacted with
Scheme 1 Mukaiyama aldol reaction between enol equivalents 2 or 3 and aldehydes 4.
Table 1 Mukaiyama aldol trial reactions of 2 (or 3) with 4a
Entry
Reactant ratioa
1 (mol %)
Solvent/t (h)
Products, Yields (%)b
drc
1
2
3
4
5
6
7
8
2:4a = 1.1 : 1
2:4a = 1.5 : 1
2:4a = 2 : 1
1
1
1
Neat/4
Neat/4
Neat/4
CH2Cl2/48
Tol/5
MeCN/5
CH2Cl2/48
Neat/2
Neat/2
Neat/2
6a, 49 7a, 11
57 : 43
55 : 53
50 : 50
6a, 56 7a (n.d.)
6a, 68 7a, 5
d
2:4a = 2 : 1
1–10
1–5
1–10
1–10
1–5
2
d
e
e
2:4a = 2 : 1
3:4a = 1.1 : 1
3:4a = 1.1 : 1
3:4a = 1.1 : 1
3:4a = 1.3 : 1
2:4a = 2 : 1
9a, 60
9a, 87
6a, 38 7a, 5
9a, 63
9
10
11
2f
50 : 50
3:4a = 1.3 : 1
4f
Neat/4
a Unless otherwise stated, the reactions were carried out on 2 mmol of 4a, at rt (20–25 ◦C). After completion of the reaction, the reaction mixture was
1
treated with 2 N HCl (2 mL) to hydrolyze 5a to 6a or 8a to 9a. b Products identified by H and 13C NMR spectra; yields % of isolated products (flash
chromatography; PE/AcOEt = 7 : 3). c dr (syn/anti) determined by 1H NMR spectroscopy. d Expected products were identified, but in low amounts. e In
MeCN 3 decomposes completely to acetophenone, whilst in CH2Cl2 the acid hydrolysis of 8a does not proceed to completion. f 2,4-Dinitrobenzenesulfonic
acid was used as the catalyst.
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Table 2 Mukaiyama aldol reaction of enol ethers 2 or 3 with aldehydes 4
Entry
Reactantsa
1 (mol %)
t (h)
Products, Yields (%);b overall yield
drc
Lit. [%]d
1
2
3
4
5
6
7
8
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4a
4b
4c
4d
4e
4a
4b
4c
4d
4e
4f
1
2
2
3
5
2
2
3
4
4
2
4
4
1
2
4
4
6a, 68; 7a, 5; overall 73
50 : 50
59 : 41
57 : 43
50 : 50
46 : 54
6b, 68; 7b, 16; overall 84
6
6c, 51; 7c, 19; overall 70
6d, 48; 7d, 15; overall 63
58(56 : 44),8 87 (80 : 20)3a
3e
6
6e, 48; 7e, 14; overall 62
9a, 87
2
1
2
2
2
3
6
1
973d
9b, 88
933a,d
963a,d
983a,d
9c, 80
9
9d, 91
10
11
12
13
14
15
9e, 96
9f, 98
953a,d
4g
4h
4i
9g, 80
9h, 89
913d
923d
1.5
24
9i, 80; 10, 16
11g
12,f 32
a Unless otherwise stated, the reactions were carried out on 2 mmol of 4, at rt (20–25 ◦C). The reactant ratio was 2: 4 = 2 : 1 and 3: 4 = 1.3 : 1. After
completion of the reaction, the reaction mixture was treated with 2 N HCl (2 mL) to hydrolyze 5 to 6 or 8 to 9. b Yields % refer to isolated products (flash
chromatography; eluent: PE:AcOEt = 7 : 3 in entries 1–5, 7, 9–10, 14 and PE:AcOEt = 8 : 2 in entries 6, 8, 11–13). c dr (syn/anti) determined by 1H NMR
spectroscopy. d Yields obtained in Brønsted acid-catalyzed Mukaiyama aldol reactions; dr in parentheses. e Reaction temperature was 50 ◦C. f Hexanal
(11) was the starting aldehyde.
was the starting enol equivalent, syn and anti diastereomers 6a
were obtained, but no significant stereocontrol of the Mukaiyama
aldol reaction was observed in the presence of 1 as the catalyst.
All these reactions gave the by-product 7a, as an acid-catalyzed
dehydration product of the aldol 6a.
In order to evaluate the role of the acidity of 1 on the
catalytic activation of the Mukaiyama reaction, the optimized
conditions of entries 3 and 9 were tested in the presence of 2,4-
dinitrobenzenesulfonic acid, a Brønsted acid commonly used as
an organocatalyst.11 As reported in entries 10 and 11 respectively,
greater amounts of catalyst were used, longer reaction times and
lower product yields were observed.
The optimized reaction conditions were then applied to the
Mukaiyama aldol reaction of a number of representative aromatic
aldehydes. Aldehydes 4b–g, bearing both electron-donating or
electron-withdrawing substituents (Scheme 1), were reacted with
the enol equivalents 2 (Table 2, entries 1–5) and 3 (Table 2, entries
6–12).
In general, larger amounts of catalyst (entries 4–5 and 9–10)
and heating (entry 4) were required in the presence of electron-
withdrawing groups. Lower yields and lower overall conversions
were also observed. Dehydration products 7 were always isolated
along with the predominant aldol products when 2 was reacted
(entries 1–5), whereas, higher selectivity and better aldol product
yields were obtained from 3. o-Substituted aldehydes were also
reacted with 3 (4f and 4g; entries 11–12). Longer reaction times
were required and, due to the electron-withdrawing effect of the
substituent group on 4g, a larger amount of catalyst was needed.
In the light of these results, the applicability of the acid catalyzed
Mukaiyama reaction of 3 with a heteroaromatic and an a,b-
unsaturated aldehyde was studied (2-thiophenecarboxaldehyde,
4h and cinnamaldehyde, 4i). Good results were also obtained
in these cases. Interestingly, in the reaction with 4i, 5-oxo-3,5-
diphenylpentanal (10) (Fig. 2) was isolated as the Mukaiyama-
Michael addition product in 16% yield (entry 14). In order to favor
the 1,2-addition over to the 1,4-, the reaction temperature was
Fig. 2 5-Oxo-3,5-diphenylpentanal (10).
lowered to 0 ◦C and then to -30 ◦C, but no appreciable variation
in the ratio of 9i to 10 was observed.
The literature yields of the aldol products 6 and 9, obtained in
Brønsted acid catalyzed Mukaiyama reactions, are also reported
in Table 2 for ease of comparison. Only few examples have been
recovered and the yields are comparable.
Owing to these encouraging results, some aliphatic aldehydes
were then tested, although only the bulky tris(trimethylsilyl)silyl
enol ethers of acetaldehyde and propanal have so far been reported
to react in a Mukaiyama reaction with aliphatic aldehydes
under similar reaction conditions (HNTf2 or TTMSSNTf2 as the
catalysts).3b
Unfortunately, phenylacetaldehyde, cyclohexanecarbaldehyde,
and pivalaldehyde never reacted, even under various reaction
conditions (neat or in MeCN, in the presence of 2–5 mol % of
1 at rt or by heating to 50 ◦C, prolonged times). Only hexanal (11)
gave the expected aldol product 12 in reaction with 3 in 32% yield
(Table 2, entry 15). Keeping in mind that dimethyl acetals have
been used as aldehyde surrogates,10a the dimethyl acetals of some
aliphatic aldehydes were then reacted with 3 in neat conditions
and in the presence of 1 as the catalyst (Scheme 2). The reaction
was achieved, although modest to good results were obtained, as
reported in Table 3.
Furthermore, although (R)-2,2¢-binaphthyldisulfonimide 1512
(Fig. 3) does not show any evidence of an enantiomeric induction,
the model Mukaiyama reaction between 2 and 4a was carried
out in its presence in the same optimized catalytic amounts of
1. Binaphthyl-derived chiral disulfonimides have recently received
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Table 3 Mukaiyama aldol-type reaction of 3 with dimethyl acetals 13
Entry
Reactantsa
1 (mol %)
t (h)
Yieldsb of 14 (%)
1
2
3
3
3
3
13a
13b
13c
2
2
3
30
4
24
14a, 81
14b, 61
14c, 33
a The reactions were carried out on 2 mmol of 13, at rt (20–25 ◦C). The reactant ratio was 3: 13 = 1.3 : 1. b Yields % refer to isolated products (flash
chromatography; eluent: PE:AcOEt = 9 : 1).
In order to differentiate between Lewis and Brønsted acid
catalysis, the reaction between 1-trimethylsilyloxystyrene (3) and
2-methylbenzaldehyde (4f) was first performed in the presence of
2,6-di-t-butyl-4-methylpyridine (DBMP) (Table 4, entry 1). This
hindered base is known to act as a proton scavenger that inhibits
any protic acid catalysis.3a–b,4 Under reaction conditions of entry
11, Table 2, and in the presence of 5 mol % of DBMP, the
Scheme 2 Mukaiyama-aldol type reaction catalyzed by 1.
reaction did not proceed to completion within the same time (1 h).
Moreover, when it was quenched after 24 h, traces of 3 and low
amounts of 4f were still recovered. Acid hydrolysis gave the aldol
product 9f in a 83% yield.
Then, in order to assess the transfer of the trimethylsilyl group
from 2 or 3 to 1 and therefore the in situ formation of the
Lewis acid catalyst 16, 1 (1.0 equiv) was added to the enol
1
ether 2 (or 3). H NMR spectra (anhydrous CDCl3) showed the
immediate hydrolysis of the silyl enol ethers 2 or 3 (with the
respective disappearance of singlets at 0.12 ppm and 0.23 ppm)
Fig. 3 (R)-2,2¢-Binaphthyldisulfonimide (15).
and the appearance of a new singlet centered at 0.59 ppm, which
growing interest as Brønsted acid organocatalysts.4,13 In general,
has been attributed to the Me3Si group of N-trimethylsilyl-1,2-
the presence of bulky aryl substituents at the 3,3¢-positions is
needed for effective enantioselective catalysis. So it was not a
surprise to isolate, from the reaction mixture, a diastereomeric
mixture of syn and anti 6a in a ratio which was unaltered with
respect to entry 1 in Table 2.
Finally, some mechanistic studies have been undertaken in order
to clarify the real nature of the catalyst involved. The results are
reported in Table 4 and illustrated in Scheme 3.
benzenedisulfonimide (16) (Fig. 4).14 Afterwards, a 1 : 1 mixture
of 1 and 2 (or 3) (2 mol % with respect to remaining reagents) was
1
prepared and then 2 and 4b (or 3 and 4f) were added. H NMR
spectra of both reaction mixtures showed the immediate formation
of 16 and both reactions proceeded in a similar fashion. In both
cases, the reagent 2 (or 3) was consumed more quickly, but with
lower product yields with respect to results obtained previously
(see entries 2 and 3 of Table 4 and entries 2 and 11 of Table 2).
Fig. 4 N-Trimethylsilyl-1,2-benzenedisulfonimide (16).
Finally, several attempts were made to prepare and isolate
derivative 16 by treating 1 with allyltrimethylsilane in MeCN at rt,
Scheme 3 Mechanistic studies between 2 or 3 and 4b or 4f.
Table 4 Mechanistic studies
but unsuccessfully.15 Although 1H NMR spectra showed a singlet
Entry
Reactantsa
1 (mol %)
t (h)
Products; Yields (%)b
1
2
3
3
2
3
4f
4b
4f
2c
2d
2d
24
2
0.3
9f; 83
6b, 60 (54 : 46);e 7b, 23
9f; 83
a The reactions were carried out on 2 mmol of 4, at rt (20–25 ◦C), following reaction conditions as in Table 2. b Yields % refer to isolated products (flash
chromatography; eluent: PE:AcOEt = 8 : 2 in entries 1–3 and PE:AcOEt = 7 : 3 in entry 2). c The reaction was run in the presence of 4-methyl-2,6-di(t-
butyl)pyridine 5 mol %. d Reactions performed by previously preparing in situ Lewis acid 16 as the catalyst. e In parentheses dr (syn/anti) determined by
1H NMR spectroscopy.
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at 0.59 ppm, other signals, probably due to the decomposition of
16, were always predominant.
Structure and purity of all isolated products were confirmed by
comparison of their physical and spectral data (IR, MS and H
1
Compared to literature reports, our results are in better agree-
ment with those of Yamamoto and coworkers3a,3d (which obtained
them by using the same silyl enol ether as the enol equivalent)
than with those of List and coworkers.4 In our conditions, the
in situ formed Lewis acid catalyst appears to be less efficient than
the parent imide. This behaviour could be interpreted as a result
of many possible reasons. The low nucleophilicity of its conjugate
base could prevent the inter and intramolecular transfer of the silyl
group. This topic has been previously discussed in Mukaiyama
reactions induced by silyl Lewis acid catalysts with conjugate
bases of various nucleophile strengths.16 In neat conditions, acid 1
could activate electrophilic aldehydes through hydrogen bonding.
Nevertheless, experimental findings suggest that the Brønsted acid
itself is a more efficient catalyst than the silylated one.
NMR) with those reported in literature. See ESI for details.†
General procedure for Mukaiyama aldol reaction
A mixture of aldehyde 4 (2.0 mmol), trimethylsilyl enol ether
2 (0.68 g, 4.0 mmol) or 3 (0.50 g, 2.6 mmol), and o-
benzenedisulfonimide (1, mol % as in Table 2) was stirred at r.t.
in a vial until TLC and GC analyses showed almost complete
conversion of 4. The reaction mixture was then treated with 2 N
HCl (2 mL) and stirred at rt for 5–20 min. After TLC analyses
showed complete hydrolysis of 5 to 6 (or 8 to 9), the mixture
was extracted with CH2Cl2 (3 ¥ 10 mL). The organic extracts
were washed with aqueous NaHCO3 (20 mL), dried with Na2SO4
and concentrated under reduced pressure. The crude residue was
purified by flash chromatography on a short column of silica gel
(eluent reported in footnote of Table 2).
Conclusions
Representative
experimental
data:
2-[(4-chlorophenyl)-
In summary, a new application of the organocatalyst o-
benzenedisulfonimide (1) has been reported. This strong bench-
stable Brønsted acid has been shown to efficiently catalyze the
Mukaiyama aldol reaction between various aromatic aldehydes
and silyl enol ethers as enol equivalents, in solvent-free conditions.
In the case of less reactive aliphatic aldehydes, the corresponding
dimethyl acetals have been used as source of highly electrophilic
oxocarbenium ions, in the presence of catalytic amounts of 1.
Mechanistic studies are in better agreement with the involvement
of a Brønsted acid than a Lewis acid catalysis.
(hydroxy)methyl]cyclohexan-1-one (6a). White solid, 68%
yield; dr (syn/anti) = 50 : 50, determined by H NMR analysis
of title compound isolated partially as pure syn and anti
diastereomers, and partially as a mixture.
1
syn-6a:19 1H NMR (200 MHz, CDCl3): d = 1.13–1.25 (m, 1H),
1.40–1.88 (m, 5H), 1.98–2.10 (m, 1H), 2.30–2.50 (m, 3H), 5.29 (d,
J = 2.4 Hz, 1H), 7.12–7.28 (m, 4H); 13C NMR (50 MHz, CDCl3):
d = 24.7, 25.8, 27.7, 42.5, 56.8, 69.9, 127.0 (2C), 128.1 (2C), 132.1,
139.8, 214.4. FT-IR (CHCl3, cm-1): 3584, 3539, 3016, 2946, 2870,
1698, 1494, 1208, 1091, 702.
anti-6a:19 1H NMR (200 MHz, CDCl3): d = 1.11–1.40 (m, 1H),
1.42–1.80 (m, 5H), 1.98–2.10 (m, 1H), 2.15–2.55 (m, 3H), 4.70 (d,
J = 8.8 Hz, 1H), 7.14–7.29 (m, 4H). 13C NMR (50 MHz, CDCl3):
d = 24.5, 27.5, 30.5, 42.4, 57.1, 73.8, 128.2 (2C), 128.3 (2C), 133.3,
139.4, 215.1. FT-IR (CHCl3, cm-1): 3584, 3539, 3025, 2946, 2869,
1697, 1491, 1211, 1089, 781.
Experimental
General experimental
All the reactions were conducted in vials using analytical grade
reagents, and were monitored by GC and GC-MS spectrometry.
GC-MS spectra were recorded with an AT5973N mass selective
detector connected to an AT6890N GC cross-linked methyl
silicone capillary column. IR spectra were recorded using a Perkin
Elmer Spectrum BX FT-IR spectrometer in neat conditions or
as solutions in CHCl3. 1H NMR and 13C NMR spectra were
recorded in CDCl3 with a Bruker Avance 200 spectrometer at
200 MHz and 50 MHz, respectively; chemical shifts are given
in ppm relative to CDCl3. TLC were performed on Fluka silica
gel TLCPET foils GF 254, 2–25 mm, layer thickness 0.2 mm,
medium pore diameter 60 A◦. Plates were visualized using UV light
(254 nm) or treatment with an appropriate revelatory agent (p-
anisaldehyde), followed by heating. Column flash chromatography
was carried out on SiO2 (particle size 0.032–0.063 mm/230–
400 mesh). Petroleum ether refers to the fraction boiling in
the range 40–60 ◦C and is abbreviated as PE. Commercially
available reagents and solvents were purchased from Aldrich
and were used without purification or distillation prior to use;
Dowex 50 ¥ 8 ion-exchange resin was purchased from Fluka. o-
Benzenedisulfonimide (1) was prepared as described in literature.17
Moisture-sensitive 3 was prepared following literature;18 flasks and
all equipment used for its generation were dried by electric heat gun
under Ar; THF was distilled from Na/benzophenone ketyl. Acetal
13a was prepared following a previously optimized procedure.9b
2-(4-Chlorobenzylidene)cyclohexan-1-one (7a)20. Yield 5%. 1H
NMR (200 MHz, CDCl3): d = 1.64–1.74 (m, 2H), 1.78–1.90 (m,
2H), 2.45 (t, J = 6.8 Hz, 2H), 2.71 (td, J = 6.4 and 2.2 Hz, 2H),
7.20–7.30 (m, 4H), 7.34 (t, J = 2.2 Hz, 1H). MS m/z (%): 220
[M+](88), 129 (100).
3-(4-Chlorophenyl)-3-hydroxy-1-phenylpropan-1-one (9a)3◦d,21
.
White needles, mp 99.4–100.4 ◦C (CH2Cl2–PE) [lit.22 96–96.5 C].
Yield 87%.
1H NMR (200 MHz, CDCl3): d = 3.20 (br s, 1H), 3.28 (d, J =
6.0 Hz, 2H), 5.20–5.31 (m, 1H), 7.26–7.32 (m, 4H), 7.35–7.45 (m,
2H), 7.48–7.55 (m, 1H), 7.80–7.93 (m, 2H). 13C NMR (50 MHz,
CDCl3): d = 47.1, 69.2, 127.0 (2C), 128.0 (2C), 128.5 (2C), 128.6
(2C), 133.1, 133.6, 136.2, 141.3, 199.8. FT-IR (CHCl3, cm-1): 3584,
3550, 3010, 2905, 1677, 1598, 1582, 1494, 1450, 1093, 1014, 800,
668.
General procedure for Mukaiyama aldol-type reaction
A mixture of aldehyde dimethyl acetal 13 (2.0 mmol), trimethylsilyl
enol ether 3 (0.50 g, 2.6 mmol), and o-benzenedisulfonimide (1,
mol % as in Table 3) was stirred at rt in a vial until TLC and
GC analyses showed almost complete conversion of 13. The
mixture was extracted with CH2Cl2 (3 ¥ 10 mL). The organic
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extracts were dried with Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by flash chromatography
on a short column of silica gel (eluent reported in footnote of
Table 3).
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Representative experimental data: 3-cyclohexyl-3-methoxy-1-
phenylpropan-1-one (14b)10b
.
Colorless oil, 61% yield.
1H NMR (200 MHz, CDCl3): d = 0.90–1.18 (m, 5H), 1.45–1.72
(m, 6H), 2.84 (dd, J = 16.2 and 4.0 Hz, 1H), 3.13 (overlapped dd,
J = 16.2 and 7.8 Hz, 1H), 3.23 (s, 3H), 3.59–3.68 (m, 1H), 7.32–
7.46 (m, 3H), 7.85–7.92 (m, 2H); 13C NMR (50 MHz, CDCl3):
d = 26.1 (2C), 26.4, 28.3, 28.42, 40.6, 41.7, 58.1, 81.6, 128.0 (2C),
128.3 (2C), 132.7, 137.3, 199.2. MS m/z (%): 246 [M+] (2), 231
[M+-15] (10), 105 (100). FT-IR (CHCl3, cm-1): 3013, 2905, 2856,
1684, 1598, 1582, 1450, 1232, 1095.
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Acknowledgements
This work was supported by Italian MIUR and by Universita`
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