Synthesis of chiral ortho-(p-tolylsulfinyl) benzyl ketones

Article abstract of DOI:10.1016/j.tet.2004.07.050

(S)-ortho-(p-Tolylsulfinyl)benzyl alkyl (and aryl) ketones 1a-e were prepared in good yields by reaction of esters or nitriles with the lithium benzyl carbanion derived from 2-(p-tolylsulfinyl) methylbenzene. α-Methylbenzyl ketones 2 were prepared as ca. 1:1 diastereoisomeric mixtures by methylation of the unsubstituted ketones 1 with NaH/MeI. The use of the ethylbenzene derivative as the starting material afforded complex mixtures. The obtention of pure (S,(S)S)-2 diastereoisomers could be attained in good yields by oxidation with PCC of the alcohols (epimeric mixtures at the hydroxylic carbon) obtained from reactions of aldehydes with the lithium carbanion derived from 2-(p-tolylsulfinyl)ethylbenzene. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.07.050

Tetrahedron 60 (2004) 10067–10075
Synthesis of chiral ortho-(p-tolylsulfinyl) benzyl ketones
´
Jose L. Garcıa Ruano, Jose Aleman, M. Teresa Aranda, M. Angeles Fernandez-Iban˜ez,
*
´
´
´
´
M. Mercedes Rodrıguez-Fernandez and M. Carmen Maestro
´
*
´
´
´
´ ´ ´
Departamento de Quımica Organica(C-I), Universidad Autonoma, Cantoblanco, 28049 Madrid, Spain
Received 3 June 2004; accepted 21 July 2004
Available online 11 September 2004
Dedicated to the late Dr. Martina Vicente for her valuable contribution to asymmetric organic synthesis
Abstract—(S)-ortho-(p-Tolylsulfinyl)benzyl alkyl (and aryl) ketones 1a–e were prepared in good yields by reaction of esters or nitriles with
the lithium benzyl carbanion derived from 2-(p-tolylsulfinyl) methylbenzene. a-Methylbenzyl ketones 2 were prepared as ca. 1:1
diastereoisomeric mixtures by methylation of the unsubstituted ketones 1 with NaH/MeI. The use of the ethylbenzene derivative as the
starting material afforded complex mixtures. The obtention of pure (S,(S)S)-2 diastereoisomers could be attained in good yields by oxidation
with PCC of the alcohols (epimeric mixtures at the hydroxylic carbon) obtained from reactions of aldehydes with the lithium carbanion
derived from 2-(p-tolylsulfinyl)ethylbenzene.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The use of the sulfinyl group as a diastereo- and
enantiocontrolling element in asymmetric synthesis has
been profusely developed since 1980.1 For reactions taking
place on electrophilic or nucleophilic centers close to the
chiral sulfur (1,22- or 1,3-related3–6), numerous highly
Scheme 1.
stereoselective methods have been reported. Much smaller
is the number of reports concerning induction processes
promoted by the sulfinyl group at remote positions (1,n-
stereocontrol, with nO3). 1,4-Asymmetric induction on
electrophilic centers are involved in the reductions7 and
other nucleophilic additions8 to g-ketosulfoxides. Recently
we have demonstrated that the sulfinyl groups are also able
to control the stereoselectivity of the additions of ortho-
sulfinyl benzyllithium carbanions to different electrophiles.9
These good results prompted us to evaluate the ability of the
sulfinyl group to control 1,5-asymmetric induction pro-
cesses, that, to our knowledge, lack of precedents in the
literature. In this paper we describe different approaches to
the synthesis of the optically pure ortho-(p-tolylsulfinyl)-
benzyl alkyl (and aryl) ketones 1a–1d, the ortho-(p-
tolylsulfinyl)phenylacetaldehyde (1e), and their correspond-
ing a-methyl derivatives (2) (Scheme 1). The use of these
compounds as chiral electrophiles will be reported in due
course.
2. Results and discussion
The synthesis of ketones 1a–d was performed from (S)-2-
methyl-1-(p-tolylsulfinyl)benzene (3)9c,10 by deprotonation
at K78 8C with lithium diisopropylamide (LDA) followed
by reaction with different electrophiles. The use of 10 equiv
of nitriles (method A, Table 1), allowed us to obtain good
yields of ketones 1a and 1d. However the results obtained
with n-Pr-CN and i-Pr-CN were unsuccessful (starting
material was recovered). We tried to improve these results
by using 1:1 mixtures of R-CN:BF3$OEt2 as the electro-
philes (method B, Table 1). Compounds 1b (41%) and
1c (31%) could be so obtained with 1.5 equiv of
R-CN:BF3$OEt2. A higher number of equivalents scarcely
improved the yields.
Surprisingly, the reactions performed with esters as the
electrophiles were more successful (method C, Table 1).
Keywords: Stereoselective ketone synthesis; Chiral benzyl ketones; Chiral benzyllithium.
* Corresponding authors. Tel.: C34914974701; fax: C34914973966; e-mail: joseluis.garcia.ruano@uam.es; carmen.maestro@uam.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.050

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10068
Table 1. Synthesis of ortho-(p-Tolylsulfinyl)benzyl ketones 1
Scheme 3.
R
Compound
Isolated yield (%)
A
B
C
reaction with menthyl [(S)S]-p-toluenesulfinate. Hydrolysis
of 7 with formic acid afforded the aldehyde 1e in
quantitative yield. Enantiomeric purity of 1e (eeR99%)
was determined by chiral HPLC with a Chiralcel AD
column.†
Me
n-Pr
i-Pr
Ph
1a
1b
1c
1d
1e
75
0
0
87
—
—
41
31
—
—
81
81
80
—
14
H
The synthesis of the sulfinylketones 2, bearing a methyl
group at the benzylic position, was tried by the two routes
shown in Scheme 3, involving the acylation of 2-(p-
tolylsulfinyl)ethylbenzene 9 (route A) and the alkylation of
the ketones 1 previously obtained (route B), respectively.
However, good yields could be obtained in all cases only by
using a large excess of ester (15 equiv).
The synthesis of the aldehyde 1e from ethyl formate
(method C) was troublesome, mainly due to its unstability as
well as its reactivity (it reacted with a second equivalent of
the benzyl carbanion yielding a secondary alcohol). When
the reaction was performed by addition of a highly diluted
solution of the benzylic anion on a large excess of the ethyl
The reaction of compound 9 with LDA and subsequent
addition of R-CO2Et (RZMe, n-Pr, i-Pr, Ph) or R-CN (RZ
Me, COMe, Ph) did not afford the expected ketones 2 in
good yields. A detailed study of the reaction with ethyl
acetate was performed. Initially, we observed the formation
of not easily reproducible complex mixtures, compounds
10, 11 and 12 being their three main components (Scheme
4), in a ratio which was strongly dependent upon the
experimental conditions. Significant amounts of the starting
material 9, and the desired ketone 2a in a very low
proportion, were also obtained in most of cases. After
exhaustive experimental research we found out that
compound 10, resulting from a double addition of the
anion to the ester, could be obtained in 68% yield, when neat
ethyl acetate was quickly added into the preformed anion at
K78 8C. It indicates that the difference of reactivity
between 2a and ethyl acetate is so large that it cannot be
compensated with the excess of the latter. Remarkably, only
one diastereoisomer was formed in these reactions, which
1
formiate (40 equiv), the H NMR spectrum of the reaction
crude showed the formation of 1e as the main product, but
only a 14% yield could be isolated after chromatographic
purification. By using DMF as the electrophile11 the isolated
yield of 1e slightly increased (25%). Other formylation
agents such as N-formylpiperidine,12 or paraformaldehyde
followed by oxidation,13 were not successful. We prepared
enantiomerically pure compound 1e from o-bromobenz-
aldehyde 4, following a Wittig based strategy (Scheme 2).
The reaction of 4 with (methoxy)triphenylphosphoranyl-
idenemethane yields 5 which evolves into the corresponding
2-o-bromophenylacetaldehyde dimethylacetal (6)14 by reac-
tion with methanol and p-toluenesulfonic acid. This
compound could be easily transformed into the sulfinyl
acetal 7 upon treatment with butyllithium and further
Scheme 2.
† Racemic 1e was prepared by sulfenylation of lithium derivative obtained from 6.

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10069
O
Scheme 4.
suggests that the anion derived from 9 reacts with both ethyl
acetate and 2a in a completely diastereoselective manner.‡
On the other hand, the slow addition of the electrophile
(solved in THF) into the lithium derivative gave mainly
the unaltered starting material. It is worth mentioning the
surprising change produced by the inverse addition of the
reagents. In fact, when the anion derived from 9 was added
into a solution containing ethyl acetate, compound 12 was
the major component of the mixture (tertiary alcohol 10 was
not detected), traces of compound 11¶ being also observed.
However, the proportion of both compounds was not
coincident in the different experiences which were
performed and the reactions were not reproducible in our
hands. It is worth mentioning that the alcohol 12 was always
obtained as a sole diastereoisomer, and in some cases with a
62% isolated yield.
because it had been reported to give the best results in the
a-alkylation of b-ketosulfoxides.3c Deprotonation of keto-
sulfoxides 1 with NaH followed by reaction with MeI
afforded ketosulfoxides 2 as an almost equimolecular
mixture of epimers at the benzylic carbon (A and B, Table
2). In those experiences yielding a significant amount of
dimethylderivative (entry 3) the A/B ratio became 1:3, thus
suggesting that the second alkylation was easier for isomer
A than for isomer B. The best conditions, optimized from
ketosulfoxide 1a, were achieved by using 1.7 equiv of base
and 3.6 equiv of the electrophile at K40 8C (entry 2).
Smaller amounts of the hydride (!1.4 equiv) gave low
conversions (%55%, entry 1), whereas more than 2 equiv
of both reagents yielded a significant proportion of the
bismethylated ketone (entry 3, Table 2).
Chromatographic separation of diastereoisomers A and B,
obtained from the methylation with methyl iodide, is not an
easy task. It was unsuccessful in our hands except for the
Then we tried to obtain the ketones 2 by alkylation of 1
(method B, Scheme 3). NaH was chosen as the base§
‡ The fact that reactions from compound 3, under similar conditions, only evolved into ketones 1 instead of producing alcohols such as 10, could be due to the
immediate enolization of 1, once formed from 3. The lower stability of the enolates derived from 2, containing a tetrasubstituted double bond, could account
for their more difficult enolization.
¶ The formation of compound 11 can be explained by the intramolecular attack of the benzylic carbanion to the sulfinylated ring and subsequent protonation of
the resulting anion. The electronic transfer from the carbanion to produce an anion-radical on the tolyl ring cannot be discarded. With the aim of verifying that
the formation of compound 11 does not require the electrophile participation, we directly dropped the lithium derivative of 9 (formed, as usually, with LDA at
–78 8C during 1 h) over a preparative TLC of silica gel, and left to dry overnight. Under these conditions a mixture of compounds 11 and 110 were obtained as
the major products.
§ The use of LDA did not improve the results.

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10070
Table 2. Synthesis of g-methyl d-ketosulfoxide 2a–d by alkylation of 1
Entry
NaH (equiv)/CH3I (equiv)
Ketone (R)
A:B ratioa
Conversion (yield %)
1
2
3
4
5
6
1.4/2.4
1.7/3.6
2.2/2.4
1.8/2.4
1.8/3.6
1.8/3.6
2a (CH3)
2a (CH3)
2a (CH3)
2b (n-Pr)
2c (i-Pr)
2d (Ph)
46:54
47:53
29:71
47:53
44:56
59:41
55
100 (78)
100 (37)b
100 (67)
100 (87)
100 (77)
a
1
Established from the H NMR spectra of the reaction crudes.
a,a0-Dimethyl ketone was obtained as the major product (53%).
b
Table 3. Synthesis of g-methyl d-ketosulfoxide 2A by PCC oxidation of synCanti mixtures of g-methyl d-hydroxysulfoxides 14
Entry
Aldehyde (R)
anti-14: syn-14a
PCC (equiv)
Time (h)
Ketone (yield %)
1
2
3
4
5
13d (Ph)
13f (n-Bu)
13g (t-Bu)
13h (p-OMeC6H4)
13i (2,6-diMeC6H3)
85:15
37:63
24:76
84:16
67:33
1.5
2.0
2.0
1.5
1.5
5
21
21
6
2dA (65)
2fA (74)
2gA (73)
2hA (74)
2iA (71)
7
a
Data taken from Ref. 15.
epimers 2aA and 2aB (RZMe), that were obtained
diastereomerically pure by using a hexane:ethyl acetate
2:1 mixture as the eluent, 2aA being the isomer with higher
Rf. Configurational assignment of the epimers A and B
based on of their NMR parameters proved to be difficult.
NMR parameters are those corresponding to the diastereo-
isomers denoted as A in the mixture obtained by
methylation of 1d, which differ significantly from those of
the epimer B only in the chemical shift of the methyl group
(see Table 4). On this base, the configurational assignments
Taking into account the above-mentioned difficulties to
obtain diastereomerically pure compounds 2b–d, we
decided to exploit the reported high stereoselectivity at the
benzylic position of the reactions of the lithium carbanion
derived from 9 with aldehydes.15 As these reactions
afforded alcohols 14 as epimeric mixtures at the hydroxylic
carbon, both with the same S configuration at the benzylic
carbon, the oxidation of their hydroxylic groups would yield
enantiomerically pure ketones 2 of known configuration. As
expected, the use of pyridinium chlorochromate (PCC) at
room temperature in dichloromethane afforded the desired
diastereomerically pure ketones 2 in excellent yields
(Table 3).
Table 4. Significant 1H NMR parameters for the configurational assign-
ment of g-methyl d-ketosulfoxides 2
Compound
R
d (H2)
d (CH3)
2aA
2aB
2bA
2bB
2cA
2cB
2dA
2dB
2fA
2gA
2hA
2iA
CH3
CH3
n-Pr
n-Pr
i-Pr
i-Pr
Ph
Ph
n-Bu
t-Bu
(p-OMe)C6H4
(2,6-diMe)C6H3
4.25
4.14
4.13
4.13
4.37
4.29
5.14
5.05
4.21
4.84
5.08
5.16
1.11
0.94
1.13
0.94
1.10
0.90
1.41
1.07
1.21
1.22
1.37
1.64
The resulting ketones exhibit the S configuration at the
1
benzylic carbon.15In the case of 2d, its spectroscopic H

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10071
(12.90 mmol) and boron trifluoride etherate (13.00 mmol)
in CH2Cl2 over the carbanion. The reaction mixture was
stirred for 30 min. The work up to extract the crude was
performed as in method A.
Method C. By reaction of (S)-1-methyl-2-(p-tolylsulfinyl)-
benzene with RCO2Et. A solution of n-BuLi (5.19 mmol,
2.5 M in hexane) was added into a solution of i-Pr2NH
(7.70 mmol) in THF (26.0 mL) at 0 8C. After stirring for
30 min, the mixture was cooled at K78 8C. A solution of the
sulfoxide 3 (4.34 mmol) in THF (17.3 mL) was then added.
The reaction flask was stirred at the same temperature for
1 h, before adding the corresponding carbanion over the
ester (65.1 mmol) at K78 8C. The reaction flask was
maintained 30 min under stirring before quenching with
saturated aqueous NH4Cl. The crude ketone was extracted
with CH2Cl2 (3!40 mL), the extracts dried (MgSO4), and
the solvent evaporated. The residue was purified by flash
chromatography (the eluent was indicated in each case).
Scheme 5.
of the compounds 2aA, 2aB; 2bA, 2bB and 2cA, 2cB (as a
mixture) could be made unambiguously (Scheme 5).
In summary we have described the synthesis of the d-keto-
sulfoxides 1 and 2 in optically pure form, as well as the
problems related to some of the involved reactions. The use
of these compounds as chiral electrophiles and nucleophiles
under different conditions will be reported at a later date.
3. Experimental
3.1. General
3.2.1. (S)-1-[2-(p-Tolylsulfinyl)phenyl)propan-2-one (1a).
It was prepared following method C. Eluent: hexane–ethyl
acetate 1:1. Yield: 81%; white solid; mp: 77–79 8C (diethyl
ether); [a]2D0ZK9.6 (c 1.1, CHCl3); IR (NaCl): 2922, 1722,
1473, 1034 cmK1; 1H NMR: d 7.77 (m, 1H), 7.55–7.40 (m,
5H), 7.24 (d, JZ8.0 Hz, 1H), 7.15 (m, 1H), 4.04 and 3.89
(AB system, JZ17.3 Hz, 2H), 2.34 (s, 3H), 2.11 (s, 3H); 13C
NMR: d 204.5, 143.8, 141.5, 140.9, 133.2, 131.7, 131.5,
130.0, 128.5, 126.7, 125.7, 46.5, 29.6, 21.3; MS (EIC) m/z:
273 (MC); HRMS [MC]: calcd for C16H16O2S: 273.0871;
found, 273.0949.
NMR spectra were obtained in a Bruker spectrometer (300
and 75 MHz for 1H and 13C, respectively) in CDCl3
solutions. Melting points were measured using a Gallem-
kamp apparatus in open capillary tubes. Mass spectra (MS)
were determined by FABC, APCI or EI (70 eV). Specific
rotations were measured in a Perkin–Elmer 241 MC
polarimeter. De’s were evaluated by integration of well-
separated signals of the NMR spectra. All reactions were
carried out in anhydrous solvents under argon atmosfere.
THF and diethyl ether were distilled from sodium-
benzofenone under argon. CH2Cl2 was distilled from
P2O5. Flash column chromatography was perfomed using
silica gel Merck-60 (230–400 mesh).
3.2.2. (S)-1-[2-(p-Tolylsulfinyl)phenyl]pentan-2-one (1b).
It was prepared following method C. Eluent: hexane–ethyl
acetate 2:1. Yield: 81%; white solid; mp: 40–41 8C;
[a]2D0ZK97.6 (c 0.5, CHCl3); IR (KBr): 2969, 1703,
1
1409, 1034 cmK1; H NMR: d 7.78–7.69 (m, 1H), 7.47–
7.33 (m, 4H), 7.25–7.10 (m, 3H), 3.97 and 3.84 (AB system,
JZ17.2 Hz, 1H), 2.35–2.26 (m, 2H), 2.31 (s, 3H), 1.52 (s,
JZ7.5 Hz, 2H), 0.82 (t, JZ7.5 Hz, 3H); 13C NMR: d 206.4,
143.6, 141.3, 140.8, 133.1, 131.4, 131.2, 129.7, 128.2,
126.3, 125.5, 45.5, 44.1, 21.1, 16.8, 13.4; MS (FAB) m/z:
301 [MC1]C; HRMS [MC1]C: calcd for C18H21O2S:
301.1184; found, 301.1255. Anal. calcd for C18H20O2S: C,
71.96; H, 6.71; S, 10.67. Found: C, 71.73; H, 6.69; S, 10.51.
3.2. Synthesis of d-ketosulfoxides
Method A. By reaction of (S)-1-methyl-2-(p-tolylsulfinyl)-
benzene with RCN. A solution of n-BuLi (5.19 mmol, 2.5 M
in hexanes) was added into a solution of i-Pr2NH
(7.70 mmol) in THF (26.0 mL) at 0 8C. After stirring for
30 min, the mixture was cooled at K78 8C and a solution of
the sulfoxide 3 (4.34 mmol) in THF (17.3 mL) was then
added. The mixture was stirred at the same temperature for
1 h, before adding the corresponding nitrile (43.40 mmol) at
K78 8C. The reaction mixture was stirred for 30 min,
quenched (5% aqueous HCl solution, 30 mL) and stirred for
12 h. The crude product was extracted with CH2Cl2 (3!
40 mL), dried (MgSO4) and the solvent was evaporated. The
residue was purified by flash chromatography (the eluent
was indicated in each case).
3.2.3. (S)-3-Methyl-1-[2-(p-tolylsulfinyl)phenyl]butan-2-
one (1c). It was prepared following method C. Eluent:
hexane–ethyl acetate 2:1. Yield: 80%; white solid; mp:
46–47 8C; [a]2D0ZK98.3 (c 1.0, CHCl3); IR (NaCl): 2962,
1
1715, 1083, 1035 cmK1; H NMR: d 7.70–7.67 (m, 1H),
7.48–7.37 (m, 4H), 7.24–7.21 (m, 2H), 7.40–7.11 (m, 1H),
4.11 and 3.94 (AB system, JZ17.3 Hz, 1H), 2.66 (sp, JZ
6.8 Hz, 1H), 2.33 (s, 3H), 1.09 (d, 6H); 13C NMR: d 210.2,
143.8, 141.2, 140.8, 133.5, 131.4, 131.3, 129.7, 128.3,
126.5, 125.5, 43.4, 40.6, 21.2, 18.2, 18.1; MS (FAB) m/z:
301 (MC1)C; HRMS (MC1)C: calcd for C18H21O2S:
301.1184; found, 301.1274. Anal. calcd for C18H20O2S: C,
71.96; H, 6.71; S, 10.67. Found: C, 71.82; H, 6.68; S, 10.65.
Method B. By reaction of (S)-1-methyl-2-(p-tolylsulfinyl)-
benzene with RCN-BF3. A solution of n-BuLi (5.19 mmol,
2.5 M in hexanes) was added into a solution of i-Pr2NH
(7.70 mmol) in THF (26.0 mL) at 0 8C. After stirring for
30 min, the mixture was cooled at K78 8C and a solution of
the sulfoxide 3 (4.34 mmol) in THF (17.3 mL) was then
added. The reaction mixture was stirred at the same
temperature for 1 h, before adding a mixture, previously
stirred (1 h) at K78 8C, of the corresponding nitrile
3.2.4. (S)-1-Phenyl-2-[2-(p-tolylsulfinyl)phenyl]ethan-1-
one (1d). It was prepared following method A. Eluent:
hexane–ethyl acetate 2:1. Yield: 87%; white solid; mp:

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10072
106–108 8C; [a]2D0ZK120.2 (c 1.0, CHCl3); IR (KBr):
(65.1 mmol) was added quickly at K78 8C over the purple
lithium derivative of compound 9. The reaction flask was
stirred for 30 min. The reaction was quenched (saturated
NH4Cl), extracted with diethyl ether (3!20 mL), dried
(MgSO4), and the solvent was evaporated to yield a crude
mixture of compounds 10 and 2aA (1H NMR). The residue
was purified by flash chromatography (hexane–ethyl acetate
1:3) to afford pure compound 10. Yield: 68%; colorless oil;
[a]2D0ZC31.9 (c 0.2, CH3COCH3); IR (NaCl): 3329, 1592,
1492, 810 cmK1; 1H NMR: d 8.02 (dd, JZ7.9, 1.4 Hz, 1H),
7.73 (dd, JZ7.6, 1.4 Hz, 2H), 7.51 (m, 13H), 5.18 (bs, 1H),
3.72 (q, JZ7.1 Hz, 1H), 3.52 (q, JZ7.1 Hz, 1H), 2.40 (s,
6H), 1.19 (d, JZ7.1 Hz, 3H), 0.77 (d, JZ7.1 Hz, 3H), 0.47
(s, 3H); 13C NMR: d 145.7, 145.5, 142.4, 142.1, 141.6,
141.3, 141.2, 140.5, 132.2, 132.1, 131.4, 130.8, 130.4,
129.8, 126.9, 126.4, 126.3, 126.2, 125.4, 124.3, 75.9, 40.1,
39.7, 21.4, 21.2, 19.9, 16.5, 15.9. Anal. calcd for
C32H34O3S2: C, 72.42; H, 6.46; S, 12.08. Found: C, 72.48;
H, 6.50; S, 12.10.
1
3424, 1686, 1323, 1077 cmK1; H NMR: d 7.91–7.88 (m,
2H), 7.82–7.29 (m, 1H), 7.57–7.53 (m, 1H), 7.45–7.38 (m,
6H), 7.20–7.11 (m, 3H), 4.58 and 4.48 (AB system, JZ
16.9 Hz, 2H), 2.29 (s, 3H); 13C NMR: d 195.7, 143.6, 141.1,
140.6, 135.9, 133.5, 133.2, 131.6, 131.2, 129.7, 128.4,
128.2, 128.0, 126.5, 125.5, 41.3, 21.1; MS (FAB) m/z: 335
[MC1]C; HRMS [MC1]C: calcd for C21H19O2S:
335.1027; found, 335.1103. Anal. calcd for C21H18O2S: C,
75.42; H, 5.42; S, 9.59. Found: C, 75.29; H, 5.49; S, 9.47.
3.3. Synthesis of sulfinyl aldehyde 1e
3.3.1. (S)-1-(2,2-Dimethoxyethyl)-2-(p-tolylsulfinyl)ben-
zene (7). A solution of bromide 6 (0.40 mmol) in THF
(0.4 mL) at K78 8C was added into a solution of n-BuLi
(0.40 mmol, 2.5 M in hexane), and the reaction flask was
stirred for 45 min at the same temperature before the
addition over a solution of (1R,2S,5R)-(K)-menthyl (S)-p-
toluenesulfinate (0.34 mmol) in THF (0.2 mL) at K78 8C.
The reaction mixture was stirred for 6 h at K78 8C until
completion, and then it was hydrolyzed with a saturated
aqueous NH4Cl solution (0.5 mL), extracted with CH2Cl2
(3!0.5 mL), dried (MgSO4), and the solvent was evapo-
rated. The residue was purified by flash chromatography
with hexane–ethyl acetate 1:1 as the eluent. Yield: 70%;
yellow oil; [a]2D0ZK31.8 (c 3.2, CHCl3); IR (NaCl): 2956,
3.5. Protocols for the synthesis of ketones 2
Method A. General procedure for methylation of ketones 1.
A solution (0.26 M in THF) of d-ketosulfoxides 1a–d was
added into a stirred suspension of NaH (1.7 or 1.8 equiv,
free of paraffin) in THF (2 mL) at room temperature. After
stirring for 1 h, the mixture was cooled at K40 8C and
methyl iodide (3.6 or 2.4 equiv) was injected under stirring
at the same temperature (see Table 2 in the text for
proportions). Then, an aqueous saturated solution of NH4Cl
was added, and the mixture was left under stirring to reach
room temperature. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3!10 mL). The
combined extracts were dried (MgSO4) and the solvent
evaporated. The residue was purified by flash chroma-
tography (the eluent was indicated in each case).
1
2934, 1439, 1118 cmK1; H NMR: d 7.82–7.79 (m, 1H),
7.44–7.15 (m, 7H), 4.34–4.30 (m, 1H), 3.24 (s, 3H), 3.20 (s,
3H), 3.08–2.95 (m, 2H), 2.27 (s, 3H); 13C NMR: d 143.6,
141.5, 141.2, 134.9, 130.8, 130.7, 129.6, 127.6, 125.6,
125.0, 104.1, 53.7, 53.3, 35.3, 21.0; MS (FAB) m/z: 273
[(MC1)KMeOH]C.
3.3.2. (S)-2-[2-(p-Tolylsulfinyl)phenyl]acetaldehyde (1e).
A solution of the acetal 7 (0.83 mmol) in formic acid
(41.57 mmol) was stirred for 1 h at room temperature. Then,
the mixture was diluted with dichloromethane, washed
(NaHCO3 saturated aqueous solution) and the solvents
evaporated under reduced pressure. The residue was
purified by flash chromatography using as the eluent
hexane–ethyl acetate 2:1. Enantiomeric purity (eeR99%)
was determined by HPLC (Chiralcel AD column) with
Method B. General procedure for oxidation of alcohols 14.
The epimeric mixture of alcohols 14, obtained following the
previously described procedure,15 was solved in dry CH2Cl2
and PCC was added (1.5 or 2.0 equiv for aromatic or
aliphatic derivatives, respectively). The mixture was stirred
at room temperature (see reaction times in Table 3) and then
the solvent was partially evaporated and the residue was
chromatographied.
70:30 hexane–isopropanol as the eluent (1 mL minK1
,
35 8C; (S): tRZ6.1; (R): tRZ6.8(. Yield: 99%; yellow oil;
[a]2D0ZK21.0 (c 0.5, CHCl3); IR (NaCl): 3331, 2924,
1723 cmK1; 1H NMR: d 9.46 (t, JZ1.6 Hz, 1H), 7.88–7.83
(m, 1H), 7.47–7.39 (m, 4H), 7.22–7.13 (m, 3H), 3.91 (dd,
JZ17.3 Hz, 1.6 Hz, 1H) 3.82 (dd, 1H). 2.30 (s, 3H); 13C
NMR: d 197.2, 143.6, 141.6, 140.4, 131.7, 131.4, 130.9,
129.9, 128.5, 126.3, 125.5, 46.0, 21.1; MS (FAB) m/z: 259
(MC1)C; HRMS (MC1)C: calcd for C15H15O2S:
259.0715; found, 259.0802.
3.5.1. [3S,(S)S] and [3R,(S)S]-3-[2-(p-Tolylsulfinyl)-
phenyl]butan-2-one (2aA) and (2aB). They were obtained
as a 47:53 epimeric mixture by methylation of ketone 1a
and separated by flash chromatography (hexane–ethyl
acetate 3:1).
Compound [3S,(S)S]-(2aA). It was obtained as a white solid.
Yield: 26%; mp: 87–90 8C; [a]2D0ZC103 (c 0.8, CHCl3);
1H NMR: d 7.90 (m, 1H), 7.45–7.37 (AA’BB0 system, 4H),
7.19 (m, 2H), 7.05 (m, 1H), 4.25 (q, 1H, JZ6.9 Hz,
CH3CH), 2.31 (s, 3H, CH3Ar), 1.63 (s, 3H, CH3CO), 1.12
(d, JZ6.9 Hz, 3H, CH3CH); 13C NMR: d 207.5, 142.7,
142.1, 141.3, 139.6, 131.9, 130.1, 128.5, 128.1, 126.9,
126.1, 47.6, 28.4, 21.3, 17.5; MS (APCIC) m/z: 287.1 [MC
1]C; HRMS: calcd for C17H19O2S: 287.1100. Found:
287.1114.
3.4. Protocol for obtaining dimeric sulfoxide 10
3.4.1. ((S)S,2S,4S)-2,4-Bis-[2-(p-tolylsufinyl)phenyl]-3-
methylpentan-3-ol (10). To a solution of n-BuLi
(5.19 mmol, 2.5 M in hexane) was added i-Pr2NH
(7.70 mmol) in THF (5.0 mL) at 0 8C. After stirring for
30 min, the mixture was cooled at K78 8C. A solution of the
sulfoxide 9 (4.34 mmol) in THF (5.0 mL) was then added,
and the mixture was stirred for 1 h. Ethyl acetate

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10073
1
Compound [3R,(S)S]-(2aB). It was obtained as a colorless
1683, 1499, 1180, 1083, 1032 cmK1; H NMR: d 7.94 (m,
1H), 7.58 (m, 2H), 7.46–7.34 (m, 5H), 7.21–7.16 (m, 5H),
5.14 (q, JZ6.9 Hz, 1H, CH3CH), 2.35 (s, 3H, CH3Ar), 1.41
(d, JZ6.9 Hz, 3H, CH3CH); 13C NMR: d 199.6, 141.8,
141.5, 140.8, 140.1, 135.8, 132.8, 131.8, 130.0, 128.7,
128.5, 128.3, 127.9, 126.5, 126.4, 42.6, 21.3, 18.9. MS
(EIC) m/z: 348 (MC, 16), 243 (43), 225 (76), 135 (39), 105
(100), 91 (36), 77 (93); HRMS: calcd for C22H20O2S:
348.1184. Found: 348.1184.
oil. Yield: 53%; [a]D20ZK248 (c 3.9, CHCl3); H NMR: d
1
7.95 (dd, JZ7.7, 1.6 Hz, 1H), 7.45–7.35 (m, 4H), 7.19 (d,
JZ7.7 Hz, 2H), 7.06–7.02 (m, 1H), 4.14 (q, 1H, JZ6.7 Hz,
CH3CH), 2.30 (s, 3H, CH3Ar), 1.92 (s, 3H, CH3CO), 0.94
(d, 3H, JZ6.7 Hz, CH3CH); 13C NMR: d 206.7, 142.6,
141.9, 141.2, 138.7, 131.6, 130.0, 128.2, 127.8, 126.0,
125.6, 47.4, 28.3, 21.2, 16.5; MS (APCIC) m/z: 287.1 [MC
1]C. Anal. calcd for C17H18O2S: C, 71.30; H, 6.34; S, 11.20.
Found: C, 71.38; H, 6.35; S, 10.70.
Compound [2R,(S)S]-(2dB) from a mixture of ACB,
1
obtained following method A; H NMR: d 8.03 (dd, JZ
3.5.2. [2S,(S)S] and [2R,(S)S]-2-[2-(p-Tolylsulfinyl)-
phenyl]hexan-3-one (2bA) and (2bB). They were obtained
as a 47:53 epimeric mixture by methylation from ketone 1b.
Chromatographic purification (hexane–ethyl acetate 3:1)
afforded the mixture of 2bA and 2bB as a yellow oil.
7.7, 1.6 Hz, 1H), 7.60–7.33 (m, 8H), 7.27–7.17 (m, 5H),
5.05, (q, JZ6.6 Hz, 1H, CH3CH), 2.34 (s, 3H, CH3Ar), 1.07
(d, JZ6.6 Hz, 3H, CH3CH); 13C NMR: d 189.9, 142.3,
141.9, 141.2, 139.4, 135.7, 133.1, 131.6, 130.9, 130.2,
128.2, 128.1, 126.6, 126.2, 125.6, 42.4, 21.4, 18.4; MS
(APCIC) m/z: 349.0 [MC1]C. Anal. calcd for C22H20O2S:
C, 75.83; H, 5.79; S, 9.20. Found: C, 75.54; H, 5.96; S, 8.95.
1
Overall yield: 67%; H NMR: d 7.97–7.92 (m, 2H), 7.43–
7.33 (m, 8H), 7.21–7.18 (m, 4H),7.06–7.03 (m, 2H), 4.13 (q,
JZ6.8 Hz, 2H, CH3CH), 2.29 (s, 6H, CH3Ar), 2.19–2.16
(m, 2H, CH2–CO), 1.73–1.67 (m, 2H, CH2CO), 1.47–1.33
(m, 2H, CH2CH2CO), 1.29–1.18 (m, 2H, CH2CH2CO), 1.13
(d, JZ6.9 Hz, 3H, CH3CHCO, A), 0.94 (d, JZ6.7 Hz, 3H,
CH3CHCO, B), 0.69 (t, JZ7.5 Hz, 3H, CH3CH2, B), 0.55 (t,
JZ7.3 Hz, 3H, CH3CH2, A); 13C NMR: d 209.5, 209.0,
142.2, 142.0, 141.9, 141.5, 141.4, 139.5, 138.9, 131.7,
131.6, 130.1, 130.0, 128.3, 128.2, 128.0, 127.9, 126.4,
126.3, 126.0, 125.6, 46.8, 43.3, 42.9, 21.3, 17.7, 17.1, 16.9,
16.8, 13.4, 13.3; MS (APCIC) m/z: 315.1 [MC1]C. Anal.
calcd for C19H22O2S: C, 72.57; H, 7.05; S, 10.20. Found: C,
72.07; H, 7.03; S, 10.04.
3.5.5. [2S,(S)S]-2-[2-(p-Tolylsulfinyl)phenyl]heptan-3-
one (2fA). Obtained by oxidation of a 37:63 mixture of
anti- and syn-14f. Reaction time: 21 h. Eluent for chroma-
tography: hexane–ethyl acetate 3:2. Yield: 74%. [a]2D0:
C152.5 (c 1, CHCl3); IR: 2930, 1714, 1468, 1083,
1033 cmK1; H NMR:0d 8.00 (m, 1H), 7.51–7.42 (m, 2H),
1
7.47 and 7.27 (AA’BB system, 4H), 7.12 (m, 1H), 4.21 (q,
JZ6.9 Hz, 1H, CH3CH), 2.37 (s, 3H, CH3Ar), 1.80 (m, 2H,
COCH2), 1.33–1.18 (m, 2H, CH2CH2CH2), 1.21 (d, JZ
6.9 Hz, 3H, CH3CH), 1.06–0.93 (m, 2H, CH2CH3), 0.72 (t,
JZ7.3 Hz, 3H, CH3CH2); 13C NMR: d 209.6, 142.2, 142.0,
141.5, 139.5, 131.7, 130.1, 128.3, 127.9, 126.4, 126.3, 46.9,
40.7, 25.5, 21.9, 21.3, 17.8, 13.6; MS (EIC) m/z: 328 (MC,
15), 243 (33), 225 (100), 211 (52), 151 (44), 135 (94), 91
(54), 77 (27); HRMS: calcd for C20H24O2S: 328.1496.
Found: 328.1497.
3.5.3. [4S,(S)S] and [4R,(S)S]-2-Methyl-4-[2-(p-tolylsulfi-
nyl)phenyl]pentan-3-one (2cA) and (2cB). They were
obtained as a 44:56 epimeric mixture by methylation of
ketone 1c. Chromatographic purification (hexane–ethyl
acetate 2:1) afforded a mixture of 2cA and 2cB as a yellow
1
oil. Overall yield: 87%; H NMR: d 7.97–7.86 (m, 2H),
7.44–7.34 (m, 8H), 7.22–7.19 (m, 4H), 7.08–7.03 (m, 2H),
4.37 (q, 1H, JZ6.7 Hz, CH3CH, A), 4.29 (q, JZ6.9 Hz, 1H,
CH3CH, B), 2.51 (s, JZ7.1 Hz, 1H, CH(CH3)2, B), 2.31 (s,
3H, CH3Ar, A), 2.30 (s, 3H, CH3Ar, B), 2.07 (s, JZ7.1 Hz,
1H, CH(CH3)2, A), 1.10 (d, JZ6.7 Hz, 3H, CH3CH, A),
1.03 (d, JZ7.1 Hz, 3H, (CH3)2CH, A), 0.90 (d, JZ6.9 Hz,
3H, CH3CH, B), 0.81 (d, JZ7.1 Hz, 3H, (CH3)2CH, A),
0.76 (d, JZ7.1 Hz, 3H, (CH3)2CH, B), 0.69 (d, JZ7.1 Hz,
3H, (CH3)2CH, B); 13C NMR: d 209.6, 209.1, 142.3, 142.1,
141.9, 141.5, 139.6, 138.9, 131.8, 131.6, 130.1, 128.4,
128.2, 128.1, 127.9, 125.7, 46.9, 43.4, 42.9, 21.4, 21.3, 17.8,
17.2, 16.9, 16.8, 13.5, 13.4; MS (APCIC) m/z: 315.1 [MC
1]C; HRMS [MC1]C: calcd for C19H23O2S: 315.1413.
Found: 315.1419.
3.5.6. [4S,(S)S]-2,20-Dimethyl-4-[2-(p-tolylsulfinyl)-
phenyl]pentan-3-one (2gA). Obtained by oxidation from
a 24:76 mixture of anti- and syn-14g. Reaction time: 21 h.
Eluent for chromatography: hexane–ethyl acetate 3:2.
Yield: 73%. [a]2D0:C75.1 (c 1, CHCl3); IR: 2970, 1703,
1470, 1084, 1054 cmK1; 1H NMR: d 7.83 (m, 1H), 7.52 (m,
2H), 7.45–7.30 (m, 5H), 4.84 (q, JZ6.9 Hz, 1H, CH3CH),
2.41 (s, 3H, CH3Ar), 1.22 (d, JZ6.9 Hz, 3H, CH3CH), 0.93
(s, 9H, (CH3)3); 13C NMR: d 215.8, 141.8, 141.3, 140.7,
140.6, 131.8, 130.0, 128.0, 127.7, 127.3, 126.1, 45.0, 40.6,
26.2, 21.3, 20.5; MS (EIC) m/z: 328 (MC, 10), 243 (31), 225
(100), 211 (31), 151 (23), 135 (69), 91 (44), 77 (22); HRMS:
calcd for C20H24O2S: 328.1500. Found: 328.1497.
3.5.7. [1S,(S)S]-1-(p-Methoxyphenyl)-2-[2-(p-tolysul-
finyl)phenyl)]propanone (2hA). It was obtained by
oxidation of a 84:16 mixture of anti- and syn-14h. Reaction
time: 6 h. Eluent for chromatography: hexane–ethyl acetate
1:1. Yield: 74%; mp: 139–140 8C (diethyl ether–hexane).
[a]2D0:C183.2 (c 1, CHCl3); IR: 1674, 1600, 1510, 1263,
1084, 10030 cmK1; 1H NMR: d 7.94 (m, 1H), 7.57 and 7.45
(AA’BB system, 4H), 7.38 (m, 2H), 7.22 and 6.57 (part of
AA’BB0 system, 4H), 7.19 (m, 1H), 5.08 (q, JZ6.9 Hz, 1H,
CH3CH), 3.77 (s, 3H, OCH3), 2.37 (s, 3H, CH3Ar), 1.37 (d,
3H, CH3CH); 13C NMR: d 198.1, 163.2, 141.8, 141.3,
140.8, 140.5, 131.8, 130.9, 130.1, 128.7, 127.8, 126.5,
3.5.4. [2S,(S)S] and [2R,(S)S]-1-Phenyl-2-[2-(p-tolylsulfi-
nyl)phenyl]propan-1-one (2dA) and (2dB). They were
obtained as a 59:41 epimeric mixture by methylation of
ketone 1d. Chromatographic purification (hexane–ethyl
acetate 1:1) afforded a mixture of 2dA and 2dB as a
colorless oil. Overall yield: 77%.
Compound [2S,(S)S]-(2dA). Obtained by oxidation from a
85:15 mixture of anti- and syn-14d. Reaction time: 5 h.
Eluent for chromatography: hexane–ethyl acetate 1:1.
Yield: 65%. [a]2D0:C236.1 (c 1, CHCl3); IR: 3058, 2979,

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10074
126.4, 113.5, 53.3, 42.3, 21.3, 19.0. Anal. calcd for
C23H22O3S: C, 72.99; H, 5.86; S, 8.47. Found: C, 73.05;
H, 5.37; S, 8.00; MS (EIC) m/z: 378 (MC, 2), 243 (22), 225
(21), 135 (100), 91 (9), 77 (17); HRMS: calcd for
C23H22O3S: 378.1290. Found: 378.1295.
3.7. Protocol for the synthesis of alcohol 12
3.7.1. Compound [1S,(S)S]-1-[2-(p-tolylsulfinyl)phenyl]-
ethanol (12).7f To a solution of n-BuLi (0.33 mmol, 2.5 M
in hexanes) was added i-Pr2NH (0.49 mmol) in THF
(1.7 mL) at 0 8C. After stirring for 30 min, the mixture
was cooled at K78 8C and a solution of the sulfoxide 9
(0.27 mmol) in THF (1.1 mL) was added. After stirring for
1 h the purple carbanion 9 was slowly added, into a solution
of ethyl acetate (10.9 mmol) in THF (1.1 mL) at K78 8C.
The reaction was stirred for 30 min and quenched with
saturated NH4Cl, extracted with CH2Cl2 (3!20 mL), dried
(MgSO4) and the solvent evaporated. The residue was
purified by flash chromatography (ethyl acetate–hexane 6:4)
to afford alcohol 12 as a colorless oil. Yield: 62%. [a]2D0Z
3.5.8. (2S,(S)S)-1-(2,6-Dimethylphenyl)-2-[2-(p-tolysulfi-
nyl)phenyl)]propanone (2iA).15 It was obtained by oxi-
dation of a 67:33 mixture of anti- and syn-14i. Reaction
time: 7 h. Eluent for chromatography: hexane–ethyl acetate
1:1. Yield: 71%; mp: 106–107 8C (diethyl ether–hexane).
[a]2D0: K48.2 (c 0.75, CHCl3); IR: 1698, 1466, 1085,
1
1033 cmK1; H NMR: d 7.57–7.51 (m, 2H), 7.47 (dt, JZ
1.6, 8.1 Hz, 1H), 7.35 (dt, JZ1.6, 8.1 Hz, 1H), 7.15 (t, JZ
7.7 Hz, 1H), 7.03 and 6.92 (AA’BB0 system, 4H), 6.84 (d,
JZ8.1 Hz, 2H), 5.16 (q, JZ6.9 Hz, 1H, CH3CH–), 2.32 (s,
3H, CH3Ar), 2.00 (s, 6H, 2 CH3Ar), 1.64 (d, JZ6.9 Hz, 3H,
CH3–CH–); 13C NMR: d 208.2, 144.7, 141.4, 140.9, 140.6,
138.1, 133.4, 131.6, 129.7, 128.9, 128.6, 128.0, 127.3,
124.7, 48.1, 21.3, 19.5, 18.5. Anal. calcd for C24H24O2S: C,
76.56; H, 6.42; S, 8.52. Found: C, 76.73; H, 6.27; S, 8.06;
MS (EIC) m/z: 376 (MC, 5), 243 (10), 225 (24), 133 (100),
105 (36), 91 (10), 77 (13); HRMS: calcd for C24H24O2S:
376.1497. Found: 376.1491.
1
K37 (c 9.1, CHCl3); H NMR: d 7.86 (d, JZ7.7 Hz, 1H),
7.59–7.23 (m, 7H), 5.26 (dq, JZ6.5, 3.6 Hz, 1H, CH–CH3),
2.99 (d, JZ3.6 Hz, 1H, OH), 2.36 (s, 6H, CH3Ar), 1.46 (d,
JZ6.5 Hz, 3H, CHCH3); 13C NMR: d 144.1, 142.0, 141.3,
131.9, 129.9, 128.4, 126.5, 126.4, 126.3, 125.3, 65.1, 23.2,
21.3; MS (FABC) m/z: 261 [MC1]C, 260 (4), 243 (100),
242 (88). Anal. calcd for C15H16O2S: C, 69.20; H, 6.19; S,
12.32. Found: C, 69.22; H, 6.47; S, 11.75.
Acknowledgements
3.6. Protocol for obtaining compounds 11 and 110
We thank the CICYT (Grant BQU2003-04012) for financial
support. J.A. thanks Spanish Ministerio de Ciencia y
To a solution of n-BuLi (0.86 mmol, 2.5 M in hexane) was
added i-Pr2NH (1.28 mmol) in THF (5.1 mL) at 0 8C. After
stirring for 30 min, the mixture was cooled at K78 8C and a
solution of the sulfoxide 9 (0.71 mmol) in THF (2.5 mL)
was added. After stirring for 40 min the purple carbanion 9
was added slowly with a syringe to a preparative TLC plate
of silica gel. After 12 h the mixture was extracted with ethyl
acetate, and filtered. The solvent was evaporated and the
residue was separated by flash chromatography (ethyl
acetate–hexane 2:1) to afford pure compounds 11 and 110.
´
Tecnologıa and M.A.F.-I. thanks Comunidad Autonoma
de Madrid, both for predoctoral fellowships.
´
References and notes
´
1. (a) Carren˜o, M. C. Chem. Rev. 1995, 1717. (b) Fernandez, I.;
Khiar, N. Chem. Rev. 2003, 103, 3651.
2. (a) Kusuda, S.; Ueno, Y.; Toru, T. Tetrahedron 1994, 50,
1045. (b) Garcia-Ruano, J. L.; Barros, D.; Maestro, M. C.;
´
Martın Castro, A. M.; Raithby, P. R. Tetrahedron: Asymmetry
3.6.1. Compound 11. It was obtained as a colorless oil.
Yield: 22%; H NMR: d 7.70 (dd, JZ7.6, 1.6 Hz, 1H),
1
7.40–7.20 (m, 3H), 6.01 (dd, JZ9.6, 4.7 Hz, 1H, CHZCH–
C–CH3), 5.84 (d, JZ9.6 Hz, 1H, CHZCH–C–CH3), 5.09
(m, 1H, CHZC–CH3), 3.83 (ddd, JZ12.3, 4.7, 1.7 Hz, 1H,
CHSO), 3.47 (dq, JZ7.2, 2.9 Hz, 1H, CHCH3), 3.26 (m,
1H, CH–CH–CH3), 1.61 (m, 3H, CHZC–CH3), 1.29 (d, JZ
7.2 Hz, 3H, CHCH3); 13C NMR: d 141.8, 141.7, 130.9,
130.4, 126.9, 126.8, 126.6, 120.6, 120.5, 64.9, 38.4, 36.7,
21.3, 16.9.
´
2000, 11, 4385. (c) Garcıa Ruano, J. L.; Alcudia, A.; del Prado,
´
M.; Barros, D.; Maestro, M. C.; Fernandez, I. J. Org. Chem.
2000, 65, 2856.
3. For the reduction of b-ketosulfoxides: (a) Solladie, G.;
´
´
Frechou, C.; Demailly, G.; Greck, C. J. Org. Chem. 1986,
51, 1912 and references cited therein. (b) Carren˜o, M. C.;
´ ´ ´
Garcıa Ruano, J. L.; Martın, A. M.; Pedregal, C.; Rodrıguez,
´
´
J. H.; Rubio, A.; Sanchez, J.; Solladie, G. J. Org. Chem. 1990,
55, 2120. (c) Barros, D.; Carren˜o, M. C.; Garcia-Ruano,
J. L.; Maestro, M. C. Tetrahedron Lett. 1992, 33, 2733.
(d) Nakamura, S.; Nakayama, J.; Toru, T. J. Org. Chem.
2003, 68, 5766.
3.6.2. Compound 110. It was obtained as a white solid.
Yield: 20%; [a]2D0ZK129 (c 0.54, CHCl3); 1H NMR: d 7.77
(dd, JZ7.3, 1.5 Hz, 1H), 7.55–7.25 (m, 3H), 6.91 (t, JZ
9.6 Hz, 1H, CHZC–S), 5.46 (m, 1H, CHZC–CH3),
3.91 (m, 1H, CH3–CH–CH), 3.10 (dq, JZ7.1, 4.1 Hz, 1H,
CH–CH3), 2.85 (m, 2H, CH2–CH–CH3), 1.78 (s, 3H, CHZ
C–CH3), 0.96 (d, JZ7.1 Hz, 3H, CH–CH3); 13C NMR: d
142.2, 137.8, 131.7, 131.4, 131.2, 130.1, 129.9, 127.8,
120.7, 40.0, 32.7, 32.3, 22.7, 18.7; MS (APCIC) m/z: 245.1
[MC1]C. Anal. calcd for C15H16OS C, 73.73; H, 6.60; S,
13.12. Found: C, 72.92; H, 6.60; S, 12.64; HRMS: calcd for
C15H16OS: 244.0922. Found: 244.0917.
4. For the alkylation of b-ketosulfoxides: (a) Bueno, A. B.;
´
Carren˜o, M. C.; Fischer, J.; Garcıa Ruano, J. L.; Pen˜a, B.;
Pen˜as, L.; Rubio, A. Tetrahedron Lett. 1991, 32, 3191.
´
(b) Bueno, A. B.; Carren˜o, M. C.; Garcıa Ruano, J. L. Ann.
´
´
Quım 1994, 90, 442. (c) Carren˜o, M. C.; Garcıa Ruano, J. L.;
´
´
Maestro, M. C.; Perez Gonzalez, M.; Bueno, A. B.; Fisher, J.
Tetrahedron 1993, 49, 11009. (d) Kunieda, N.; Nokami, J.;
Kinoshita, M. Chem. Lett. 1974, 4, 369. (e) Fujisawa, T.;
Fujimura, A.; Ukaji, Y. Chem. Lett. 1988, 9, 1541.

´
J. L. Garcıa Ruano et al. / Tetrahedron 60 (2004) 10067–10075
10075
´
5. For the of hydrocyanation b-ketosulfoxides: (a) Garcıa Ruano,
´ ´
J. L.; Martın Castro, A. M.; Rodrıguez, J. H. J. Org. Chem.
Masaki, Y.; Shiro, M. J. Chem. Soc., Perkin Trans. 1 1995,
2913, and references cited therein. (b) Nakamura, S.; Yasuda,
H.; Watanabe, Y.; Toru, T. Tetrahedron Lett. 2000, 41, 4157.
(c) Girodier, L. D.; Rouessac, F. P. Tetrahedron: Asymmetry
1994, 5, 1203. (d) Arai, Y.; Masuda, T.; Masaki, Y. Synlett
´
1992, 57, 7235. (b) Garcıa Ruano, J. L.; Martın Castro,
´
´
A. M.; Rodrıguez, J. H. Recent Res. Dev. Org. Chem. 2000,
4, 261.
6. For the aldol reaction of b-ketosulfoxides: (a) Garcıa Ruano,
J. L.; Barros, D.; Maestro, M. C.; Araya-Maturana, R.; Fischer,
´
´
1997, 1459. (e) Almorın, A.; Carren˜o, M. C.; Somoza, A.;
Urbano, A. Tetrahedron Lett. 2003, 44, 5597.
´
J. J. Org. Chem. 1996, 61, 9462. (b) Garcıa Ruano, J. L.;
´
9. (a) Garcıa Ruano, J. L.; Carren˜o, M. C.; Toledo, M. A.;
´
Barros, D.; Maestro, M. C.; Alcudia, A.; Fernandez, I.
Tetrahedron: Asymmetry 1998, 9, 3445.
Aguirre, J. M.; Aranda, M. T.; Fischer, J. Angew. Chem. Int.
´ ´
Ed. 2000, 39, 2736. (b) Garcıa Ruano, J. L.; Aleman, J.;
´
Soriano, J. F. Org. Lett. 2003, 5, 677. (c) Garcıa Ruano,
´
J. L.; Aleman J. Org. Lett. 2003, 5, 4513.
7. For reduction: (1,4 asymmetric induction) (a) Arai, Y.; Suzuki,
A.; Masuda, T.; Masaki, Y.; Shiro, M. Chem. Pharm. Bull.
´
1996, 44, 1765. (b) Solladie, G.; Collobert, F.; Somny, F.
´
Tetrahedron Lett. 1999, 40, 1227. (c) Solladie, G.; Hanquet,
10. (a) Andersen, K. K.; Gaffield, W.; Papanikolau, N. E.; Foley,
J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637.
(b) Mislow, K.; Green, M. M.; Laur, P.; Melillo, J. T.; Ternay,
A. L. J. Am. Chem. Soc. 1965, 87, 1958.
G.; Izzo, I.; Crumbie, R. Tetrahedron Lett. 1999, 40, 3071. For
the use of the bulky (2,4,6-triisopropylphenyl)sulfinyl group as
the chiral auxiliary instead of the usual p-tolyl group see:
(d) Nakamura, S.; Kuroyanagy, M.; Watanabe, Y.; Toru, T.
J. Chem. Soc., Perkin Trans. 1 2000, 3143. (e) Nakamura, S.;
Oda, M.; Yasuda, H.; Toru, T. Tetrahedron 2001, 57, 8469.
(1,6 asymmetric induction): (f) Iwata, C.; Moritani, Y.;
Sugiyama, K.; Fujita, M.; Imanishi, T. Tetrahedron Lett.
1987, 28, 2255.
11. Olah, G. A.; Surya Prakash, G. K.; Arvanaghi, M. Synthesis
1984, 228.
12. Olah, G. A.; Arvanaghi, M. Angew. Chem. Int. Ed. 1981, 20,
878.
13. Pfeffer, P. E.; Kinsel, E.; Silbert, L. S. J. Org. Chem. 1972, 37,
1256.
14. Wu¨nsch, B. Arch. Pharm. 1990, 323, 493.
´
15. Garcıa Ruano, J. L.; Aranda, M. T.; Aguirre, J. M. Tetrahedron
2004, 60, 5383.
8. For nucleophilic additions on aromatic aldehydes: (1,4
asymmetric induction) (a) Arai, Y.; Suzuki, A.; Masuda, T.;