Influence of the reaction conditions on the evolution of the michael addition of β-keto sulfones to α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/ejoc.201000502

We have studied the influence of different reaction conditions on the conjugated addition of β-keto sulfones to a,βunsaturated aldehydes catalyzed by silyl prolinol ethers. Small changes in the starting material and/or in the experimental protocol are able to produce significant variations in the structures of the final products. The high chemical versatility of the resulting Michael adducts make possible their use in a variety of tandem and one-pot reactions to afford polysubstituted cyclic products bearing multiple chiral centers.

Full text of DOI:10.1002/ejoc.201000502

FULL PAPER
DOI: 10.1002/ejoc.201000502
Influence of the Reaction Conditions on the Evolution of the Michael Addition
of β-Keto Sulfones to α,β-Unsaturated Aldehydes
José Alemán,*[a] Vanesa Marcos,[a] Leyre Marzo,[a] and José Luis García Ruano*[a]
Keywords: Organocatalysis / Michael addition / Aldehydes / Keto sulfones
We have studied the influence of different reaction condi-
tions on the conjugated addition of β-keto sulfones to α,β-
unsaturated aldehydes catalyzed by silyl prolinol ethers.
Small changes in the starting material and/or in the experi-
mental protocol are able to produce significant variations in
the structures of the final products. The high chemical versa-
tility of the resulting Michael adducts make possible their
use in a variety of tandem and one-pot reactions to afford
polysubstituted cyclic products bearing multiple chiral cen-
ters.
material and/or in the experimental protocol. In this sense
there are many examples based on initial organocatalytic
processes followed by different reactions (not necessarily or-
ganocatalytic processes) of the resulting products to give
structurally diverse compounds,[4] one of the landmark syn-
theses being that of (–)-Oseltamivir by Hayashi and co-
workers.[4g]
Introduction
The development of cascade, tandem, and one-pot reac-
tions[1] is currently considered a new direction in organocat-
alysis.[2] One-pot procedures[3] have reached this status be-
cause they lead to highly functionalized products contain-
ing multiple stereocenters in a single stroke.[3] This is the
case for the organocatalytic stereoselective preparation of
To be successful, highly versatile reagents must be in-
complex molecules with several stereocenters mediated by volved in the first organocatalytic step. We have focused our
mechanistically diverse processes.[4] One of the most strik- attention on β-keto sulfones, which have recently been used
ing features of one-pot or tandem reactions is the possibil- in some interesting nucleophilic addition reactions[5] be-
ity of achieving significant structural modifications in the cause they present in the same structure two versatile func-
final products by introducing small changes in the starting tions in organic chemistry (ketone and sulfone).
Scheme 1. Transformations of the primary adducts, formed by the addition of β-keto sulfones to α,β-unsaturated aldehydes, into different
products by one-pot or tandem reactions.
Methylenebis(sulfones) have recently been shown to be
[a] Departamento de Química Orgánica (C-I), Universidad Autó-
noma de Madrid,
highly efficient in the organocatalytic β-methylation of α,β-
unsaturated aldehydes.[6] Thus, we reasoned that the use of
β-keto sulfones in this reaction[7] would also be successful
and the initial adducts could intervene in a range of one-
pot or tandem reactions allowing the preparation of com-
pounds with different structures by introducing small
Cantoblanco, 28049 Madrid, Spain
Fax: +34-91-4973966
E-mail: jose.aleman@uam.es
joseluis.garcia.ruano@uam.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000502.
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Michael Addition of Keto Sulfones to α,β-Unsaturated Aldehydes
changes in the reaction conditions. In connection with this
We were unable to establish the enantiomeric excess of
topic, the direct organocatalytic addition of methyl phenyl the two epimers 4a/4aЈ by chiral HPLC, which would have
ketone (pKa = 24.7) to α,β-unsaturated aldehydes was not provided information about the stereoselectivity of the reac-
possible in our hands, presumably due to the low acidity of tion at the β position of the aldehyde. However, their
its methyl protons. The ability of the sulfonyl group to in- derivatization to dihydropyran 10a did allow the determi-
crease the pKa of its C-α protons and the easy elimination nation of the enantiomeric excess (see later, Table 2). The
of the sulfonyl group makes β-keto sulfones ideal as a syn- use of weaker bases, such as LiOAc, provided full conver-
thetic equivalent of methyl ketones in organocatalysis sion (91% isolated yield), increased the enantiomeric excess
(Scheme 1). In this paper we present our results on the silyl (91%), and shortened the reaction time to 2 days (entry 7),
prolinol ether catalyzed addition of β-keto sulfones to α,β- thus providing the best conditions in basic media. The
unsaturated aldehydes and the multiple transformations of Michael addition of 1a to 2a could also take place in acidic
the primary adducts into different products by one-pot or media (benzoic acid as additive, entry 8). Under these con-
tandem reactions (Scheme 1).
ditions, the reaction was faster (20 h) than in the basic me-
dium with a good but lower isolated yield (81%) and a sim-
ilar enantiomeric excess (90%).
Results and Discussion
To remove the sulfone moiety, we considered the Julia
elimination of β-keto sulfones with Mg and methanol,[9] but
the high reactivity of the formyl group in 4 made necessary
its a priori transformation. The formation of the dimethyl
acetal 5 by nucleophilic addition followed by Julia elimi-
nation[9] yielded olefin 6 in a moderate yield and high
stereoselective control in a one-pot procedure (Scheme 2).
On the other hand, the reduction of the aldehyde with
NaBH4 is also compatible with the other two reactions, al-
lowing an efficient one-pot synthesis of the alcohol 8. Both
processes can be considered as formal alkenylation reac-
tions of α,β-unsaturated aldehydes.[7]
The α-chiral center in the sulfone can also be eliminated
by a process that involves intramolecular ketalization and
subsequent dehydration of the alcohol groups in 7 (Table 2).
This process provides sulfonyl hydropyrans 10, which can
be considered as precursors of polyfunctionalized pyrans,
important subunits in many natural products, for example,
carbohydrates, alkaloids, polyether antibiotics, and phero-
mones.[10]
The search for the optimal conditions for the addition of
β-keto sulfones to α,β-unsaturated aldehydes was per-
formed by using 2-pentenal (1a) and phenylsulfonylace-
tophenone (2a) as the starting materials (Table 1). The silyl
prolinol ether 3[8] (Table 1) was used as the catalyst because
it had provided the best results in the addition reactions of
methylenebis-sulfones.[6] Full conversion could not be
achieved with alkaline hydroxides in CHCl3 or EtOH (en-
tries 1–4), however, this problem was solved in THF (en-
tries 5 and 6). A mixture of diastereoisomers (50:50) at the
carbon flanked by the carbonyl and sulfonyl group (4a/4aЈ)
were obtained in all cases. These epimers could not be sepa-
rated because they are in equilibrium due to the high acidity
of the methinic proton as occurs with β-keto esters.[8]
Table 1. Screening of phenylsulfonylacetophenone (2a).[a]
Benzoic acid was used as an additive (20 h) and the re-
duction was performed with NaBH3CN to yield compound
10a in moderate yield and with excellent optical purity (en-
try 1, Table 2). The enantiomer of this compound (ent-10a)
could be analogously obtained by using ent-3 (with the R
configuration) as the catalyst in the first step (entry 2,
Table 2). Other alkyl chains can also be introduced at C-4
of the dihydropyran with excellent enantioselectivities and
moderate yields (entries 3 and 4, Table 2). Nevertheless,
phenyl-substituted alkene 1e did not react under these con-
ditions.
The use of α-sulfonylated dialkyl ketones 2b–d as starting
materials afforded different results to those shown in
Scheme 2 and Table 2. After 6 days, the reaction of 1a with
2b (R3 = H, Scheme 3) under basic conditions afforded a
1:1 mixture of cyclohexanes 11a and 11aЈ, epimers at the
hydroxylic carbon (see later), in a 71% combined yield
(their separation was not possible). As we could not deter-
mine the enantiomeric excess of the two diastereomers by
chiral HPLC, their dehydration to only one compound 13
was necessary (see later, Scheme 4), obtained with 92% ee.
The formation of this compound could be explained by a
Michael addition reaction catalyzed by 3 followed by an
Entry Additive (20 mol-%) Solvent Time [h] Conv. [%] ee [%][b]
1
2
3
4
5
6
7
8
LiOH
CsOH
KOH
CsOH
CsOH
LiOH
LiOAc
C6H5CO2H
HCCl3
HCCl3
HCCl3
EtOH
THF
THF
THF
THF
72
72
72
72
72
72
48
20
51
Nr
30
71
Ͼ99
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
84
74
91
90
Ͼ99
Ͼ99 (91)[d]
Ͼ99 (81)[d]
[a] Performed with 1a (0.20 mmol), 2a (0.4 mmol), additive
(20 mol-%), and catalyst 3 (20 mol-%) in the indicated solvent
(0.2 mL) at room temperature. [b] The enantiomeric excess was de-
termined by chiral stationary phase HPLC after transformation of
the epimeric mixture 4a/4aЈ to the dihydropyran 10a (see Table 2).
[c] Not determined. [d] Isolated combined yields (4a/4aЈ) after flash
chromatography.
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J. Alemán, V. Marcos, L. Marzo, J. L. García Ruano
FULL PAPER
Scheme 2. Organocatalytic enantioselective alkenylation by Julia olefination.
Table 2. One-pot synthesis of hydropyrans 10a,c,d from β-keto sul-
fone 2a and unsaturated aldehydes 1.[a]
Scheme 3. Synthesis of six-membered rings with three and four chi-
ral centers.
silica gel neutralized with Et3N), we observed its instan-
taneous transformation into the same mixture 11a and 11aЈ
(the reaction occurred during the purification process). This
result is similar in terms of yield and enantioselectivity to
those obtained directly after 6 days with LiOAc, thus pro-
viding a faster method to obtain the same compounds.
Other keto sulfones, such as 2c (R3 = Me) and 2d (R3 =
Ph), showed the same evolution, giving mixtures of 11c/11cЈ
and 11d/11dЈ under similar conditions. In both cases, the
enantioselectivities and yields were similar to those ob-
tained with 2b, whereas a slightly better diastereoselectivity
was achieved with 2d (dr = 3:1, R3 = Ph).
Entry
Aldehyde (R1)
Product (% yield)
ee [%][b]
1
1a (Et)
1a (Et)
1c (nPr)
1d (nBu)
1e (Ph)
10a (41)
ent-10a (44)
10c (46)
10d (42)
n.r.[d]
90
90
90
91
–
2[c]
3
4
5
[a] Performed with 2a (0.20 mmol),
1
(0.4 mmol), PhCO2H
(20 mol-%), and catalyst 3 (10 mol-%) in THF (0.2 mL). [b] The
enantiomeric excess was determined by chiral stationary phase
HPLC. [c] This reaction was carried out with the ent-3 catalyst (R
configuration). [d] No reaction.
Interestingly, when the reactions of 2d (R3 = Ph) with
interchange of protons, which makes possible an intramo- aldehydes 1a–e were performed in acidic media (PhCO2H
lecular aldol reaction with low diastereoselectivity that af- as additive instead of LiOAc), we observed a faster reaction
fords mixtures of 11a/11aЈ, which are epimers at the alcohol that yielded cyclohexenones 12a–e as the only products
moiety.
(Table 3). This indicates that the product could occur by
1
We followed the reaction by H NMR spectroscopy to a Michael–aldol/dehydration tandem process[11] under mild
check that the starting sulfone 2b had disappeared after conditions in good yields and diastereoselectivities (trans
40 h. When we tried to isolate the Michael adduct (with compounds were obtained as the major products).
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Michael Addition of Keto Sulfones to α,β-Unsaturated Aldehydes
Table 3. Scope of various aldehydes in a tandem process.[a]
mixture of 11d and 11dЈ, which afforded the same 3:1 mix-
ture of 17 and 17Ј. This means that the hydroxylic carbon
(C-4) in compounds 11 is the epimeric carbon. As the mix-
tures of 11 and 11Ј could not be easily separated, we de-
cided to eliminate the hydroxy group to solve the problem
of the mixture of the diastereoisomers. In this way, dehy-
dration in an acidic medium would provide dia-
stereomerically pure α,β-unsaturated ketones 12a, 13–15
with high optical purity (the same as that of the starting
11). The reaction of the 1:1 diastereomeric mixture 11d/11dЈ
with TsOH in toluene (80 °C) afforded 12a. Unfortunately,
this compound was also obtained as a mixture of diastereo-
isomers (dr = 90:10) in a thermodynamic equilibrium easily
established due to the high acidity of the proton of the β-
keto sulfone moiety. Similar results were obtained with 11a/
11aЈ, 11b/11bЈ, and 11c/11cЈ, which yielded compounds 13,
14, and 15, respectively, in yields ranging between 76 and
88% (Scheme 4). The ee values of the resulting cyclohex-
enones are very high and similar to those of the starting
cyclohexanones. Thus, desulfonylation and dehydration can
be run as a one-pot process with the epimeric mixtures of
11 to obtain 2,5-disubstituted cyclohexenones with high op-
tical purity. This is illustrated with the reaction of 11d/11dЈ,
which furnished 18 (Scheme 4).
The absolute configuration of cyclohexane 11d (major
diastereoisomer), which contains four chiral centers, was
unequivocally established as 2S,3R,5R,6S (see the Support-
ing Information) in view of the low value obtained for the
Flack parameter (0.004) in its X-ray structure.[12] The other
compounds were assumed to be identical because they fol-
lowed the same stereochemical course in this reaction,
yielding the same configuration as at the chiral center at the
α position of the sulfone moiety and at the β position of
the aldehyde.
Entry Aldehyde (R1) Additive Product (% yield) dr[b] ee [%][c]
1
2
3
4
5
6
7
1a (Et)
1b (Me)
1c (nPr)
1d (nBu)
1e (n-Pent)
1f (Ph)
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
LiOAc
12a (65)
12b (68)
12c (68)
12d (63)
12e (60)
n.r.[d]
92:8
90:10
92:8
90:10
91:9
–
80
92
90
94
92
–
1f (Ph)
PhCO2H
n.r.[d]
–
–
[a] Performed with 2d (0.20 mmol), 1 (0.40 mmol), PhCO2H
(20 mol-%), and catalyst 3 (20 mol-%) in THF (0.2 mL). [b] Dia-
stereomeric ratio of the epimers at the sulfonylated carbon, as de-
termined by 1H NMR spectroscopy. [c] The enantiomeric excess
was determined by chiral HPLC. [d] No reaction.
The yields and enantioselectivities are almost identical
for all the aliphatic aldehydes, regardless of the nature of
R1 (entries 1–5, Table 3). The acidic media and the higher
tendency of the phenyl derivatives to dehydrate explain this
evolution. As in previous cases, aromatic α,β-unsaturated
aldehydes do not react with α-sulfonylated dialkyl ketones
under acidic or basic conditions (entries 6 and 7).
Compounds 11 were obtained as mixtures of two dia-
stereoisomers that could be epimers at C-2 (due to the high
acidity of 2-H) or C-5 (due to the low stereoselectivity of
the aldol reaction). To identify the epimeric carbon we elim-
inated the sulfone group from a 1:1 mixture of 11b and 11bЈ
In Scheme 5 we have summarized how slight modifica-
(R1 = n-Pent) and obtained a 1:1 mixture of 16 and 16Ј. tions to the reaction conditions are able to produce signifi-
This result indicates that C-2 is not the epimeric carbon. cant changes in the reaction pathways and thereby afford
The same conclusion was drawn from the reaction of a 3:1 different compounds. When the Michael addition was car-
Scheme 4. Synthesis of optically active cyclohexenones.
Eur. J. Org. Chem. 2010, 4482–4491
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J. Alemán, V. Marcos, L. Marzo, J. L. García Ruano
FULL PAPER
Scheme 5. Summary of the different β-keto sulfones reactions.
ried out in the presence of benzoic acid and R2 was a benzyl The resulting products from the addition of β-keto sulfones
group, the adduct 4 could not be isolated because it suffers are highly versatile intermediates able to participate in di-
a tandem intramolecular aldol/dehydration process (favored verse tandem and one-pot reactions to afford products with
by conjugation) to afford compounds 12. In contrast, the significant structural differences by introducing small
reactions of substrates with R2 = alkyl, conducted with changes in the starting materials and/or in the experimental
LiOAc, yielded compounds 4, which, after purification with protocol.
neutralized silica gel, evolved to cyclohexanones 11 as a
consequence of an intramolecular aldol reaction without
dehydration. The in situ reduction of adducts 4 followed by Experimental Section
acidic treatment of the reaction crude containing 7 yielded
dihydropyrans 10 (hemiacetalization and further dehy-
dration), whereas if the crude 7 was exposed to reductive
1
General Methods: H and 13C NMR spectra were acquired with a
Bruker 300 spectrometer at 300 and 75 MHz, respectively. Chemi-
cal shifts (δ) are reported in ppm relative to residual solvent signals
(CHCl3: 7.26 ppm for H NMR; CDCl3: 77.0 ppm for 13C NMR).
13C NMR spectra were acquired in broad-band decoupled mode.
Analytical thin-layer chromatography (TLC) was performed using
precoated aluminium-backed plates (Merck Kieselgel 60 F254) and
visualized by ultraviolet irradiation or KMnO4 dip. The reaction
products were purified by flash chromatography (FC) using silica
gel (Merck 60) that had previously been neutralized with 10 mol-
% of Et3N in hexane. Optical rotations were measured with a Per-
1
conditions, β-alkenylation product 8 was formed by a clas-
sic Julia olefination process.[9]
Conclusions
The α-sulfonyl group is a good activator of ketones and
allows the β-alkylation of unsaturated aldehydes with the
ketone moiety (CH2–CO–R) in organocatalytic processes. kin–Elmer 241 polarimeter. The enantiomeric excesses (ee) of the
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Michael Addition of Keto Sulfones to α,β-Unsaturated Aldehydes
products were determined by chiral stationary phase HPLC (Daicel
Chiralpak AD or Daicel Chiralcel IC columns). Catalyst 3 and all
the starting materials were purchased from Aldrich. Compounds
2c–d have previously been synthesized.[13]
10.6 ppm. MS (TOF ES+): calcd. for C15H23O2 [M + H]+ 235.0603;
found 235.0593.
(R,E)-3-Methyl-5-phenylpent-4-en-1-ol (8): The product was ob-
tained as a single diastereoisomer following the standard procedure
as a colorless oil (16 mg, 46% yield) after FC (AcOEt/hexane =
2:1). The ee value was determined by HPLC using a Chiralpak
OD column (hexane/iPrOH = 99:1); flow rate: 1.0 mL/min; τmajor
= 8.1 min, τminor = 10.4 min (88% ee). [α]2D0 = –15.4 (c = 0.4,
CHCl ). IR (neat): ν = 3147 (br s), 2933, 1681, 1493, 1127 cm–1.
General Procedure for the Synthesis of Compound 4a (see Table 1):
The α,β-unsaturated aldehyde 1a (0.4 mmol) was added to a stir-
ring solution of catalyst 3 (0.02 mmol), additive (0.02 mmol), and
the corresponding sulfone 2a (0.2 mmol) in the indicated solvent
(0.2 mL; Table 1) in an ordinary vial at room temperature. After
the complete consumption of the sulfone derivative (as monitored
by 1H NMR spectroscopy; time is indicated in Table 1), the solvent
was eliminated under reduced pressure. Then the crude was purified
by FC (EtOAc/hexane = 2:3) to give the pure compound.
˜
3
1H NMR (CDCl3): δ = 7.29–7.18 (m, 4 H, Ar), 7.15–7.12 (m, 1 H,
Ar), 6.30 (d, J = 15.8 Hz, 1 H, 1-H), 6.02 (dd, J = 15.8, 8.2 Hz, 1
H, 2-H), 3.63 (t, J = 6.4 Hz, 2 H, CH2-O), 2.47–2.38 (m, 1 H, 3-
H), 1.63–1.57 (m, 2 H, 4-H), 1.05 (dd, J = 6.8, 2.0 Hz, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 137.1, 135.5, 128.2,
128.1, 126.6, 125.6, 60.8, 39.3, 33.8, 20.4 ppm. MS (TOF ES+):
calcd. for C12H17O [M + H]+ 177.1279; found 177.1275.
(4R/4S,3S)-3-Ethyl-5-oxo-5-phenyl-4-(phenylsulfonyl)pentanal (4a/
4aЈ): The product was obtained following the standard procedure
as a colorless oil (63 mg, 91% yield) after FC. The ee was deter-
mined by HPLC by derivatization to the product 6 (ee = 91%, see
General Procedure for the Synthesis of the Dihydropyrans 10 (see
Table 2): The corresponding aldehyde 1 (0.4 mmol) was added to a
stirring solution of catalyst 3 (0.02 mmol), additive (0.02 mmol),
and the corresponding sulfone 2a (0.2 mmol) in THF (0.2 mL) in
an ordinary vial at room temperature. After the complete consump-
tion of the sulfone derivative (as monitored by 1H NMR spec-
troscopy; time is indicated in Table 2,), THF (1 mL) and
NaBH3CN (5.0 equiv.) were added. The reaction was followed by
TLC and when it was finished, the reaction mixture was extracted
with AcOEt (2ϫ5 mL) and washed with water (2ϫ5 mL). The sol-
vent was eliminated under reduced pressure. Then the crude mix-
ture was treated with pTsOH (20 mol-%) in toluene (1 mL) at 80 °C
for 24 h. Finally, the crude was purified by FC (hexane/AcOEt =
4:1), to give the pure compound.
1
below). [α]2D0 = –10.0 (c = 1.0, CH2Cl2). First diastereoisomer: H
NMR (CDCl3): δ = 9.83 (s, 1 H, CHO), 7.83–7.33 (m, 10 H, Ar),
5.59 (d, J = 9.4 Hz, 1 H, 4-H), 3.27–3.04 (m, 1 H, 2-H), 2.85–2.77
(m, 1 H, 2-H), 2.50 (dd, J = 18.8, J = 7.8 Hz, 1 H, 3-H), 1.63–1.52
(m, 2 H, CH2), 0.80 (t, J = 7.5 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3) δ = 200.7, 193.0, 137.6, 136.8, 133.7, 133.6,
129.2, 128.7, 128.5, 128.1, 70.5, 42.5, 35.1, 24.0, 11.1 ppm. Second
diastereoisomer: 1H NMR (CDCl3): δ = 9.69 (s, 1 H, CHO), 7.83–
7.33 (m, 10 H, Ar), 5.34 (d, J = 4.9 Hz, 1 H, 4-H), 3.27–3.04 (m,
1 H, 2-H), 2.95–2.87 (m, 1 H, 3-H), 2.95–2.87 (m, 1 H, 2-H), 1.52–
1.42 (m, 2 H, CH2), 0.90 (t, J = 7.3 Hz, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 200.4, 192.60, 138.0, 137.0, 133.8, 133.7,
129.0, 128.5, 128.4, 128.2, 69.8, 44.2, 34.2, 25.3, 10.9 ppm. MS
(TOF ES+): calcd. for C19H19O4S [M – H] 343.1040; found
343.1007.
(S)-4-Ethyl-3,4-dihydro-6-phenyl-5-(phenylsulfonyl)-2H-pyran (10a):
The product was obtained following the standard procedure as a
colorless oil (27 mg, 41% yield) after FC. The ee was determined
by HPLC using a Chiralpak AD column (hexane/iPrOH = 99:1);
flow rate: 1.0 mL/min, τminor = 10.8 min, τmajor = 11.8 min (90%
Procedure for the Synthesis of Compounds 6 and 8 (see Scheme 2):
The corresponding aldehyde (0.4 mmol) was added to a stirring
solution of catalyst 3 (0.02 mmol), 2-(phenylsulfonyl)acetophenone
(0.2 mmol), and LiOAc (0.02 mmol) in THF (0.2 mL) in an ordi-
nary vial at room temperature. After the complete consumption
ee). [α]2D0 = +27.0 (c = 1.0, CH2Cl2). H NMR (CDCl3): δ = 7.37–
1
7.06 (m, 10 H, Ar), 4.26–4.11 (m, 2 H, CH2-O), 3.00–2.90 (m, 1 H,
4-H), 2.22–2.11 (m, 1 H, 3-H), 2.01–1.85 (m, 1 H, 3-H), 1.58–1.43
(m, 2 H, CH2-CH3), 1.06 (t, J = 7.4 Hz, 3 H, CH2-CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 162.9, 143.0, 134.1, 131.8, 129.7,
129.3, 128.1, 127.5, 127.0, 119.9, 64.1, 33.4, 28.1, 24.9, 11.5 ppm.
MS (TOF ES+): calcd. for C19H21O3S [M + H]+ 329.1205; found
329.1196.
1
of the 2-(phenylsulfonyl)acetophenone (as monitored by H NMR
spectroscopy), MeOH (1 mL) and BF3·Et2O (10 mol-%) were
added for compound 6 or NaBH4 (5.0 equiv.) for compound 8. The
1
reaction was followed by H NMR spectroscopy and when it was
finished, the reaction mixture was extracted with AcOEt (2ϫ5 mL)
and washed with water (2ϫ5 mL). Then the solvent was eliminated
under reduced pressure. Next, the crude mixture was treated with
activated magnesium (10 equiv.) in MeOH (5 mL) overnight. Then
the crude was purified by FC (hexane/AcOEt = 2:1) to give the
pure compound.
(R)-4-Ethyl-3,4-dihydro-6-phenyl-5-(phenylsulfonyl)-2H-pyran (ent-
10a): The product was obtained following the standard procedure
as a colorless oil (29 mg, 44% yield) after FC. The spectral data
are identical to those of compound 10a. The ee was determined by
HPLC using a Chiralpak AD column (hexane/iPrOH = 99:1); flow
rate: 1.0 mL/min; τmajor = 10.8 min, τminor = 11.8 min (90% ee).
[α]2D0 = –27.0 (c = 1.0, CH2Cl2).
(R,E)-(3-Ethyl-5,5-dimethoxypent-1-enyl)benzene (6): The product
was obtained following the standard procedure as a mixture of dia-
stereoisomers (95:5) as a colorless oil (19 mg, 40% yield) after FC
(AcOEt/hexane = 2:1). The ee was determined by HPLC using a
Chiralpak AS column (hexane/iPrOH = 99:1); flow rate: 1.0 mL/
min; τminor = 3.9 min, τmajor = 5.6 min (90% ee). [α]2D0 = –2.3 (c =
(S)-3,4-Dihydro-6-phenyl-5-(phenylsulfonyl)-4-propyl-2H-pyran
(10c): The product was obtained following the standard procedure
as a yellow oil (32 mg, 46% yield) after FC. The ee was determined
by HPLC using a Chiralpak IC column (hexane/iPrOH = 99:1);
0.3, CHCl ). IR (neat): ν = 3407, 2927, 1737, 1672, 1458,
˜
3
1127 cm–1. H NMR (CDCl3): δ = 7.30–7.20 (m, 4 H, Ar), 7.15– flow rate: 1.0 mL/min (90% ee). [α]2D0 = +21.8 (c = 1.0, CH2Cl2).
1
1
7.12 (m, 1 H, Ar), 6.30 (d, J = 15.8 Hz, 1 H, 1-H), 5.89 (dd, J =
15.8, 8.2 Hz, 1 H, 2-H), 4.34 (dd, J = 7.4, 7.4 Hz, 1 H, 5-H), 3.26
(s, 3 H, MeO), 3.23 (s, 3 H, MeO), 2.42–2.26 (m, 1 H, 4-H), 1.93–
IR (NaCl): ν = 2961, 1718, 1683, 1941 cm–1. H NMR (CDCl ): δ
˜
3
= 7.30–7.00 (m, 10 H, Ar), 4.21–4.00 (m, 2 H, CH2-O), 3.03–2.88
(m, 1 H, 4-H), 2.14–2.02 (m, 1 H), 1.95–1.85 (m, 1 H), 1.54–1.13
1.71 (m, 1 H, 4-H), 1.60–1.48 (m, 3 H, 3-H, CH2-CH3), 0.75 (t, J (m, 4 H), 0.94 (t, J = 6.8 Hz, 3 H, CH2-CH3) ppm. 13C NMR
= 7.4 Hz, 3 H, CH2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = (75 MHz, CDCl3): δ = 162.4, 142.6, 133.7, 131.3, 129.2, 128.8,
137.1, 134.3, 131.2, 129.3, 129.0, 127.8, 104.1, 42.3, 39.0, 30.1, 29.8,
127.7, 127.0, 126.6, 119.4, 63.6, 37.0, 31.1, 25.0, 19.7, 13.6 ppm.
Eur. J. Org. Chem. 2010, 4482–4491
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4487

J. Alemán, V. Marcos, L. Marzo, J. L. García Ruano
FULL PAPER
MS (TOF ES+): calcd. for C20H23O3S [M + H]+ 343.1362; found
343.1370.
4.13–4.06 (m, 1 H, OH), 3.73 (s, 1 H), 3.62 (s, 1 H), 3.38–3.37 (m,
1 H), 3.13–3.02 (m, 1 H), 2.70–2.50 (m, 6 H), 2.42 (s, 6 H), 1.98–
1.92 (m, 1 H), 1.78–1.73 (m, 1 H), 1.27–0.77 (m, 16 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 202.7, 202.1, 145.4, 145.3, 135.1,
134.8, 129.9, 129.8, 128.3, 128.2, 77.7, 75.8, 72.0, 72.0, 53.6, 49.2,
38.7, 34.7, 34.3, 32.6, 29.1, 26.4, 21.6, 12.2, 11.5, 10.5, 10.4 ppm.
MS (TOF ES+): calcd. for C16H22O4NaS [M + Na]+ 333.1131;
found 333.1127.
(S)-4-Butyl-3,4-dihydro-6-phenyl-5-(phenylsulfonyl)-2H-pyran (10d):
The product was obtained following the standard procedure as a
colorless oil (30 mg, 42% yield) after FC. The ee was determined
by HPLC using a Chiralpak IC column (hexane/iPrOH = 99:1);
flow rate: 1.0 mL/min (91% ee). [α]2D0 = +21.0 (c = 0.9, CH2Cl2).
IR (neat): ν = 2959, 2928, 1620, 1592, 1491 cm–1
.
1H NMR
˜
(CDCl3): δ = 7.30–6.99 (m, 10 H, Ar), 4.19–4.02 (m, 2 H, CH2-O),
(2S,3R,5R/5S,6S)-3-Ethyl-5-hydroxy-6-phenyl-2-tosylcyclohexanone
2.93–2.89 (m, 1 H, 4-H), 2.13–2.08 (m, 1 H, 3-H), 1.91–1.85 (m, 1 (11d/11dЈ): The product was obtained as a mixture of diastereoiso-
H, 3-H), 1.47–1.07 (m, 6 H, CH2-CH2-CH2-CH3), 0.89 (t, J = mers (3:1) following the standard procedure as a colorless oil
6.6 Hz, 3 H, CH2-CH2-CH2-CH3) ppm. 13C NMR (75 MHz, (49 mg, 65% yield) after FC (AcOEt/hexane = 2:1). [α]2D0 = +31.7
CDCl3) δ = 162.8, 143.0, 134.1, 131.7, 129.6, 129.2, 128.1, 127.5,
127.0, 119.9, 64.0, 34.9, 31.7, 29.2, 25.3, 22.6, 14.1 ppm. MS (TOF
ES+): calcd. for C21H25O3S [M + H]+ 357.1518; found 357.1525.
(c = 0.3, CHCl ). IR (neat): ν = 1714, 1672, 1209 cm–1. Major
diastereoisomer: H NMR (CDCl3): δ = 7.63 (d, J = 8.3 Hz, 2 H,
˜
3
1
Ar), 7.32–7.20 (m, 5 H, Ar), 7.09 (d, J = 6.6 Hz, 2 H), 4.18 (d, J
= 10.0 Hz, 1 H, 5-H), 4.11–4.05 (m, 1 H, OH), 3.70 (s, 1 H, 2-H),
2.80–2.78 (m, 1 H, 4-H), 2.70–2.60 (m, 1 H, 4-H), 2.34 (s, 3 H,
CH3-C6H4-SO2), 2.33–2.10 (m, 1 H), 2.00–1.80 (m, 1 H), 1.50–1.31
(m, 2 H, CH2-CH3), 0.91 (t, J = 7.4 Hz, 3 H, CH2-CH3) ppm. 13C
NMR (75 MHz, CDCl3) δ = 199.2, 130.8, 129.9, 129.7, 128.8,
128.3, 127.0, 126.1, 124.5 70.6, 65.4, 50.1, 37.7, 32.8, 26.3, 21.8,
11.2 ppm. MS (TOF ES+): [calcd. for C21H24O4NaS M + Na]+
395.1287; found 395.1282.
General Procedure for the Synthesis of Compounds 11a–d (see
Scheme 3): The corresponding aldehyde 1 (0.4 mmol) was added to
a stirring solution of catalyst 3 (0.02 mmol), β-keto sulfone 2b–d
(0.2 mmol), and LiOAc (0.04 mmol) in THF (0.2 mL) in an ordi-
nary vial at room temperature. After the complete consumption of
1
the corresponding keto sulfone derivatives (as monitored by H
NMR spectroscopy), the crude was directly purified by FC (silica
gel neutralized with 10% Et3N in hexane; 2:1 hexane/AcOEt) to
afford the pure product. The ee values of compounds 11a–d were
determined after derivatization to products 12a, 13–15 (see
Scheme 4).
General Procedure for the Synthesis of Compounds 12a–e (see
Table 3): The corresponding aldehyde (0.4 mmol) was added to a
stirring solution of catalyst 3 (0.04 mmol), keto sulfone 2d
(0.2 mmol), and benzoic acid (0.04 mmol) in THF (0.2 mL) in an
ordinary vial at room temperature. After the complete consump-
tion of the corresponding keto sulfone derivatives (as monitored by
1H NMR spectroscopy, about 24 h) the crude was directly purified
by FC (hexane/AcOEt = 2:1) to afford the pure products.
(2S,3R,5S/5R)-3-Ethyl-5-hydroxy-2-(phenylsulfonyl)cyclohexanone
(11a/11aЈ): The product was obtained as a mixture of diastereoiso-
mers (1:1) following the standard procedure as a colorless oil
(42 mg, 72% yield) after FC (AcOEt/hexane = 2:1). IR (neat): ν =
˜
2964, 2930, 1671, 1596, 1148 cm–1. Mixture of diastereoisomers
(1:1): 1H NMR (300 MHz, CDCl3): δ = 7.82–7.79 (m, 4 H, Ar),
7.67–7.64 (m, 2 H, Ar), 7.58–7.53 (m, 4 H, Ar), 4.59–4.57 (m, 1 H,
5Ј-H), 4.07–4.02 (m, 1 H, 5-H), 3.67 (s, 1 H), 3.57 (s, 1 H), 3.30–
3.24 (m, 1 H), 3.06–2.98 (m, 1 H), 2.87–2.74 (m, 1 H), 2.56–2.36
(5R,6S)-5-Ethyl-2-phenyl-6-tosylcyclohex-2-enone (12a): The prod-
uct was obtained following the standard procedure as a colorless
oil (46 mg, 65% yield) after FC (AcOEt/hexane = 2:1). The ee was
determined by HPLC using a Chiralpak AD column (hexane/iP-
(m, 1 H), 2.16–1.74 (m, 4 H), 1.67–1.53 (m, 4 H), 1.37–1.20 (m, 4 rOH = 99:1); flow rate: 1.0 mL/min; τmajor = 25.2 min, τminor
=
H), 0.94–0.83 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 30.0 min (80% ee). [α]2D0 = –16.8 (c = 1.1, CHCl ). IR (neat): ν =
˜
3
201.1, 200.5, 137.9, 137.7, 134.3, 134.2, 129.4, 129.3, 128.4, 128.1,
76.5, 76.4, 69.5, 65.9, 50.5, 48.6, 36.9, 34.7, 34.1, 32.7, 29.1, 26.5,
11.9, 11.5 ppm. MS (TOF ES+): calcd. for C14H19O4S [M + H]+
283.1004; found 283.1014.
2964, 2930, 1668, 1280, 1146 cm–1. 1H NMR (CDCl3): δ = 7.70 (d,
J = 8.4 Hz, 2 H, Ar), 7.35–7.21 (m, 7 H, Ar), 7.04–7.00 (m, 1 H,
3-H), 3.88 (s, 1 H, 6-H), 3.38–3.35 (m, 1 H, 4-H), 3.31–3.01 (m, 1
H, 4-H), 2.51–2.43 (m, 1 H, 5-H), 2.44 (s, 3 H, CH3-C6H4-SO2),
1.63–1.50 (m, 2 H, CH2-CH3), 0.99 (t, J = 7.4 Hz, 3 H, CH2-
CH3) ppm. 13C NMR (75 MHz, CDCl3) δ = 187.9, 147.3, 145.1,
139.2, 135.7, 135.6, 129.8, 128.7, 128.4, 128.1, 127.8, 75.3, 29.7,
28.7, 26.8, 21.7, 11.7 ppm. MS (TOF ES+ ): calcd. for
C21H22O3NaS [M + Na]+ 377.1181; found 377.1176.
(2S,3R,5S/5R)-5-Hydroxy-3-pentyl-2-(phenylsulfonyl)cyclohexanone
(11b/11bЈ): The product was obtained as a mixture of diastereoiso-
mers (1:1) following the standard procedure as a colorless oil
(41 mg, 63% yield) after FC (AcOEt/hexane = 2:1). IR (neat): ν =
˜
2956, 2858, 1714, 1674, 1309 cm–1. Mixture of diastereoisomers
(1:1): 1H NMR (300 MHz, CDCl3): δ = 7.83–7.79 (m, 4 H, Ar),
7.68–7.65 (m, 2 H, Ar), 7.59–7.54 (m, 4 H, Ar), 4.61–4.59 (m, 1 H,
5-H), 4.11–4.00 (m, 1 H, 5Ј-H), 3.68 (s, 1 H), 3.55 (s, 1 H), 3.31–
3.25 (m, 1 H), 3.08–2.99 (m, 1 H), 2.88–2.82 (m, 1 H), 2.59–2.40
(5R,6S)-5-Methyl-2-phenyl-6-tosylcyclohex-2-enone (12b): The
product was obtained following the standard procedure as a color-
less oil (60 mg, 68% yield) after FC (AcOEt/hexane = 2:1). The ee
was determined by HPLC using a Chiralpak AD column (hexane/
(m, 1 H), 2.07–1.55 (m, 8 H), 1.25–1.86 (m, 16 H), 0.86–0.84 (m, iPrOH = 80:20); flow rate: 1.0 mL/min; τmajor = 9.2 min, τminor
=
6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 201.1, 200.5, 137.9,
137.8, 134.3, 134.3, 129.4, 129.3, 128.5, 128.4, 76.5, 76.4, 69.5, 66.2,
50.5, 48.6, 36.1, 35.3, 34.6, 33.4, 33.1, 32.9, 31.3, 31.2, 27.0, 26.5,
22.5, 22.4, 13.9, 13.8 ppm. MS (TOF ES+): calcd. for C17H25O4S
[M + H]+ 325.1637; found 325.1640.
15.0 min (92% ee). [α]2D0 = –27.7 (c = 1.5, CHCl3). 1H NMR
(CDCl3): δ = 7.70 (d, J = 8.4 Hz, 2 H, Ts), 7.35–7.25 (m, 7 H, Ar
and Ts), 7.04–7.00 (m, 1 H, 3-H), 3.80 (s, 1 H, 6-H), 3.44–3.41 (m,
1 H, 4-H), 3.36–3.30 (m, 1 H, 4-H), 2.48–2.32 (m, 1 H, 5-H), 2.45
(s, 3 H, CH3-C6H4-SO2), 1.24 (d, J = 7.3 Hz, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 187.9, 146.9, 145.2, 139.0, 135.7,
135.6, 129.8, 128.7, 128.4, 128.1, 127.9, 76.4, 31.0, 28.7, 21.7,
20.4 ppm. MS (TOF ES+): calcd. for C20H20O3NaS [M + Na]+
363.1025; found 363.1034.
(2S,3R,5R/5S,6S)-3-Ethyl-5-hydroxy-6-methyl-2-tosylcyclo-
hexanone (11c/11cЈ): The product was obtained as a mixture of dia-
stereoisomers (1:1) following the standard procedure as a colorless
oil (39 mg, 65% yield) after FC (AcOEt/hexane = 2:1). Mixture of
1
diastereoisomers (1:1): H NMR (CDCl3): δ = 7.67 (d, J = 7.8 Hz, (5R,6S)-2-Phenyl-5-propyl-6-tosylcyclohex-2-enone (12c): The prod-
4 H, Ar), 7.34 (d, J = 7.4 Hz, 4 H, Ar), 4.37–4.31 (m, 1 H, OH), uct was obtained following the standard procedure as a colorless
4488
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4482–4491

Michael Addition of Keto Sulfones to α,β-Unsaturated Aldehydes
oil (50 mg, 68% yield) after FC (AcOEt/hexane = 2:1). The ee was
determined by HPLC using a Chiralpak AD column (hexane/
H, CH2-CH3), 0.94 (t, J = 7.4 Hz, 3 H, CH2-CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 188.6, 150.2, 138.4 134.0, 129.1, 128.6,
128.4, 74.1, 35.0, 27.9, 26.5, 11.7 ppm. MS (TOF ES+): calcd. for
C14H17O3S [M + H]+ 265.0898; found 265.0898.
iPrOH = 99:1); flow rate: 1.0 mL/min; τmajor = 7.3 min, τminor
=
8.1 min (90% ee). [α]2D0 = –24.4 (c = 0.9, CHCl ). IR (neat): ν =
˜
3
2960, 2931, 2873, 1670, 1146 cm–1. 1H NMR (CDCl3): δ = 7.64 (d,
J = 8.4 Hz, 2 H, Ts), 7.29–7.19 (m, 7 H, Ar and Ts), 6.97–6.95 (m,
1 H, 3-H), 3.79 (s, 1 H, 6-H), 3.33–3.23 (m, 1 H, 4-H), 3.10–2.98
(m, 1 H, 4-H), 2.43–2.32 (m, 1 H, 5-H), 2.39 (s, 3 H, CH3-C6H4-
SO2), 1.47–1.28 (m, 4 H, CH2-CH2-CH3), 0.84 (t, J = 7.4 Hz, 3 H,
CH2-CH2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 187.9,
147.3, 145.1, 139.2, 135.8, 135.7, 129.8, 128.7, 128.4, 128.1, 127.9,
75.4, 35.8, 33.4, 29.1, 21.7, 20.2, 13.7 ppm. MS (TOF ES+): calcd.
for C22H24O3NaS [M + Na]+ 391.1338; found 391.1330.
(5R,6S)-5-Pentyl-6-(phenylsulfonyl)cyclohex-2-enone (14): The
product was obtained following the standard procedure as a color-
less oil (50 mg, 82% yield) after FC (AcOEt/hexane = 2:1). The ee
was determined by HPLC using a Chiralpak AD column (hexane/
iPrOH = 99:1); flow rate: 1.0 mL/min; τmajor = 9.1 min, τminor
=
10.4 min (92% ee). [α]2D0 = –15.4 (c = 0.4, CHCl3). 1H NMR
(CDCl3): δ = 7.75 (d, J = 7.2 Hz, 2 H, Ar), 7.61 (tt, J = 7.4, 1.2 Hz,
1 H, Ar), 7.49 (dt, J = 7.2, 1.4 Hz, 2 H, Ar), 6.97–6.92 (m, 1 H, 3-
H), 6.04 (dd, J = 10.4, 3.0 Hz, 2-H), 3.64 (s, 1 H, 6-H), 3.15–3.05
(m, 1 H, 4-H), 2.97 (q, J = 6.8 Hz, 1 H, 4-H), 2.30–2.20 (m, 1 H,
5-H), 1.39–1.13 (m, 8 H, CH2-CH2-CH2 CH2-CH3), 0.79 (t, J =
7.4 Hz, 3 H, CH2-CH2-CH2 CH2-CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 188.7, 150.2, 138.5 134.1, 129.1, 128.8, 128.4, 74.3,
33.5, 31.4, 30.9, 28.4, 26.8, 22.4, 13.9 ppm. MS (TOF ES+): calcd.
for C17H23O3S [M + H]+ 307.1360; found 307.1362.
(5R,6S)-5-Butyl-2-phenyl-6-tosylcyclohex-2-enone (12d): The prod-
uct was obtained following the standard procedure as a colorless
oil (41 mg, 63% yield) after FC (AcOEt/hexane = 2:1). The ee was
determined by HPLC using a Chiralpak AD column (hexane/
iPrOH = 99:1); flow rate: 1.0 mL/min; τminor = 25.3 min, τmajor
=
38.9 min (94% ee). [α]2D0 = –13.4 (c = 0.4, CHCl ). IR (neat): ν =
˜
3
2958, 2856, 1716, 1670, 1144 cm–1. 1H NMR (CDCl3): δ = 7.95 (d,
J = 8.4 Hz, 2 H, Ts), 7.29–7.19 (m, 7 H, Ar and Ts), 6.97–6.95 (m,
1 H, 3-H), 3.79 (s, 1 H, 6-H), 3.33–3.23 (m, 1 H, 4-H), 3.10–2.98
(m, 1 H, 4-H), 2.43–2.32 (m, 1 H, 5-H), 2.39 (s, 3 H, CH3-C6H4-
SO2), 1.47–1.28 (m, 6 H, CH2-CH2-CH2-CH3), 0.84 (t, J = 7.4 Hz,
3 H, CH2-CH2-CH2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
187.9, 147.3, 145.1, 139.2, 135.8, 135.7, 129.8, 128.7, 128.4, 128.1,
127.9, 75.4, 33.4, 29.3, 29.1, 22.4, 21.7, 20.2, 13.9 ppm. MS (TOF
ES+): calcd. for C23H26O3NaS [M + Na]+ 405.1494; found
405.1498.
(5R,6S)-5-Ethyl-2-methyl-6-(p-tolylsulfonyl)cyclohex-2-enone (15):
The product was obtained following the standard procedure as a
colorless oil (49 mg, 88% yield) after FC (AcOEt/hexane = 2:1).
The ee was determined by HPLC using a Chiralpak AD column
(hexane/iPrOH = 99:1); flow rate: 1.0 mL/min; τmajor = 9.9 min,
τminor = 11.4 min (90% ee). [α]2D0 = –11.6 (c = 1.4, CHCl3). 1H
NMR (CDCl3): δ = 7.64 (d, J = 7.9 Hz, 2 H, Ts), 7.61 (d, J =
7.9 Hz, 2 H, Ar), 6.75–6.71 (m, 1 H, 3-H), 3.72 (s, 1 H, 6-H), 3.18–
3.08 (m, 1 H, 4-H), 2.91 (q, J = 6.8 Hz, 1 H, 4-H), 2.44 (s, 3 H,
CH3-C6H4-SO2), 2.30–2.20 (m, 1 H, 5-H), 1.79 (t, J = 1.3 Hz, 3 H,
CH3-C6H4-SO2), 1.52–1.38 (m, 2 H, CH2-CH3), 0.92 (t, J = 7.4 Hz,
3 H, CH2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 189.4,
145.0, 145.0, 135.7, 134.6, 129.7, 128.7, 74.6, 35.5, 28.0, 26.6, 21.7,
16.1, 11.7 ppm. MS (TOF ES+): calcd. for C16H21O3S [M + H]+
293.1211; found 293.1218.
(5R,6S)-5-Pentyl-2-phenyl-6-tosylcyclohex-2-enone (12e): The prod-
uct was obtained following the standard procedure as a colorless
oil (48 mg, 60% yield) after FC (AcOEt/hexane = 2:1). The ee was
determined by HPLC using a Chiralpak AD column (hexane/
iPrOH = 99:1); flow rate: 1.0 mL/min; τminor = 24.8 min, τmajor
=
28.3 min (92% ee). [α]2D0 = –22.6 (c = 1.6, CHCl ). IR (neat): ν =
˜
3
General Procedure for the Synthesis of 16 and 17 (see Scheme 4): A
diastereomeric solution of 11 (0.2 mmol) in THF/H2O (10 mL, 9:1)
was added at room temperature to an Al (Hg) amalgam (800 mg
of Al) formed a priori by a standard procedure. After completed
consumption of β-keto sulfone (usually 2–4 h), the solvent was
eliminated under reduced pressure and the crude was directly puri-
fied by FC to afford the pure product.
1670, 1597, 1144 cm–1. 1H NMR (CDCl3): δ = 7.60 (d, J = 8.4 Hz,
2 H, Ts), 7.27–7.13 (m, 7 H, Ts and Ar), 7.03–7.01 (m, 1 H, 3-H),
3.76 (s, 1 H, 6-H), 3.28–3.19 (m, 1 H, 4-H), 3.05–2.94 (m, 1 H, 4-
H), 2.40–2.32 (m, 1 H, 5-H), 2.34 (s, 3 H, CH3-C6H4-SO2), 1.21–
1.06 (m, 8 H, CH2-CH2-CH2-CH2-CH3), 0.84 (t, J = 7.4 Hz, 3 H,
CH2-CH2-CH2-CH2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
187.9, 147.4, 145.1, 139.2, 135.7, 135.6, 129.8, 128.7, 128.4, 128.1,
127.9, 75.4, 33.7, 33.6, 31.4, 29.2, 26.7, 22.4, 21.7, 13.9 ppm. MS
(TOF ES+): calcd. for C24H28O3NaS [M + Na]+ 419.1651; found
419.1635.
(R)-3-Hydroxy-5-pentylcyclohexanone (16/16Ј): The product was
obtained from 11b/bЈ following the standard procedure as a mix-
ture of diastereoisomers (1:1) as a colorless oil (27 mg, 81% yield)
after FC (AcOEt/hexane = 2:1). IR (neat): ν = 3434 (br s), 2962,
˜
2927, 1709, 1496 cm–1. Mixture of diastereoisomers: 1H NMR
(CDCl3): δ = 3.64–3.54 (m, 2 H), 2.46–2.12 (m, 6 H, 2-H and 5-
H), 2.03–1.67 (m, 8 H, CH2-CO-CH2), 1.33–1.24 (m, 16 H, CH2-
CH2-CH2-CH2-CH3), 0.89 (t, J = 7.4 Hz, 6 H, CH2-CH2-CH2-
CH2-CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 212.3 (2 C),
70.8, 67.0, 46.7, 45.3, 41.8, 41.7, 39.3, 39.2, 38.9, 38.8, 37.3, 37.2,
36.3, 35.8, 32.4, 29.6, 29.5, 27.2, 11.7, 11.4 ppm. MS (TOF ES+):
calcd. for C11H21O2 [M + H]+ 184.1456; found 184.1446.
General Procedure for the Synthesis of 12a and 13–15 (see
Scheme 4): The corresponding cyclohexanone (0.2 mmol) was
added to a stirring solution of TsOH (0.04 mmol) in toluene (1 mL)
in an ordinary vial and heated at 80 °C overnight. The crude was
directly purified by FC (hexane/AcOEt = 2:1) to afford the pure
products (see below).
(5R,6S)-5-Ethyl-6-(phenylsulfonyl)cyclohex-2-enone (13): The prod-
uct was obtained following the standard procedure as a colorless
oil (42 mg, 76% yield) after FC (AcOEt/hexane = 2:1). The ee was
determined by HPLC using a Chiralpak AD column (hexane/
(2S,5R)-5-Ethyl-3-hydroxy-2-phenylcyclohexanone (17/17Ј): The
product was obtained from 11d/dЈ following the standard procedure
as a mixture of diastereoisomers (3:1) as a colorless oil (35 mg,
iPrOH = 99:1); flow rate: 1.0 mL/min; τminor = 11.1 min, τmajor
=
13.6 min (92% ee). [α]2D0 = –9.7 (c = 1.4, CHCl ). IR (neat): ν =
79% yield) after FC (AcOEt/hexane = 2:1). IR (neat): ν = 3413 (br
˜
˜
3
2966, 2935, 1716, 1673, 1148 cm–1. 1H NMR (CDCl3): δ = 7.80 (d,
s), 1708, 1524 cm–1. Major diastereoisomer: 1H NMR (CDCl3): δ
J = 7.2 Hz, 2 H, Ar), 7.65 (tt, J = 7.4, 1.2 Hz, 1 H, Ar), 7.55 (dt, = 7.31–7.19 (m, 4 H, Ar), 7.06 (d, J = 7.4 Hz, 1 H, Ar), 4.19 (td,
J = 7.2, 1.4 Hz, 2 H, Ar), 7.04–6.98 (m, 1 H, 3-H), 6.10 (dd, J =
10.4, 3.0 Hz, 2-H), 3.72 (s, 1 H, 6-H), 3.21–3.10 (m, 1 H, 4-H), 2.97
(q, J = 6.8 Hz, 1 H, 4-H), 2.38–2.32 (m, 1 H, 5-H), 1.58–1.41 (m, 2
J = 8.7, 3.7 Hz, 1 H, CH-OH), 3.49 (d, J = 8.4 Hz, 1 H, 2-H),
2.55–2.49 (m, 1 H, 6-H), 2.37–2.25 (m, 1 H, 6-H), 2.14–2.04 (m, 2
H, 4-H), 1.96–1.86 (m, 1 H, 5-H), 1.34–1.25 (m, 2 H, CH2-CH3),
Eur. J. Org. Chem. 2010, 4482–4491
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4489

J. Alemán, V. Marcos, L. Marzo, J. L. García Ruano
FULL PAPER
0.88 (t, J = 7.4 Hz, 3 H, CH2-CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 208.3, 135.3, 129.2, 128.8, 127.6, 71.7, 65.9, 45.4, 36.2,
34.2, 26.9, 11.8 ppm. MS (TOF ES+): calcd. for C14H18O2 [M]+
218.1307; found 218.1306.
47, 4638; m) P. Melchiorre, M. Marigo, A. Carlone, G. Bartoli,
Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed. 2008,
47, 6138; n) S. Bertelsen, K. A. Jørgensen, Chem. Soc. Rev.
2009, 38, 2178.
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a) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem.
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Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119,
General Procedure for the Synthesis of Compound 18 (see
Scheme 4): A solution of 11d/11dЈ (0.2 mmol) in THF/H2O (10 mL,
9:1) was added at room temperature to an Al amalgam (800 mg)
formed a priori by standard procedure. After the completed con-
sumption of β-keto sulfone (usually 2–4 h), the solvent was elimin-
ated under reduced pressure and the crude was added to a stirring
solution of TsOH (0.04 mmol) in toluene (1 mL) and heated at
80 °C overnight. The crude was directly purified by FC (hexane/
AcOEt = 2:1) to afford the pure product.
1590; Angew. Chem. Int. Ed. 2007, 46, 1570; c) see also ref.[11]
;
d) see also ref.[2n] in which Jørgensen et al. pointed out the
concept of one-pot organocatalytic reactions.
For some recent examples, see: a) H. Jiang, P. Elsner, K. L.
Jensen, A. Falcicchio, V. Marcos, K. A. Jørgensen, Angew.
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ture Chem. 2009, 1, 225; e) H. Jiang, A. Falcicchio, K. L. Jen-
sen, M. Paixao, S. Bertelsen, K. A. Jørgensen, J. Am. Chem.
Soc. 2009, 131, 7153; f) Y.-G. Wang, T. Kumano, T. Kano, K.
Maruoka, Org. Lett. 2009, 11, 2027; g) H. Ishikawa, T. Suzuki,
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snard, N. Krause, A. Alexakis, Angew. Chem. Int. Ed. 2009, 48,
8923.
(S)-5-Ethyl-2-phenylcyclohex-2-enone (18): The product was ob-
tained following the standard procedure as a colorless oil (27 mg,
67% yield) after FC (AcOEt/hexane = 2:1) along with an unidenti-
1
fied impurity. [α]2D0 = –21.6 (c = 0.9, CHCl3). H NMR (CDCl3): δ
= 7.46–7.15 (m, 5 H, Ar), 6.88–6.84 (m, 1 H, 3-H), 2.73–2.62 (m,
2 H, 6-H), 2.33–2.18 (m, 2 H, 4-H), 1.55–1.40 (m, 3 H), 2.37–2.25
(m, 1 H), 2.14–2.04 (m, 2 H), 1.10 (t, J = 6.0 Hz, 3 H, CH2-
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 198.3, 145.8, 130.1,
129.3, 125.5, 120.5, 115.2, 37.0, 30.1, 28.6, 15.4 ppm. (TOF ES+):
calcd. for C14H16 [M]+ 200.1201; found 200.1200.
[5]
[6]
For some recent publications, see: a) E. S. Gladkov, V. A. Cheb-
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Supporting Information (see also the footnote on the first page of
this article): 1H and 13C NMR spectra for compounds 4a, 6, 8,
10a–d, 11a–d, 12a–e, 13–18, HPLC chromatographs for compounds
6, 8, 10a, ent-10a, 10c, 12a, 12c–e, 15, and ORTEP diagram of
compound 11c.
Acknowledgments
Financial support of this work by the Ministerio de Educación y
Ciencia (MEC) (CTQ-2009-12168) is gratefully acknowledged.
V. M. and J. A., respectively, thank the Ministerio de Ciencia e In-
novación (MICCINN) for a predoctoral fellowship and a Juan de
la Cierva contract. L. M. thanks the Ministerio de Educación, Polí-
tica Social y Deporte for an undergraduate fellowship.
[7]
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Recently and during the preparation of this manuscript,
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and β-alkynylation of α,β-unsaturated aldehydes. They used a
modified Julia-Kocienski protocol which requires the synthesis
of a β-keto-heteroarylsulfone. Our reaction proceeds from com-
mercial β-keto sulfones in a normal Julia elimination procedure
underreductive conditions (see ref.[9]).
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CCDC-724352 (for 11d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Received: April 13, 2010
Published Online: June 25, 2010
Eur. J. Org. Chem. 2010, 4482–4491
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4491