Remote stereocontrol mediated by a sulfinyl group: Synthesis of allylic alcohols via chemoselective and diastereoselective reduction of γ-methylene δ-ketosulfoxides

Article abstract of DOI:10.1021/jo802378s

The efficiency of the sulfinyl group as a remote controller of the chemoselectivity and diastereoselectivity of the reduction of α,β-unsaturated α-[2-(p-tolylsulfinyl)phenyl] substituted ketones 1 has been demonstrated in reactions carried out under NaBH<

Full text of DOI:10.1021/jo802378s

Remote Stereocontrol Mediated by a Sulfinyl Group: Synthesis of
Allylic Alcohols via Chemoselective and Diastereoselective Reduction
of γ-Methylene δ-Ketosulfoxides
´
Jose´ L. Garc´ıa Ruano,* M. Angeles Ferna´ndez-Iba´n˜ez, Jose´ A. Ferna´ndez-Salas,
M. Carmen Maestro,* Pablo Ma´rquez-Lo´pez, and M. Mercedes Rodr´ıguez-Ferna´ndez
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco, 28049 Madrid, Spain
joseluis.garcia.ruano@uam.es; carmen.maestro@uam.es
ReceiVed October 23, 2008
The efficiency of the sulfinyl group as a remote controller of the chemoselectivity and diastereoselectivity
of the reduction of R,ꢀ-unsaturated R-[2-(p-tolylsulfinyl)phenyl] substituted ketones 1 has been
demonstrated in reactions carried out under NaBH4 in the presence of Yb(OTf)3 as the chelating agent.
The starting unsaturated ketones have been prepared from the corresponding 2-(p-tolylsulfinyl) benzyl
alkyl (and aryl) ketones 2 by insertion of the methylidene group under modified Mannich conditions,
exploiting ultrasound irradiation to obtain the aminomethylation adducts and silica gel treatment to produce
its complete elimination. Desulfinylation of the reduction products yielded the corresponding vinyl carbinols
with high enantiomeric purity.
Introduction
Enantioselective processes have been reported with chiral
catalysts, including both asymmetric hydrogenation5 and enzy-
matic6 procedures. In regard to reagents, boron hydrides have
been the most frequently used,7 and a number of synthetic
applications have appeared using this strategy as a key step.8
Despite the large attention devoted to these types of compounds,
the number of reports concerning the synthesis of ꢀ-unsubsti-
tuted-R,ꢀ-unsaturated allylic alcohols is rather limited. 3e,4d,7c,h
It is mainly due to the larger tendency of these compounds to
Chiral allylic alcohols are highly interesting targets1 because
of the stereocontrol exerted by the hydroxyl group in the
functionalization of the double bond,2 as well as their numerous
synthetic applications.3 As a consequence, many efficient
methodologies for preparing optically pure allylic alcohols have
been developed in the past decades. Among them, included as
the most important ones are kinetic resolution methods4 and
mainly chemoselective reduction of R,ꢀ-unsaturated ketones.
(5) (a) Ohkuma, T.; Ikehira, H.; Ikariya, T.; Noyori, R. Synlett 1997, 467.
(b) Ohkuma, T.; Ooka, H.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
10417. (c) von Arx, M.; Mallat, T.; Baiker, A. J. Mol. Catal. A 1999, 148, 275.
(6) Pollard, D. J.; Telari, K.; Lane, J.; Humphrey, G.; McWilliams, C.;
Nidositko, S.; Salmon, P.; Moore, J. Biotechnol. Bioeng. 2006, 93, 674.
(7) See for example: (a) Luche, J. L.; Rodr´ıguez-Hahn, L.; Crabbe´, P.
J. Chem. Soc., Chem. Commun. 1978, 601. (b) Luche, J. L. J. Am. Chem. Soc.
1978, 100, 2226. (c) Komiya, S.; Tsutsumi, O. Bull. Chem. Soc. Jpn. 1987, 60,
3423. (d) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1977, 42, 1197. (e)
Singh, J.; Kaur, I.; Kaur, J.; Bhalla, A.; Kad, G. L. Synth. Commun. 2003, 33,
191. (f) Zeynizadeh, B.; Yahyaei, S. Z. Naturforsch., B: Chem. Sci. 2004, 59,
699. (g) Kamal, A.; Sandbhor, M.; Shaik, A. A.; Sravanthi, V. Tetrahedron:
Asymmetry 2003, 14, 2839. (h) Blake, A. J.; Cunningham, A.; Ford, A.; Teat,
S. J.; Woodward, S. Chem. Eur. J. 2000, 6, 3586. (i) Hara, R.; Furukawa, T.;
Horiguchi, Y.; Kuwajima, I. J. Am. Chem. Soc. 1996, 118, 9186. (j) Sato, T.;
Kido, M.; Otera, J. Angew. Chem., Int. Ed. Engl. 1995, 34, 2254. (k) Chung,
S.-K.; Kang, D.-H. Tetrahedron: Asymmetry 1997, 8, 3027. (l) Simpson, A. F.;
Szeto, P.; Lathbury, D. C.; Gallagher, T. Tetrahedron: Asymmetry 1997, 8, 673.
(m) Ravikumar, K. S.; Baskaran, S.; Chandrasekaran, S. J. Org. Chem. 1993,
58, 5981. (n) Nutaitis, C. F.; Bernardo, J. E. J. Org. Chem. 1989, 54, 5629.
(1) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(b) Bauer, K.; Garbe, D.; Surburg, H., Common Fragance and FlaVor Materials;
Wiley-VCH: Weinheim, 1997. (c) Ullmann′s Encyclopedia of Industrial Chem-
istry, 7th ed., electronic release; Wiley-VCH: 2008, Vol. 2, p 191.
(2) (a) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703. (b) Katsuki, T.;
Martin, V. S. Org. React. 1996, 48, p 1. (c) Charette, A. B.; Marcoux, J.-F.
Synlett 1995, 1197.
(3) (a) Parker, K. A.; Fokas, D. J. Org. Chem. 2006, 71, 449. (b) Sousa,
S. E.; O’Brien, P.; Pilgram, C. D. Tetrahedron Lett. 2001, 42, 8081. (c) Kazmaier,
U.; Schneider, C. Synlett 1996, 975. (d) Lu, X.; Zhu, G.; Wang, Z. Synlett 1998,
115. (e) Corey, E. J.; Guzman-Perez, A.; Lazerwith, S. E. J. Am. Chem. Soc.
1997, 119, 11769.
(4) (a) Gais, H.-J. In Asymmetric Synthesis; Christmann, M., Braese, S., Eds.;
Wiley-VCH: Weinheim, 2007, p 84. (b) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; p 231. (c) Dittmer, D. C.; Discordia, R. P.; Zhang, Y.; Murphy, C. K.;
Kumar, A.; Pepito, A. S.; Wang, Y. J. Org. Chem. 1993, 58, 718. (d) Gao, Y.;
Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B.
J. Am. Chem. Soc. 1987, 109, 5765.
1200 J. Org. Chem. 2009, 74, 1200–1204
10.1021/jo802378s CCC: $40.75 2009 American Chemical Society
Published on Web 12/29/2008

Remote Stereocontrol Mediated by a Sulfinyl Group
SCHEME 1
FIGURE 1. Retrosynthetic pathway of enantiomerically pure allylic
carbinols.
suffer other side reactions decreasing the yield (polymerization,
or 1,4-addition) and the usually lower stereoselectivity observed
for compounds lacking substituents at the ꢀ-position.3e Ad-
ditionally, kinetic resolution (enzymatic,9 chemoenzymatic,10
or chemical11) of these nonencumbered allylic alcohols proceeds
with poor enantiodiscrimination and sometimes provokes their
isomerization to saturated ketones during the racemisation step
(promoted by transition metals).10
In the course of our studies on asymmetric induction using
remote chiral sulfoxides,12 we reported the reduction of ketones
2a-d and both epimers of 3a (Scheme 1) with DIBAL and
L-Selectride13 and their hydrocyanation with diethylaluminum
cyanide.14 In most of the cases, the presence of stoichiometric
quantities of the Lewis acid Yb(OTf)3 proved to be essential to
attain high yields and selectivities, as a result of the formation
of stable chelated species with the metal joined to the sulfinyl
and carbonyl oxygens,12,15 which are highly reactive and provide
a strong facial discrimination toward the attack of nucleophiles.
The excellent results obtained under catalyzed conditions
prompted us to extend the scope of these 1,5-induction processes
to substrates containing additional functionalities, compounds
1, with the double bond conjugated with the carbonyl moiety,
being one of the most interesting ones because they would give
access to the corresponding enantiomerically pure R-phenyl-
substituted allylic carbinols depicted in Figure 1.
The comparison of the results obtained in reduction of
compounds 1 with those previously reported for compounds
213,14 would make it possible to evaluate how the structural
modification involving the change of the benzyl carbon from
tetrahedral to trigonal would influence the reduction of δ-ke-
tosulfoxides. It would also be interesting to check whether the
formation of chelated species with Lewis acids has any influence
on the reactivity of the 1,4-additions to the enonic system, as
much as it affects the conjugation.
We report herein our results concerning the preparation of
1-alkyl (or phenyl) 2-(2-p-tolylsulfinyl)phenyl prop-2-en-1-ones
1a-d and their chemoselective and stereoselective carbonyl
group reduction using modified Luche7a,b conditions to obtain
enantiomerically pure 2-aryl-2-methylenecarbinols.
Results and Discussion
As the starting compounds for preparing sulfinyl enones 1a-d
we have used 1-alkyl (or phenyl) 2-(2-p-tolylsulfinyl)phenyl
ethanones, 2a-d, whose synthesis has been reported recently.16
We first investigated their reactions with formaldehyde (1.2
equiv) and dimethylamine (1.2 equiv) in refluxing acetonitrile.
After several hours of heating (17-24 h), the reactions afforded,
along with the expected R-methyleneketones 1a-d, the 1:1
diastereoisomeric mixtures of the corresponding ketoamines
4a-d, which presumably acted as the precursors of 1a-d.
Conversion was high, but not complete (90-95%). In order to
improve the conversion and decrease the reaction times, we
explored different conditions and found that the best ones
involved the use of a large excess of the reagents and heating
of the mixture under ultrasonic radiation.17 These conditions
were used to obtain the results indicated in Table 1. As we can
see, the ratio of compounds 1:4 ranged between 1 and 9, mainly
depending on the concentration of the starting product and the
reaction time (see Table 1), which could be explained by
assuming the formation of methyleneketones 1 from aminoke-
tones 4 in the last step of the process. Initially, this ratio was
really important because lower yields of methyleneketones 1a-d
were obtained for larger proportions of aminoketones 4a-d,
which are not recovered after chromatographic purification.
However, when the crude reaction mixtures were stirred for 12 h
with silica gel in dichloromethane at room temperature, we
observed the complete disappearance of 4a-d and the exclusive
formation of 1a-d, which could be isolated in very high yields
(89-94%). Significantly, after this treatment, the yields of the
unsaturated ketones 1a-d were identical regardless of the
composition of the starting mixtures (Table 1, entries 8-10).18
Once the procedure for preparing unsaturated ketones 1 was
optimized, we studied their reduction into the corresponding
allylic alcohols. Initially we studied the reduction of ketosul-
foxide 1a with several reagents (DIBAL, LiAlH4, L-Selectride,
NaBH4, and NaBH3CN) in THF or methanol as the solvents
(Table 2).
Reaction with DIBAL resulted in moderate conversion, even
with a large excess of the reagent. It did not afford allylic alcohol
5a but ketone 6a, resulting from the 1,4-conjugate reduction,
as the major product (entry 1). A significant amount of
compound 7a resulting from the double addition was also
obtained. The presence of Yb(OTf)3 did not improve this result,
(8) (a) Hale, K. J.; Frigerio, M.; Manaviazar, S. Org. Lett. 2001, 3, 3791.
(b) Yamamoto, T.; Hasegawa, H.; Hakogi, T.; Katsumura, S. Org. Lett. 2006,
8, 5569.
(9) (a) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1990, 112, 7434. (b)
Burgess, K.; Jennings, L. D. J. Am. Chem. 1991, 113, 6129.
(10) Bogár, K.; Hoyos Vidal, P.; Alca´ntara Leo´n, A. R.; Ba¨ckvall, J.-E. Org.
Lett. 2007, 9, 3401.
(11) Vedejs, E.; MacKay, J. A. Org. Lett. 2001, 3, 535.
(12) Garc´ıa Ruano, J. L.; Alema´n, J.; Cid, M. B.; Ferna´ndez-Iba´n˜ez, M. A.;
Maestro, M. C.; Mart´ın, M. R.; Mart´ın Castro, A. M. In Organosulfur Chemistry
in Asymmetric Synthesis; Toru, T., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008;
p 55.
(13) Garc´ıa Ruano, J. L.; Ferna´ndez-Iba´n˜ez, M. A.; Maestro, M. C.;
Rodr´ıguez-Ferna´ndez, M. M. J. Org. Chem. 2005, 70, 1796.
(14) Garc´ıa Ruano, J. L.; Ferna´ndez-Iba´n˜ez, M. A.; Maestro, M. C.;
Rodr´ıguez-Ferna´ndez, M. M. Tetrahedron 2006, 62, 1245.
(15) This high affinity of the sulfinyl oxygen for different Lewis acids had
been repeatedly evidenced in many 1,2- and 1,3-asymmetric induction processes.
See: (a) Carren˜o, M. C. Chem. ReV. 1995, 95, 1717. (b) Ferna´ndez, I.; Khiar, N.
Chem. ReV. 2003, 103, 3651. (c) Pellissier, H. Tetrahedron 2006, 62, 5559.
(16) Garc´ıa Ruano, J. L.; Alema´n, J.; Aranda, M. T.; Ferna´ndez-Iba´n˜ez,
M. A.; Rodr´ıguez-Ferna´ndez, M. M.; Maestro, M. C. Tetrahedron 2004, 60,
10067.
(17) (a) Peng, Y.; Dou, R.; Song, G.; Jiang, J. Synlett 2005, 14, 2245. For
the use of ultrasound in synthetic organic chemistry, see: (b) Mason, T. J. Chem.
Soc. ReV. 1997, 26, 443. (c) Cravotto, G.; Cintas, P. Chem. Eur. J. 2007, 13,
1902.
(18) Dienones resulting from a double Mannich reaction of the starting
ketosulfoxides 2a and 2b, through their two active methylenes, can be obtained
in good yield by increasing the reaction times (up to 6 days) and using 4.8 equiv
of Me2NH and 4.4 equiv of H2CO.
J. Org. Chem. Vol. 74, No. 3, 2009 1201

Ruano et al.
TABLE 1. Methylenation of (S)-1-[2-(p-Tolylsulfinyl)phenyl]alkan-2-ones
entry
substrate
Me2NH/CH2O equiv
ultrasound radiation (h)a
concnb
crude ratioc 1:4
optimized yield of 1d
1
2
3
4
5
6
7
8
9
2a (Me)
2a (Me)
2b (Pr)
2b (Pr)
2c (i-Pr)
2c (i-Pr)
2c (i-Pr)
2d (Ph)
2d (Ph)
2d (Ph)
2.4/2.2
2.4/2.2
2.4/2.2
2.4/2.2
2.4/2.2
4.8/4.4
4.8/4.4
2.4/2.2
2.4/2.2
4.8/4.4
3
3
3
3
4.5
6
6
4.5
6
6
0.08
0.2
90:10
70:30
90:10
47:53
80:20e
90:10
55:45
80:20
88:12
88:12
90
0.07
0.15
0.07
0.07
0.17
0.15
0.07
0.07
90
89
94
92
94
10
a Ultrasound radiation was applied at 1.5 h periods, with 10 min without radiation between periods. b Millimoles of 2a-d/mL of acetonitrile.
c
Measured by H NMR of the reaction crude. d Obtained by stirring the reaction crude with silica gel in CH2Cl2 for 12 h at rt. e 85% conversion.
1
TABLE 2. Reaction of (S)-3-[2-(p-Tolylsulfinyl)phenyl]but-3-en-2-one 1a with Hydrides
ratiob
entry
reagent
equiv
Lewis acid
solvent
conv (%)b
5a (A/B)c
6a (A/B)c
7ad
1
2
3
4
5
6
7
8
DIBALa
DIBAL
NaBH3CN
NaBH3CN
LiAlH4
8
4
THF
THF
MeOH
MeOH
THF
THF
THF
THF
40
40
80
60
100
50
100
100
100
100
100
60 (50/50)
100 (70/30)
60 (60/40)
60 (60/40)
50 (50/50)
90 (55/45)
90 (60/40)
85 (70/30)
40 (80/20)
10 (70/30)
10 (70/30)
40
Yb(OTf)3
Yb(OTf)3
CeCl3
1.2
1.2
1.2
1.2
2
40
40
10
40 (80/20)
10 (50/50)
LiAlH4
Yb(OTf)3
Yb(OTf)3
L-Selectride
L-Selectride
NaBH4
NaBH4
NaBH4
10
15
50
2
9
10
11
1.2
1.2
1.2
MeOH
MeOH
MeOH
10 (50/50)
90 (98/2)
90 (60/40)
Yb(OTf)3
CeCl3
a Room temperature. b Measured by 1H NMR of the reaction crude. c Diastereoisomeric ratio (by 1H NMR). d Diastereoisomeric ratio has not been
evaluated.
though conjugate reduction epimers were exclusively obtained
in a poor diastereoisomeric ratio (entry 2). This behavior
contrasts with that observed in reactions of DIBAL with
ketosulfoxides 2a-d, which evolved in a highly stereoselective
way, especially in the presence of Yb(OTf)3.13 Similar results
were obtained with NaBH3CN and Lewis acids such as
Yb(OTf)3 or CeCl3 (entries 3 and 4). Total conversion was
observed with LiAlH4, but the major product was 6a and the
desired 5a was obtained as a 80:20 mixture of diastereoisomers
(entry 5). The addition of Yb(OTf)3 (entry 6) reduced the
proportion of 6a in the reaction mixture and limited the
conversion to 50%. Complete conversion was observed with
L-Selectride, but the allylic alcohol was not detected (entries 7
and 8). Finally, we obtained the best results by using NaBH4 in
methanol as the reagent (entries 9-11). In the absence of Lewis
acids, 1,4-conjugate addition is faster and compound 7a was
the major product (entry 9). However, the addition of Yb(OTf)3
(entry 10) inverted the relative reactivity, and the reduction of
the carbonyl was faster than the conjugate reduction, thus
yielding the desired 5a as the major product (5a:6a ) 9:1) with
an almost complete control of the stereoselectivity (dr 98:2),
which allowed us to obtain 5a in 54% isolated yield, which
was significantly increased to 71% when the reaction was carried
out in THF as the solvent. The use of NaBH4 in the presence
of CeCl3 (entry 11) provided a similar chemoselectivity but
very low diastereoselectivity (dr 60:40).
Once the best conditions to transform 1a into allylic alcohol
5a were found, ketosulfoxides 1b-d were reduced with NaBH4
in the presence of Yb(OTf)3 at -78 °C. THF, acetonitrile,
acetonitrile-methanol mixtures, and isopropanol were tested
as the solvents, with the temperature ranging between -45 to
-78 °C (depending on the solvent). The best results were
obtained with methanol or THF, which provided a complete
conversion at -78 °C in short reaction times (20-30 min) with
high stereoselectivity and chemoselectivity favoring allylic
alcohols 5a-d.20 Under these conditions, the major diastere-
19
(19) Miura, M.; Toriyama, M.; Motohashi, S. Tetrahedron: Asymmetry 2007,
18, 1269.
(20) It is worth of mentioning the appearance of the 1,4-adduct of methanol
in the reaction mixture when the chelation time of the R-methyleneketone 1a
with the Lewis acid in methanol solution was increased up to 40 min prior to
the addition of the reducing agent.
1202 J. Org. Chem. Vol. 74, No. 3, 2009

Remote Stereocontrol Mediated by a Sulfinyl Group
TABLE 3. Reduction of 1-Methylene-1-[2-(p-tolylsulfinyl)-
phenyl]alkan-2-ones 1
SCHEME 2
ratioa
5 (A/B)b
in turn were obtained from benzyl alkyl (or phenyl) ketones
under the same conditions indicated in Table 1 for sulfinyl
ketones 2a-d.
entry
compound
solvent
6c
yield 5A (%)
1
2
3
4
5
6
7
8
1a (Me)
1a (Me)
1b (Pr)
1b (Pr)
1c (i-Pr)
1c (i-Pr)
1d (Ph)
1d (Ph)
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
90 (98/2)
90 (95/5)
85 (95/5)
90 (97/3)
80 (88/12)
90 (90/10)
90 (100/0)
100 (98/2)
10
10
15
10
20
10
10
0
54
71
77
72
Retention times for each enantiomer of compounds 8a and
8d, determined by using Chiralcel OD as a chiral column (see
Supporting Information), were compared with those previously
reported for these compounds.11,22 As in both cases the lowest
retention times correspond to the S enantiomers, we assume the
same behavior for compounds 8b and 8c. Taking into account
that enantiomers 8a-d obtained by desulfinylation of com-
pounds 5(a-d)A (Table 4) are those exhibiting the lowest
retention time, we have assigned them the S configuration, which
means that precursors 5(a-d)A must be (S,S). It is noteworthy
that this is also the configuration of the major isomers obtained
in DIBAL reductions of ketosulfoxides 2a-d in the presence
of the Yb(OTf)3,13 which suggests a similar stereochemical
course.
61
62
60
a Measured by 1H NMR of the reaction crude. b Diastereoisomeric
ratio (by H NMR). c Diastereoisomeric ratio not determined.
1
TABLE 4. Synthesis of Allyllic Alcohols 8a-d by Desulfinylation
of 5(a-d)A
Results indicated in Table 3 can be explained by assuming
the formation of a chelated species A (Scheme 2), with the metal
at the catalyst joined to the sulfinyl and carbonyl oxygens, as a
previous step of the reduction. These chelates maintain the
conjugation of the double bond with the aromatic ring but distort
the planarity of the enonic system, which would explain the
fact that the formation of the conjugate 1,4-addition product
6a, observed in reaction of 1a with NaBH4 (Table 2, entry 9),
was substantially diminished when the reaction was performed
in the presence of Yb(OTf)3 (Table 2, entry 10). The intermo-
lecular attack of the hydride to the less hindered face of
conformation A23 also accounts for the (S,S) configuration of
the major products obtained in these reactions (Scheme 2).24
As a conclusion, we have proved the efficiency of the sulfinyl
group as a remote chiral inducer in the reduction of R-aryl,
R-methylene ketones with NaBH4 in the presence of Yb(OTf)3,
according to a 1,5-asymmetric induction process. These reduc-
tions also take place with high chemoselectivity, affording the
sulfinylated allylic alcohols in good yields. The synthesis of
the starting R-methylene ketones evolves in excellent yield by
a Mannich reaction mediated by ultrasound radiation and a silica
gel treatment, essential to produce complete elimination of the
aminomethylation intermediates. Removal of the chiral auxiliary
by reaction with t-BuLi provides an excellent route to prepare
optically pure R-styryl alkyl (or aryl) allylic alcohols.
entry
compound
R
ee (%)
yield (%)
1
2
3
4
8a
8b
8c
8d
Me
Pr
i-Pr
Ph
92a
96b
97a
97a
72
60
65
83
a Determined by HPLC Chiralcel OD, 1 mL/min, 5% isopropanol/
hexane. λ ) 254 nm. b Determined by HPLC Chiralcel AD, 0.6 mL/
min, 2% isopropanol/hexane. λ ) 254 nm.
oisomer of the allylic alcohols 5a-d could be chromatographi-
cally purified and isolated in the yields indicated in Table 3.
Removal of the chiral auxiliary from 5(a-d)A allowed us to
obtain enantiomerically pure allylic alcohols 8a-d and to
establish their absolute configuration by chemical correlation.
Reaction of 5dA with 3 equiv of t-BuLi (Table 4, entry 4)
afforded the desired allylcarbinol 8d in 83% yield after
chromatographic separation from the sulfur-containing byprod-
uct,whichwasidentifiedasracemictert-butylp-tolylsulfoxide.13,21
With less than 3 equiv of t-BuLi only partial desulfinylation
was observed. These optimized conditions were applied to
remove the chiral auxiliary from compounds 5(a-c)A thus
obtaining the allylic alcohols 8a-c in good yields (Table 4,
entries 1-3).
The enantiomeric excesses (ee’s) of the desulfinylated
carbinols 8a-d, as well as their absolute configurations, were
unequivocally established by HPLC with a chiral stationary
phase (Table 4 and Supporting Information). Preparation of the
required racemic allylic alcohols (()-8a-d was performed by
NaBH4 reduction of the corresponding methyleneketones, which
Experimental Section
Methylenation of (S)-1-[2-(p-Tolylsulfinyl)phenyl]alkan-2-
one (1a-d). General Procedure. A sealed tube containing mixture
of a 40% solution of Me2NH (2.4-4.8 equiv) in H2O and a 37%
aqueous solution of HCHO (2.2-4.4 equiv) in acetonitirile
(22) Chai, Z.; Liu, X.-Y.; Zhang, J.-K.; Zhao, G. Tetrahedron: Asymmetry
2007, 18, 724.
(21) For a similar behavior of other diaryl sulfoxides, see: (a) Arroyo, Y.;
Meana, A.; Rodr´ıguez, J. F.; Santos, M.; Sanz-Tejedor, M. A.; Garc´ıa Ruano,
J. L. J. Org. Chem. 2005, 70, 3914. (b) Arroyo, Y.; Rodr´ıguez, J. F.; Santos,
M.; Sanz-Tejedor, M. A.; Garc´ıa Ruano, J. L. J. Org. Chem. 2007, 72, 1035. (c)
Furukawa, N.; Ogawa, S.; Matsumura, K.; Fujihara, H. J. Org. Chem. 1991, 56,
6341. (d) Clayden, J.; Mitjans, D.; Youssef, L. H. J. Am. Chem. Soc. 2002, 124,
5266.
(23) The approach of the borohydride to the opposite face, which would
yield compounds 6(a-d)B, is hindered by the substituents at Yb.
(24) The Posner model has been invoked to explain the stereoselectivity of
the reduction of R-alkylidene-ꢀ-ketosulfoxides: (a) Posner, G. H.; Mallamo, J. P.;
Hulce, M.; Frye, L. L. J. Am. Chem. Soc. 1982, 104, 4180. (b) Posner, G. H.;
Mallamo, J. P.; Miura, K. J. Am. Chem. Soc. 1981, 103, 2886.
J. Org. Chem. Vol. 74, No. 3, 2009 1203

Ruano et al.
(0.07-0.08 M) was partially submerged to the solvent level in the
ultrasound unit at room temperature for 5 min. A solution of the
corresponding (S)-1-[2-(p-tolylsulfinyl)phenyl]alkan-2-one 2a-d in
acetonitrile was added, and the mixture was sonicated and heated
at 85 °C in periods of 1.5 h (the number of periods of sonication,
number of equivalents, and concentration are indicated in each case).
The reaction was quenched with water, the organic layer was
separated, and the aqueous layer was extracted with EtOAc. The
combined organic extracts were dried with anhydrous MgSO4, and
the solvent was evaporated. The crude mixture was stirred at room
temperature with silica gel and CH2Cl2 for 12 h, and the solvent
was removed and purified by flash column chromatography, eluting
with hexane/EtOAc (2:1).
7.80 (m, 1H), 7.55-7.40 (m, 4H), 7.22 (d, J ) 8.3 Hz, 2H), 7.15
(m, 1H), 5.53 (s,1H), 4.87 (s, 1H), 4.65 (q, J ) 6.5 Hz, 1H), 2.65
(br s, 1H, OH), 2.37 (s, 3H), 1.22 (d, J ) 6.5 Hz, 3H). 13C NMR:
150.5, 143.3, 141.5, 141.4, 139.7, 131.0, 130.3, 129.8, 128.5, 125.8,
125.7, 116.5, 70.7, 22.3, 21.4. MS (FAB+) m/z 287 [M + 1]+ (100),
286 (24). HRMS [M + 1]+: calcd for C17H19O2S 287.1106; found
287,1104.
C-S Bond Cleavage. General Procedure. To a solution of the
corresponding hydroxysulfoxide 5(a-d)A (0.237 mmol, 1 equiv)
in THF (1.5 mL) under argon at -78 °C was added a solution 1.7
M in heptane of tert-butyllithium (0.713 mmol, 3 equiv). The
reaction was stirred for 20 min and then hydrolyzed with a saturated
aqueous solution of NH4Cl. The aqueous phase was extracted with
CH2Cl2 (3 × 2 mL). The organic layers were combined and dried
over MgSO4, the solvent was evaporated, and the crude mixture
purified by flash column chromatography, eluting with hexane/
AcOEt 10:1.
(S)-2-[2-(p-Tolylsulfinyl)phenyl]but-3-en-2-one (1a). Com-
pound 1a was obtained from compound 2a (0.37 mmol, 100 mg),
following the general procedure for methylenation (2.4 equiv of
Me2NH and 2.2 equiv of CH2O, 0.08 M in acetonitrile) with two
periods of sonication (3 h). Yield: 90%. [R]20 ) -89 (c 1.0,
(S)-3-Phenylbut-3-en-2-ol (8a).9b Compound 8a was obtained
from compound 6a, following the general procedure for C-S bond
cleavage. It was isolated by flash column chromatography as a
colorless oil. Yield: 72%. The ee was determined by HPLC11
(Chiralcel OD, 1 mL/min, 5% i-PrOH/hexane, λ ) 254 nm, tR )
D
1
CHCl3). IR (film): 2996, 1683, 1035, 749 cm-1. H NMR: 7.80
(dd, J ) 7.5 Hz, J ) 1.5 Hz, 1H), 7.55-7.40 (m, 4H), 7.22 (d, J
) 8.3 Hz, 2H), 7.15 (dd, J ) 7.5 Hz, J ) 1.5 Hz, 1H), 6.44 (s,
1H), 5.94 (s, 1H), 2.36 (s, 3H), 2.32 (s, 3H). 13C NMR: 197.9,
146.6, 144.3, 141.5, 141.0, 136.9, 131.1, 130.3, 130.1, 129.8, 129.6,
125.9, 125.6, 26.3, 21.4. MS (FAB+) m/z 285 [M + 1]+ (100),
241 (13), 91 (23). HRMS [M + 1]+: calcd for C17H17O2S 285,0949;
found 285,0936.
Reduction with NaBH4/Yb(OTf)3. General Procedure. A
solution of sulfoxide 1a-d (0.7 mmol) (0.14 M in THF or 0.08 M
in MeOH, indicated in each case) and Yb(OTf)3 (0.77 mmol, 1.1
equiv) was stirred at room temperature for 30 min. Then NaBH4
(0.77 mmol, 1.1 equiv) was added slowly to the cooled solution at
-78 °C. The resulting mixture was stirred for 30 min at this
temperature, quenched with saturated aqueous NH4Cl solution,
extracted with CH2Cl2 (3 × 5 mL), and dried over anhyd MgSO4.
The solvent was evaporated and the product purified by flash
column chromatography.
(S) 8.7 min, (R) 11.3 min), 92% ee. lit.9b [95% ee, [R]20 ) 34.2
D
1
(c 1.77, CHCl3)]. IR (film): 3386 (br), 2978, 1216, 755 cm-1. H
NMR: 7.42-7.27 (m, 5H), 5.36 (s, 1H), 5.28 (s, 1H), 4.82 (m,
1H), 1.68 (br s, 1H, OH), 1.33 (d, J ) 7.0 Hz, 3H). 13C NMR:
153.1, 139.9, 128.4, 127.6, 126.8, 111.6, 69.5, 22.6. MS (EI) m/z:
148 (35), 130 (84), 115 (88).
Acknowledgment. This investigation has been supported by
DGICYT (Grant CTQ2006-06741) and Comunidad Auto´noma
de Madrid (CCG07-UAM/PPQ-1849). M.A.F.-I. is indebted to
the Comunidad Auto´noma de Madrid for a predoctoral fellowship.
Supporting Information Available: Experimental data of
compounds 1b-d, 5(b-d)A, and 8b-d, HPLC parameters of
[2S,(S)]-3-[2-(p-Tolylsulfinyl)phenyl]but-3-en-2-ol (5aA). Com-
pound 5aA was obtained from compound 1a, following the general
procedure for reduction in THF. It was isolated diastereoisomeri-
cally pure, as a colorless oil, by flash column chromatography,
1
racemic allylic alcohols (()-8a-d, H and 13C NMR spectra
of compounds 1a-d, 5(a-d)A and 8b. This material is available
free of charge via the Internet at http://pubs.acs.org.
eluting with hexane/EtOAc (2:1). Yield: 71%. [R]20 ) -52.1 (c
D
2.0, CHCl3). IR (film): 3386 (br), 2927, 1640, 755 cm-1. 1H NMR:
JO802378S
1204 J. Org. Chem. Vol. 74, No. 3, 2009