The sulfinyl group as a remote chiral auxiliary in stereoselective conjugate additions of alkyl groups to α-methylidene carbonyl compounds initiated by Et3B/O2

Article abstract of DOI:10.1002/ejoc.201201642

Reactions of α-[2-(p-tolylsulfinyl)phenyl] α-methylidene carbonyl compounds 1 and 2 with alkyl radicals generated from Et ₃B/O₂ and RI give, after protonation, β-alkyl derivatives with a high degree of control of the configuration at the α carbon. In the case of aldehyde 2, when further combined with allylation of the carbonyl group, a one-pot radical-addition/protonation/allylation sequence provides a highly stereoselective synthesis of compounds bearing two adjacent chiral centres. The stereochemical course of the reaction is controlled by the sulfinyl group acting as a remote chiral auxiliary, and this group can be easily removed with tBuLi. The sulfinyl group can be an efficient remote chiral auxiliary in the stereoselective radical addition to α-methylidene carbonyl compounds. Radicals were generated from alkyl iodides with Et ₃B/O₂. The stereocontrol comes from the formation of chelated complexes of the Lewis acid with the carbonyl and sulfinyl oxygen atoms. This process gives access to enantiopure compounds with chiral benzylic centres. Copyright

Full text of DOI:10.1002/ejoc.201201642

FULL PAPER
DOI: 10.1002/ejoc.201201642
The Sulfinyl Group as a Remote Chiral Auxiliary in Stereoselective Conjugate
Additions of Alkyl Groups to α-Methylidene Carbonyl Compounds Initiated by
Et3B/O2
José Antonio Fernández-Salas,[a] M. Carmen Maestro,*[a]
M. Mercedes Rodríguez-Fernández,*[a] and José L. García Ruano*[a]
Dedicated to the memory of our colleague and friend Christian G. Claessens
Keywords: Radical reactions / Conjugate addition / Diastereoselectivity / Chiral auxiliaries / Allylation / Sulfoxides
Reactions of α-[2-(p-tolylsulfinyl)phenyl] α-methylidene
carbonyl compounds 1 and 2 with alkyl radicals generated
from Et3B/O2 and RI give, after protonation, β-alkyl deriva-
tives with a high degree of control of the configuration at the
α carbon. In the case of aldehyde 2, when further combined
with allylation of the carbonyl group, a one-pot radical-ad-
dition/protonation/allylation sequence provides a highly
stereoselective synthesis of compounds bearing two adjacent
chiral centres. The stereochemical course of the reaction is
controlled by the sulfinyl group acting as a remote chiral aux-
iliary, and this group can be easily removed with tBuLi.
cules, could be very interesting. With this idea in mind, we
initiated a program to investigate whether a remote sulfinyl
group could efficiently control the stereoselectivity of ionic
reactions. Most of these studies concerned 1,4- and 1,5-
asymmetric induction processes using lithium 2-p-tolylsulf-
inylbenzyl carbanions as nucleophiles,[8] but excellent re-
sults were also obtained in reactions in which the sulfinyl
moiety was incorporated into the electrophile.[9]
Introduction
The sulfinyl group has been widely used in asymmetric
synthesis as a chiral auxiliary in many types of ionic and
concerted reactions.[1] However, its use as a stereocon-
trolling group in radical processes is much more limited.[2]
Vinyl sulfoxides undergo facile inter- and intramolecular
radical conjugate additions with a variety of radicals.[3] For
some of these reactions to proceed with a good diastereo-
selectivity, the presence within the substrate of an ad-
ditional Lewis base (e.g., a keto or alkoxy group) is re-
quired. This can form a chelation complex with the Lewis
acids used as catalysts, and so provide sterically differen-
tiated diastereotopic faces.[3d,4] However, for 2-arylsulfinyl
enones,[5,6] dipolar repulsion of the C=O and S–O bonds
can control the stereoselectivity in the absence of Lewis
acids.[7] The main problem with these reactions derives from
the fact that one of the chiral centres formed in the reaction
is attached to the sulfinyl group, and is eliminated upon
removal of the chiral auxiliary. Thus, the use of a sulfinyl
group as a remote chiral auxiliary that could be removed
without affecting the chiral elements of the product mole-
With the aim of widening the scope of the remote asym-
metric induction mediated by sulfoxides, we decided to ex-
plore their efficiency in radical reactions. This paper is our
first contribution to this field. We focussed our attention
on intermolecular 1,4-radical additions to enantiomerically
pure β-unsubstituted, α,β-unsaturated ketones bearing a 2-
(p-tolylsulfinyl)phenyl group[10] (Scheme 1) at the α-posi-
tion. We wanted to study the ability of the sulfoxide moiety
to act as a remote chiral auxiliary in these radical processes,
as it is well known that it can act in that capacity in similar
ionic reactions.[11] Moreover, the almost neutral conditions
used in these radical processes could provide enantiomer-
ically pure α-alkyl benzylketones, which are not easily ob-
tained using ionic reactions due to their facile epimeri-
zation. In this paper, we describe the reactions of alkyl radi-
cals with enones 1A–1E and enal 2 (Scheme 1) to evaluate
the role of the sulfinyl group on the stereoselectivity. The
scope of these reactions for generating benzylic chiral
centres is also explored. Moreover, for compound 2, the
one-pot radical-addition/protonation/allylation (with allyl-
tributyltin) process, involving the simultaneous creation of
two chiral centres, is also reported.
[a] Departamento de Química Orgánica, Facultad de Ciencias
(Módulo 01), Universidad Autónoma de Madrid,
Cantoblanco, 28049 Madrid, Spain
Fax: +34-91-4973966
E-mail: carmen.maestro@uam.es
mercedes.rodriguez@uam.es
joseluis.garcia.ruano@uam.es
Homepage: http://www.uam.es/gruposinv/Ruano-SO/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201642.
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The Sulfinyl Group as a Remote Chiral Auxiliary
yields (Table 1). The stereoselectivity was dependent on the
size of the R group at the starting ketone. Thus, reactions
of 1A with 3a (Table 1, entry 1) and 3b (Table 1, entry 2)
gave diastereomeric mixtures of 4Aa (dr 92:8) and 4Ab (dr
90:10), respectively. Similar results were obtained in the re-
actions of 1B (R = nPr) with 3a and 3b (Table 1, entries 4
and 5), which afforded compounds 4Ba (dr 92:8) and 4Bb
(dr 90:10) exclusively. Reactions with tBuI (3a) were also
studied with 1C (Table 1, entry 7) and 1D (Table 1, entry 8),
which gave diastereoisomeric mixtures of 4Ca (dr 68:32)
and 4Da (dr 80:20), respectively. Finally, 1E did not react
with 3a (Table 1, entry 9).
Scheme 1. Synthesis of the starting materials.
Results and Discussion
The synthesis of unsaturated ketones 1A–1E has been re-
ported previously, starting from appropriate (S)-2-(p-tolyl-
sulfinyl)benzyl ketones.[12] The starting ketones were treated
with Me2NH and formaldehyde in a modified Mannich re-
action under ultrasound irradiation to give the correspond-
ing adducts. These adducts were subsequently treated with
silica gel to eliminate the dimethylamino group
(Scheme 1).[9] The synthesis of (S)-2-[2-(p-tolylsulfinyl)-
phenyl]propenal (2) was performed using the same pro-
cedure (Scheme 1).
Table 1. Reactions of enones 1A–1E with alkyl radicals.
We first studied the reaction of 1A with tert-butyl radi-
cal, generated using Et3B/O2 as the initiator system[13] and
tBuI (3a) as the radical source.[14] The initial trials, per-
formed in the presence of Bu3SnH (acting as chain-carrier
and H-atom donor[15]), gave low yields and poor stereose-
lectivities.[16] Thus, we decided to remove the Bu3SnH,
which meant that Et3B would act both as radical initiator
(providing the ethyl radicals required to generate tert-butyl
radicals from tBuI) and chain-carrier[17] (see Scheme 8).
Therefore, it would be necessary to use a protonation agent
to obtain compound 4Aa. After optimization of the reac-
tion conditions[18] (solvent, Lewis acid, protonation agent,
and reaction temperature, see SI for details), the best yields
and stereoselectivities were observed by using a 1:1 mixture
of THF and CH2Cl2 as solvent, Yb(OTf)3 as Lewis acid,
and AcOH as proton source. The protonation temperature
is the main factor controlling the stereoselectivity, with the
highest de value being obtained at room temp. As we can
see in Scheme 2, an easily separable 92:8 mixture of 4Aa
and 4ЈAa was obtained under these conditions, with the
major product being isolated in diastereomerically pure
form in 71% yield.
[b]
Entry[a]
1 (R)
3 (RЈ)
4:4Ј (dr)
Yield [%][c]
1
2
3
4
5
6
7
8
9
1A (Me) 3a (tBu)
1A (Me) 3b[d]
1A (Me)
4Aa:4ЈAa (92:8)
4Ab:4ЈAb (90:10) 78 (4Ab)
71 (4Aa)
–
4Ae:4ЈAe (70:30)
4Ba:4ЈBa (92:8)
4Bb:4ЈBb (90:10)
4Be:4ЈBe (70:30)
4Ca:4ЈCa (68:32) 61 (4Ca + 4ЈCa)
4Da:4ЈDa (80:20) 65 (4Da + 4ЈDa)
65 (4Ae)
80 (4Ba)
79 (4Bb)
78 (4Be + 4ЈBe)
1B (nPr) 3a (tBu)
1B (nPr) 3b[d]
1B (nPr)
–
1C (iPr) 3a (tBu)
1D (Ph) 3a (tBu)
1E (tBu) 3a (tBu)
–
–
[a] For experimental details, see Supporting Information. [b] Deter-
mined by 1H NMR spectroscopy. [c] Isolated yield. [d] RЈ =
Cl(CH2)3(CH3)2C–.
The behaviour of the secondary radicals was different
(Scheme 3). The reaction of 1A with iPrI (3c) gave a 90:10
mixture of the expected adduct 4Ac (dr 87:13) and com-
pound 4Ae (dr 70:30), resulting in the addition of the ethyl
radical to the starting enone 1A (Scheme 3). A similar situa-
tion was observed in the reaction of 1B with 3c, which gave
an 80:20 mixture of 4Bc (dr 85:15) and 4Be (dr 70:30). Sig-
nificant differences were observed in the reaction of 1A with
cyclohexyl iodide (3d), which also gave a 25:75 mixture of
4Ad (dr Ͼ 98:2) and 4Ae (dr 70:30), but with the expected
cylohexyl adduct 4Ad as the minor component in the reac-
Scheme 2. Optimal conditions for the conjugate addition of the
tert-butyl radical to ketone 1A.
We then evaluated the scope of the reaction, considering
the nature of the radical precursor as well as the substituent
on the carbonyl group. Regarding the radical precursor, we
found that the addition of tertiary radicals derived from 3a
and 3b, gave the expected products exclusively and in good Scheme 3. Reactions of enones 1A and 1B with secondary radicals.
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FULL PAPER
tion mixture (Scheme 3). We could not improve this result to us that allyltributyltin[22,23] would be an appropriate rea-
by changing the ratio of 3d to Et3B (see SI for details).[19] gent to trap the crude aldehyde formed in the reaction of 2
These results indicate that ethyl radicals (generated from with tert-butyl iodide (3a), in which both of these catalytic
Et3B and O2) compete with secondary radicals for the sub- species would already be present. The results are given in
strate 1A.
Table 2. Under these conditions, it was possible to obtain
The absence of adducts formed from ethyl radicals in the diastereomerically pure 6a in good yield (60%) from the
reactions reported in Table 1 suggests that the ethyl radicals 96:4 diastereomeric mixture of 6a and 7a (Table 2, entry 1).
are consumed in the very fast formation of tertiary radicals, A similar reaction with the tertiary radical generated from
which are the only species that go on to attack the substrate. 3b gave a 90:10 mixture of 6b and 7b, from which 6b was
This means that the rate of formation of tertiary radicals is isolated in 61% yield (Table 2, entry 2). Finally, the reaction
much higher than the rate of attack of the ethyl radicals on of 2 with EtI (3e) followed by treatment with the tin deriva-
the substrate. In contrast, the presumably slower formation tive, gave an 85:15 mixture of alcohols 6e and 7e (Table 2,
of the secondary radicals (by the reaction of ethyl radicals entry 3), from which pure 6e was obtained in 58% yield.
with secondary halides) would determine that the two rates We also performed reactions with iPrI and CyI (Cy = cyclo-
(i.e., the rate of formation of secondary radicals and the hexyl), but in both cases, 85:15 mixtures of 6e and 7e were
rate of reaction of ethyl radicals with the substrate) become formed exclusively. Enones 1A–1E did not react under the
similar, and ethyl and secondary radicals would be present conditions of the addition/protonation/allylation process.
simultaneously, competing for the substrate, and so forming
Table 2. Results obtained from 2 in the conjugate-addition/proton-
mixtures of reaction products. According to this explana-
tion, the presumably very slow formation of primary radi-
cals (by reaction of the appropriate R–I with the ethyl radi-
cal), compared to the rate of attack of ethyl radical on the
substrate, suggests that the almost exclusive formation of
ethyl radical adducts would be expected. We have con-
firmed this suggestion in the reactions of 1A or 1B with
several primary alkyl iodides (n-butyl, ethoxycarbonyl-
methyl, benzyl, methoxymethyl, allyl, etc).[20] In all these
cases, compounds 4Ae or 4Be were obtained exclusively. As
expected, these products were also formed from enones 1A
and 1B with Et3B/O2 in the absence of alkyl iodides
(Table 1, entries 3 and 6).
We then studied reactions of aldehyde 2 with 3a
(Scheme 4), which took place with complete chemoselectiv-
ity (compound 5e, obtained from the reaction of ethyl radi-
cal with 2 was not observed). Regioselectivity (only 1,4-rad-
ical addition products were formed) and stereoselectivity
were also very high, and a 96:4 mixture of 5a and 5Јa was
obtained. However, despite the fact that the reaction was
very clean, and conversion to the product was quantitative,
as judged from the NMR spectra of the crude reaction
ation/allylation process.
Entry[a] 3 (RЈ)
dr (6:7)[b]
Yield [%][c]
1
2
3
4
5
3a (tBu)
96:4
60 (6a)
61 (6b)
–
3b [Cl(CH2)3(CH3)2C–] 90:10
[d]
[d]
3c (iPr)
3d (Cy)
3e (Et)
–
–
–
85:15
58 (6e)
[a] For experimental details, see Supporting Information. [b] Deter-
mined by 1H NMR spectroscopy. [c] Isolated yield. [d] An 85:15
mixture of ethyl adducts 6e:7e was obtained.
Configurational Assignments
The configurational assignment of the compounds in
product, the isolated yield for 5a was rather modest (30%). Table 1 was unequivocally established as follows: com-
As this result can be attributed to the instability of the re- pound 4Ba, obtained as the major product in Table 1, en-
sulting aldehyde under the purification conditions, we de- try 4, was reduced with DIBALH (diisobutylaluminium hy-
cided to attempt the in situ transformation of the aldehyde dride) and Yb(OTf)3 to give a 70:30 mixture of two alcohols
group in 5 to obtain a more easily isolable compound.
(8 and 9), which were epimeric at the hydroxylic carbon
(Scheme 5). After their chromatographic separation, the
minor product (i.e., 9) was analysed by X-ray diffraction,[24]
which allowed us to assign it the [(S)S,4S,5S] configuration
(Scheme 5). Then, the starting material (i.e., 4Ba) should be
assigned as [(S)S,S]. We assigned the same configuration to
all the major products 4 shown in Table 1.
The configuration of compound 6a (Table 2) was une-
quivocally established to be [(S)S,4S,5S] by X-ray diffrac-
tion studies.[25] The same configuration was assigned to
major diastereoisomers 6b and 6e shown in Table 2.
Scheme 4. Reaction of aldehyde 2 with 3a.
The usually good results obtained in reactions of all- The minor diastereoisomers (i.e., 7) were assigned as
ylmetal reagents with carbonyl compounds, especially those [(S)S,4R,5S] based on the fact that the PCC oxidation of a
catalysed by Yb(OTf)3 and a carboxylic acid,[21] suggested diastereomeric mixture of 6e + 7e gave diastereomerically
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The Sulfinyl Group as a Remote Chiral Auxiliary
DIBALH reduction of 4Ae, could also be desulfinylated to
give 14 without erosion of its configurational integrity
(Scheme 7). It is remarkable that desulfinylation with tBuLi
can be applied to ketones 4 without producing epimeri-
zation, despite the high acidity of their benzylic protons.
Thus, starting from the inseparable 73:27 diastereomeric
mixture of 4Da + 4ЈDa, we obtained desulfinylated com-
pound 15 as a 73:27 enantiomeric mixture (measured by
chiral HPLC), which suggested that none of the initial dia-
stereoisomers had suffered epimerization.
Mechanistic Proposal
From the results obtained, we can conclude that proton-
ation is the most important step in the control of stereo-
selectivity. Moreover, the diastereomeric excesses are higher
when the size of the attacking radical increases (tertiary Ͼ
secondary Ͼ primary). According to the literature, Et3B
acts as chain initiator and chain carrier in the absence of
Bu3SnH,[17] capturing the enoyl radical and generating a
boron enolate[27] and an ethyl radical to carry the chain
(Scheme 8). Finally, compounds 4 and 4Ј are the result of
protonation of the boron enolates.
Scheme 5. Configurational assignment of compound 4Ba.
pure ketone 10 (Scheme 6), which indicates that 6e and 7e
were epimers at the hydroxylic carbon.
Scheme 6. PCC oxidation of an 85:15 mixture of 6e and 7e.
Desulfinylation Reactions
The carbinols shown in Table 2 can be easily desulf-
inylated with tBuLi,[26] as we have demonstrated for com-
pound 6a. Under the reaction conditions used, the configu-
rational integrity of the two chiral centres was not affected,
and compound 11 was obtained in diastereomerically pure
form (Ͼ 98% de) in high yield (Scheme 7). In a similar way,
carbinol 12, obtained as the major diastereoisomer in the
Scheme 8. Mechanism proposed for the reactions with Et3B in the
absence of Bu3SnH.[27]
Taking into account that the results indicated in
Schemes 2, 3, 4, and Table 1 were obtained in the presence
of Yb(OTf)3, the (E) and (Z) enolates will presumably form
chelated species that can adopt two main conformations, I
and II, where the sulfinyl groups are respectively located on
the re and si faces of the enolates (Scheme 9). All of these
species have only one face accessible to the approach of the
proton (the opposite face to that occupied by the sulfinyl
group), which will result in the formation of isomers 4 and
4Ј according to the mechanism shown in Scheme 9. As the
protonation rate must be similar for the different boron
enolates, the observed ratio of 4:4Ј should depend on the
relative stability of the starting enolates. Conformations II
will be favoured, in both (E) and (Z) isomers, because the
(pTol/CH2RЈ) interaction destabilizes conformations
I
Scheme 7. Desulfinylation reactions.
(Scheme 9), and this preference is higher when the R group
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Scheme 9. Chelated species formed by (E) and (Z) boron enolates with Yb(OTf)3.
becomes larger (tBu Ͼ iPr Ͼ Et). The predominance of
isomers 4 in all the reaction mixtures can be explained as
Conclusions
The results described in this paper indicate that the sulf-
being the result of the protonation of species (E)-II and
(Z)-II, which must be favoured in the equilibrium shown in
Scheme 9. The dependence of the stereoselectivity on the
protonation temperature, with a maximum stereoselectivity
being observed at room temp., can be rationalized by as-
suming a slow equilibration at lower temperatures.
Finally, the stereochemical results obtained in the one-
pot radical-addition/protonation/allylation of aldehyde 2
(Table 2) can be explained by assuming that allylation takes
place after protonation of the boron enolate formed from
the radical adduct. According to Scheme 4, protonation of
this enolate will mainly generate compounds 5, with an S
configuration at the benzylic carbon. It could form two che-
lated species, III and IIIЈ (Scheme 10), neither of which have
an interaction between the Tol and the CH2RЈ groups, but
with IIIЈ being unfavoured due to the interactions of the
Lewis acid with the aromatic ring. The approach of the all-
ylic reagent to the only accessible face of III would explain
the formation of [(S)S,S,S]-6 as the major carbinol in these
reactions.
inyl group can act as an efficient remote chiral auxiliary in
conjugate additions to 3-arylenones 1 conducted with Et3B/
O2 and alkyl iodides. This efficiency is related to the ability
of the sulfinyl group and the boron enolate formed in the
initial radical step to form chelated species with Yb(OTf)3
that have sterically well-differentiated diastereotopic faces.
The one-pot radical conjugate-addition/protonation/carb-
onyl allylation of aldehyde 2, allows the simultaneous cre-
ation of two chiral centres in a highly stereoselective man-
ner.
Experimental Section
General Methods: NMR spectra were acquired with a Bruker AC-
300 instrument at 300 and 75.5 MHz for 1H and 13C NMR, respec-
tively. Chemical shifts (δ) are reported in parts per million relative
to TMS, using residual solvent signals as references (CHCl3:
7.26 ppm for 1H, 77.0 ppm for 13C). 13C NMR spectra were ac-
quired in broadband decoupled mode. Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter. Mass spectra (MS)
were determined by FAB and ESI, as indicated in each case. High
resolution mass spectra (HRMS) were performed using a magnetic-
sector mass analyser (for FAB ionization mode) or time-of-flight
(TOF) mass analyser (for ESI ionization modes), as indicated for
each compound. Analytical thin layer chromatography (TLC) was
performed using pre-coated aluminum-backed plates (Merck Kie-
selgel 60 F254) and visualized by ultraviolet irradiation or phos-
phomolybdic acid dip. Flash column chromatography was per-
formed using silica gel (230–400 mesh). All reactions were carried
out in anhydrous solvents. THF and CH2Cl2 were dried with mo-
lecular sieves. Commercially available starting materials were used
without purification. Alkyl iodides 3a and 3c–3e were purchased
from Aldrich, and 3b[28] was synthesized.
General Procedure for Radical Conjugate Addition: A solution of
the corresponding α,β-unsaturated carbonyl compound (0.1 mmol)
and Yb(OTf)3 (0.11 mmol) in THF/CH2Cl2 (1:1, 0.05 m) was
Scheme 10. Reaction of the aldehyde adduct 5.
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The Sulfinyl Group as a Remote Chiral Auxiliary
stirred at room temp. for 30 min under an argon atmosphere. Then
the alkyl iodide (0.5 mmol), triethylborane (1 m in hexane,
0.6 mmol), and O2 (5 mL, by syringe) were added in that order at
the same temperature. When the reaction had finished (as moni-
tored by TLC), the mixture was treated with AcOH (1 mmol).
Then, after stirring for 10 min, water (5 mL) was added. The or-
ganic phase was separated, and the aqueous phase was extracted
with CH2Cl2 (3ϫ 5 mL). The organic extracts were washed with
brine (2ϫ 5 mL) and dried (MgSO4), and the solvent was evapo-
rated under reduced pressure. The residue was purified by flash
column chromatography. The eluent is indicated in each case.
[M + Na]+, 369 (100) [M + 1]+. HRMS calcd. for C30H29O2S [M
+ 1]+ 369.1882; found 369.1886.
(S)-3-{2-[(S)-p-Tolylsulfinyl]phenyl}hexan-2-one (4Ae): Compound
4Ae was obtained as the major diastereomer from enone 1A
(29 mg, 0.1 mmol). Chromatography: n-hexane/EtOAc, 3:1, yield
65%; colourless oil. [α]2D0 = +51.6 (c = 0.7, CHCl3). H NMR: δ =
1
8.04–8.01 (m, 1 H), 7.53–7.43 (m, 4 H), 7.29–7.25 (m, 2 H), 7.21–
7.17 (m, 1 H), 4.15 (t, J = 7.1 Hz, 1 H), 2.37 (s, 3 H), 1.99–1.89
(m, 1 H), 1.61 (s, 3 H), 1.42–1.20 (m, 2 H), 1.13–1.01 (m, 1 H),
0.83 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 207.2, 142.9, 142.1,
141.7, 138.0, 131.8, 130.2, 128.5, 128.1, 126.8, 126.5, 53.1, 35.3,
29.2, 21.4, 20.8, 14.0 ppm. MS (ESI): m/z (%) = 337 (33)
[M + Na]+, 315 (100) [M + 1]+. HRMS calcd. for C19H23O2S
[M + 1]+ 315.1413; found 315.1399.
(S)-5,5-Dimethyl-3-{2-[(S)-p-tolylsulfinyl]phenyl}hexan-2-one (4Aa):
Compound 4Aa was obtained as the major diastereomer from en-
one 1A (29 mg, 0.1 mmol) and tert-butyl iodide (3a). Chromatog-
raphy: n-hexane/EtOAc, 2:1, yield 71%; colourless oil. [α]2D0 = +34.7
(c = 1.9, CHCl3). 1H NMR: δ = 8.09–8.06 (m, 1 H), 7.54–7.42 (m,
4 H), 7.30–7.22 (m, 3 H), 4.11 (dd, J = 7.8, 4.0 Hz, 1 H), 2.37 (s,
3 H), 2.23 (dd, J = 14.0, 7.9 Hz, 1 H), 1.50 (s, 3 H), 1.42 (dd, J =
14.1, 4.0 Hz, 1 H), 0.88 (s, 9 H) ppm. 13C NMR: δ = 205.5, 141.6,
140.7, 140.6, 137.2, 130.4, 129.4, 127.5, 127.1, 126.2, 124.6, 48.9,
45.8, 30.2, 28.9, 28.0, 20.4 ppm. MS (ESI): m/z (%) = 362 (21)
[M + Na]+, 343 (100) [M + 1]+. HRMS calcd. for C21H27O2S [M
+ 1]+ 343.1732; found 343.1725.
(S)-7,7-Dimethyl-5-{2-[(S)-p-tolylsulfinyl]phenyl}octan-4-one (4Ba):
Compound 4Ba was obtained as the major diastereomer from en-
one 1B (31 mg, 0.1 mmol) and tert-butyl iodide (3a). Chromatog-
raphy: n-hexane/EtOAc, 2:1, yield 80%; colourless oil. [α]2D0 = +28.4
(c = 1.4, CHCl3). 1H NMR: δ = 8.12–8.09 (m, 1 H), 7.54–7.40 (m,
4 H), 7.30–7.20 (m, 3 H), 3.99 (dd, J = 8.3, 3.5 Hz, 1 H), 2.37 (s,
3 H), 2.98 (dd, J = 14.1, 8.3 Hz, 1 H), 1.70–1.60 (m, 2 H), 1.44–
1.38 (m, 1 H), 1.27–1.12 (m, 2 H), 0.87 (s, 9 H), 0.54 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR: δ = 208.5, 142.7, 141.8, 141.4, 138.3, 131.3,
130.4, 128.5, 128.0, 127.6, 125.4, 49.3, 47.0, 43.9, 31.2, 29.9, 21.4,
16.7, 13.2 ppm. MS (ESI): m/z (%) = 393 (16) [M + Na]+, 371 (100)
[M + 1]+. HRMS calcd. for C23H31O2S [M + 1]+ 371.2039; found
371.2023.
(S)-8-Chloro-5,5-dimethyl-3-{2-[(S)-p-tolylsulfinyl]phenyl}octan-2-
one (4Ab): Compound 4Ab was obtained as the major diastereomer
from enone 1A (29 mg, 0.1 mmol) and 1-chloro-4-iodo-4-methyl-
pentane (3b). Chromatography: n-hexane/EtOAc, 3:1, yield 78%;
colourless oil. [α]2D0 = +24.6 (c = 1.4, CHCl3). H NMR: δ = 8.09–
1
(S)-10-Chloro-7,7-dimethyl-5-{2-[(S)-p-tolylsulfinyl]phenyl}decan-
4-one (4Bb): Compound 4Bb was obtained as the major dia-
stereomer from enone 1B (31 mg, 0.1 mmol) and 1-chloro-4-iodo-
4-methylpentane (3b). Chromatography: n-hexane/EtOAc, 3:1,
yield 79%; colourless oil. [α]2D0 = +44.0 (c = 0.85, CHCl3). 1H
NMR: δ = 8.12–8.09 (m, 1 H), 7.56–7.41 (m, 4 H), 7.31–7.21 (m,
3 H), 4.02 (dd, J = 3.7, 8.1 Hz, 1 H), 3.49–3.44 (m, 2 H), 2.38 (s,
3 H), 2.30 (dd, J = 14.1, 8.1 Hz, 1 H), 1.75–1.60 (m, 2 H), 1.45–
1.18 (m, 7 H), 0.87 (s, 3 H), 0.83 (s, 3 H), 0.55 (t, J = 7.4 Hz, 3 H)
ppm. 13C NMR: δ = 208.4, 142.8, 141.7, 141.5, 138.2, 131.4, 130.4,
128.5, 128.1, 127.6, 125.5, 48.8, 45.9, 45.1, 43.9, 39.8, 33.5, 27.5,
27.3, 21.4, 16.7, 13.3 ppm. MS (ESI): m/z (%) = 451 (19) [M + Na]
+, 433 (100) [M + 1]+. HRMS calcd. for C25H34ClO2S [M + 1]+
433.1962; found 433.1908.
8.06 (m, 1 H), 7.55–7.42 (m, 4 H), 7.30–7.22 (m, 3 H), 4.11 (dd, J
= 4.0, 7.6 Hz, 1 H), 3.45 (t, J = 6.7 Hz, 2 H), 2.38 (s, 3 H), 2.28
(dd, J = 7.8, 14.3 Hz, 1 H), 1.77–1.64 (m, 2 H), 1.47 (s, 3 H), 1.38–
1.21 (m, 3 H), 0.87 (s, 3 H), 0.83 (s, 3 H) ppm. 13C NMR: δ =
206.4, 142.7, 141.8, 141.6, 138.2, 131.5, 130.4, 128.5, 128.5, 127.2,
125.7, 49.4, 45.8, 44.8, 39.7, 33.5, 29.0, 27.5, 27.4, 27.3, 21.5 ppm.
MS (ESI): m/z (%) = 405 (100) [M + 1]+, 315 (41). HRMS: calcd.
for C23H30ClO2S [M + 1] + 405.1649; found 405.1634.
(S)-5-Methyl-3-{2-[(S)-p-tolylsulfinyl]phenyl}hexan-2-one (4Ac):
Compound 4Ac was obtained as a 90:10 mixture of (4Ac + 4ЈAc,
74 % de) and (4Ae + 4ЈAe, 40 % de) from enone 1A (29 mg,
0.1 mmol) and isopropyl iodide (3c). Compound 4Ac was charac-
terized from a 90:10 inseparable mixture of 4Ac and 4Ae.
Chromatography: n-hexane/EtOAc, 2:1, total yield 74%; colourless
(S)- and (R)-7-Methyl-5-{2-[(S)-p-tolylsulfinyl]phenyl}octan-4-one
(4Bc + 4ЈBc): Compounds 4Bc and 4ЈBc were obtained as an 80:20
mixture of (4Bc + 4ЈBc, 74% de) and (4Be + 4ЈBe, 40% de) from
enone 1B (31 mg, 0.1 mmol) and isopropyl iodide (3c). Compounds
4Bc + 4ЈBc were characterized from an 80:20 inseparable mixture
of 4Bc + 4ЈBc and 4Be + 4ЈBe. Chromatography: n-hexane/EtOAc,
1
oil. H NMR: δ = 8.07–8.04 (m, 1 H), 7.52–7.45 (m, 4 H), 7.29–
7.19 (m, 3 H), 4.15 (t, J = 7.7 Hz, 1 H), 2.37 (s, 3 H), 1.99–1.86
(m, 2 H), 1.55 (s, 3 H), 1.49–1.37 (m, 1 H), 0.90 (d, J = 6.5 Hz, 3
H), 0.84 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR: δ = 206.5, 142.3,
142.1, 141.6, 137.2, 131.1, 129.7, 127.9, 127.6, 125.8, 125.3, 50.9,
41.9, 28.6, 25.5, 22.2, 22.1, 20.9 ppm. MS (ESI): m/z (%) = 351 (37)
[M + Na]+, 329 (100) [M + 1]+. HRMS calcd. for C20H25O2S [M
+ 1]+ 329.1569; found 329.1566.
1
3:1, total yield 60%; colourless oil. H NMR: δ = 8.09–8.07 (m, 1
H, 4), 7.88–7.85 (m, 1 H, 4Ј), 7.51–7.43 (m, 4 H), 7.28–7.19 (m, 3
H), 4.33 (dd, J = 5.0, 9.4 Hz, 1 H, 4Ј), 4.06 (t, J = 7.0 Hz, 1 H, 4),
2.38 (s, 3 H), 2.35 (m, 1 H), 2.08–1.87 (m, 1 H), 1.74–1.14 (m, 6
H), 0.90 (d, J = 6.4 Hz, 3 H, 4), 0.85 (d, J = 6.4 Hz, 3 H, 4), 0.77
(t, J = 7.4 Hz, 3 H, 4Ј), 0.76 (d, J = 6.6 Hz, 3 H, 4Ј), 0.71 (d, J =
6.6 Hz, 3 H, 4Ј), 0.58 (t, J = 7.5 Hz, 3 H, 4) ppm. 13C NMR: δ =
208.4, 208.3, 143.2, 142.9, 142.8, 142.6, 142.3, 142.1, 141.8, 141.5,
138.8, 138.2, 138.0, 132.1, 131.9, 131.8, 130.6, 128.9, 128.8, 128.6,
128.4, 127.5, 126.9, 126.8, 126.7, 125.9, 51.1, 51.0, 43.0, 41.8, 26.7,
26.4, 23.4, 23.2, 22.9, 22.5, 17.4, 17.1, 14.4, 13.7 ppm. MS (ESI):
m/z (%) = 379 (6) [M + Na]+, 357 (100) [M + 1]+. HRMS calcd.
for C22H29O2S [M + 1]+ 357.1882; found 357.1831.
(S)-4-Cyclohexyl-3-{2-[(S)-p-tolylsulfinyl]phenyl}butan-2-one (4Ad):
Diastereomerically pure 4Ad was isolated from a 25:75 mixture of
(4Ad + 4ЈAd, 98% de) and (4Ae + 4ЈAe, 40% de) obtained from
enone 1A (29 mg, 0.1 mmol) and cyclohexyl iodide (3d).
Chromatography: n-hexane/EtOAc, 3:1, yield 19%; colourless oil.
[α]2D0 = +6.9 (c = 0.75, CHCl3). H NMR: δ = 8.06–8.03 (m, 1 H),
1
7.53–7.44 (m, 4 H), 7.29–7.19 (m, 3 H), 4.19 (t, J = 7.0 Hz, 1 H),
2.37 (s, 3 H), 1.93 (dt, J = 7.4, 13.8 Hz, 1 H), 1.74–1.60 (m, 4 H),
1.58 (s, 3 H), 1.39 (dt, J = 13.8, 6.5 Hz, 1 H), 1.17–1.06 (m, 4 H),
0.89–0.83 (m, 3 H) ppm. 13C NMR: δ = 206.2, 141.5, 141.3, 140.8,
136.9, 130.6, 129.3, 127.5, 127.1, 125.7, 125.0, 49.7, 39.9, 34.4, 32.5,
32.4, 28.1, 25.4, 25.1, 25.0, 20.4 ppm. MS (ESI): m/z (%) = 391 (12)
(S)- and (R)-5-{2-[(S)-p-Tolylsulfinyl]phenyl}octan-4-one (4Be +
4ЈBe): Compounds 4Be and 4ЈBe were obtained as a 70:30
Eur. J. Org. Chem. 2013, 1796–1804
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1801

M. C. Maestro, M. M. R.-Fernández, J. L. G.-Ruano et al.
FULL PAPER
diastereoisomeric mixture from enone 1B (31 mg, 0.1 mmol).
Chromatography: n-hexane/EtOAc, 3:1, total yield 78%; colourless
oil. H NMR: δ = 8.07–8.04 (m, 1 H, 4), 7.98–7.95 (m, 1 H, 4Ј),
7.51–7.43 (m, 4 H), 7.28–7.19 (m, 3 H), 4.14 (dd, J = 9.0, 4.8 Hz,
1 H, 4Ј), 4.06 (t, J = 7.0 Hz, 1 H, 4), 2.38 (s, 3 H), 2.34–2.23 (m, 1
H), 1.99–1.86 (m, 1 H), 1.7–1.63 (m, 1 H), 1.50–1.02 (m, 5 H), 0.84
iodide (0.75 mmol), triethylborane (0.9 mmol, 1 m in hexane), and
O2 (5 mL, by syringe) were added. After 30 min, allyltributyltin
(0.12 mmol) and then AcOH (1.5 mmol) were added. After stirring
for 10 min, water (5 mL) was added, the organic phase was sepa-
rated, and the aqueous phase was extracted with CH2Cl2 (3 ϫ
5 mL). The organic extracts were washed with brine (2ϫ 5 mL)
1
(t, J = 7.2 Hz, 3 H, 4), 0.78 (t, J = 7.3 Hz, 3 H, 4Ј), 0.70 (t, J = and dried (MgSO4), and the solvent was evaporated under reduced
7.1 Hz, 3 H, 4Ј), 0.60 (t, J = 7.4 Hz, 3 H, 4) ppm. 13C NMR: δ = pressure. The residue was purified by flash column chromatog-
209.2, 209.0, 142.8, 142.7, 142.2, 141.8, 137.9, 131.6, 131.6, 130.2,
130.1, 128.5, 128.2, 128.0, 126.8, 126.5, 126.0, 125.9, 52.5, 52.4,
44.7, 43.9, 35.6, 34.6, 21.4, 21.1, 20.8, 17.1, 16.8, 14.0, 13.5,
13.5 ppm. MS (ESI): m/z (%) = 365 (22) [M + Na]+, 343 (100)
[M + 1]+. HRMS calcd. for C21H27O2S [M + 1]+ 343.1726; found
343.1698.
raphy. The eluent is indicated in each case.
(4S,5S)-7,7-Dimethyl-5-{2-[(S)-p-tolylsulfinyl]phenyl}oct-1-en-4-ol
(6a): Compound 6a was obtained as the major diastereomer from
aldehyde 2 (41 mg, 0.15 mmol) and tert-butyl iodide (3a).
Chromatography: n-hexane/EtOAc, 3:1, yield 60%; colourless oil.
1
[α]2D0 = –37.8 (c = 1.4, CHCl3). H NMR: δ = 8.05–8.02 (m, 1 H),
7.52–7.44 (m, 4 H), 7.25–7.23 (m, 3 H), 5.48–5.34 (m, 1 H), 5.01–
4.88 (m, 2 H), 3.19–3.16 (m, 1 H), 2.91 (br. s, 1 H), 2.37 (s, 3 H),
1.81–1.73 (m, 4 H), 0.79 (s, 9 H) ppm. 13C NMR: δ = 143.4, 142.3,
142.1, 141.7, 135.0, 130.8, 130.1, 128.7, 127.4, 127.2, 125.4, 117.9,
73.9, 43.9, 41.4, 39.4, 31.1, 30.1, 21.4 ppm. MS (ESI): m/z (%) =
371 (100) [M + 1]+, 353 (28). HRMS calcd. for C23H31O2S [M +
1]+ 371.2045; found 371.2047.
(S)- and (R)-2,6,6-Trimethyl-4-{2-[(S)-p-tolylsulfinyl]phenyl}heptan-
3-one (4Ca + 4ЈCa): Compounds 4Ca and 4ЈCa were obtained as
a 68:32 diastereoisomeric mixture from enone 1C (31 mg,
0.1 mmol) and tert-butyl iodide (3a). Chromatography: n-hexane/
EtOAc, 3:1, total yield 61%; colourless oil. 1H NMR: δ = 8.08–
8.06 (m, 1 H, 4), 7.72–7.69 (m, 1 H, 4Ј), 7.56–7.37 (m, 5 H), 7.31–
7.28 (m, 2 H, 4), 7.14–7.12 (m, 2 H, 4Ј), 4.66 (dd, J = 9.5, 2.5 Hz,
1 H, 4), 4.21 (dd, J = 9.0, 3.1 Hz, 1 H, 4), 2.85–2.76 (m, 1 H, 4Ј),
2.49 (dd, J = 14.0, 9.5 Hz, 1 H, 4Ј), 2.40 (s, 3 H), 2.32 (dd, J =
14.0, 8.9 Hz, 1 H, 4), 1.77–1.62 (m, 1 H, 4), 1.39 (dd, J = 14.0,
2.9 Hz, 1 H, 4), 126–1.20 (m, 1 H, 4Ј), 1.17 (d, J = 7.0 Hz, 3 H,
4Ј), 0.89 (s, 9 H, 4), 0.86 (d, J = 6.7 Hz, 3 H, 4Ј), 0.76 (d, J =
6.6 Hz, 3 H, 4), 0.75 (s, 9 H, 4Ј), 0.55 (d, J = 6.7 Hz, 3 H, 4) ppm.
13C NMR: δ = 212.5, 212.4, 142.5, 141.8, 141.6, 138.8, 131.8, 131.6,
130.2, 130.0, 128.6, 128.3, 128.1, 127.1, 126.2, 125.9, 48.4, 46.9,
45.9, 40.7, 40.4, 31.2, 30.0, 29.8, 21.4, 21.3, 19.4, 19.2, 18.6,
18.4 ppm. MS (ESI): m/z (%) = 393 (28) [M + Na]+, 371 (100)
[M + 1]+. HRMS calcd. for C23H31O2S [M + 1]+ 371.2039; found
371.2029.
(4S,5S)-10-Chloro-7,7-dimethyl-5-{2-[(S)-p-tolylsulfinyl]phenyl}-
dec-1-en-4-ol (6b): Compound 6b was obtained as the major dia-
stereomer from aldehyde 2 (41 mg, 0.15 mmol) and 1-chloro-4-
iodo-4-methylpentane (3b). Chromatography: n-hexane/EtOAc,
3:1, yield 61%; colourless oil. [α]2D0 = –46.8 (c = 0.5, CHCl3). 1H
NMR: δ = 8.04–8.03 (m, 1 H), 7.53 (m, 5 H), 7.25–7.23 (m, 2 H),
5.47–5.34 (m, 1 H), 5.02–4.87 (m, 2 H), 3.28–3.24 (m, 2 H), 3.18
(br. s, 1 H), 2.95 (br. s, 1 H), 2.37 (s, 3 H), 1.83–1.67 (m, 5 H),
1.34–1.17 (m, 3 H), 0.79 (s, 3 H), 0.77 (s, 3 H) ppm. 13C NMR: δ
= 143.2, 142.3, 142.3, 141.6, 135.0, 130.9, 130.9, 128.7, 127.5, 127.2,
125.4, 118.1, 73.8, 45.7, 41.8, 40.9, 39.5, 39.4, 33.4, 27.9, 27.8, 27.7,
21.4 ppm. MS (ESI): m/z (%) = 433 (100) [M + 1]+, 415 (22).
HRMS calcd. for C25H34O2SCl [M + 1]+ 433.1968; found 433.1962.
(S)- and (R)-4,4-Dimethyl-1-phenyl-2-{2-[(S)-p-tolylsulfinyl]-
phenyl}pentan-1-one (4Da + 4ЈDa): Compounds 4Da and 4ЈDa
were obtained as an 80:20 diastereoisomeric mixture from enone
1D (35 mg, 0.1 mmol) and tert-butyl iodide (3a). Chromatography:
(4S,5S)-5-{2-[(S)-p-Tolylsulfinyl]phenyl}oct-1-en-4-ol (6e): Com-
pound 6e was obtained as the major diastereomer from aldehyde 2
(41 mg, 0.15 mmol) and ethyl iodide (3e). Chromatography: n-hex-
ane/EtOAc, 3:1, yield 58%; colourless oil. [α]2D0 = –50.3 (c = 1.25,
CHCl3). 1H NMR: δ = 8.00–7.07 (m, 1 H), 7.49–7.43 (m, 4 H),
7.37–7.34 (m, 1 H), 7.25–7.22 (m, 2 H), 5.62–5.48 (m, 1 H), 5.02–
4.87 (m, 2 H), 3.43 (br. s, 1 H), 3.19–3.12 (m, 1 H), 2.36 (s, 3 H),
2.27 (d, J = 3.2 Hz, 1 H), 1.86–1.75 (m, 2 H), 1.36–1.42 (m, 2 H),
1.03–0.95 (m, 2 H), 0.79 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR: δ =
143.5, 142.0, 141.8, 141.7, 135.4, 131.4, 130.0, 128.4, 127.3, 126.7,
126.1, 117.8, 73.2, 45.4, 38.9, 33.7, 21.3, 20.3, 14.3 ppm. MS (ESI):
m/z (%) = 343 (100) [M + 1]+, 325 (39). HRMS calcd. for
C21H27O2S [M + 1]+ 343.1732; found 343.1731.
1
n-hexane/EtOAc, 3:1, total yield 65%; colourless oil. H NMR: δ
= 8.01–7.98 (m, 1 H, 4), 7.85–7.82 (m, 1 H, 4), 7.65–7.62 (m, 1 H,
4Ј), 7.48–7.02 (m, 11 H), 5.37 (dd, J = 2.9, 9.6 Hz, 1 H, 4Ј), 5.08
(dd, J = 4.4, 8.1 Hz, 1 H, 4), 2.51 (dd, J = 9.6, 14.0 Hz, 1 H, 4Ј),
2.36 (dd, J = 8.0, 14.0 Hz, 1 H, 4), 2.35 (s, 3 H), 1.70 (dd, J = 4.4,
14.0 Hz, 1 H, 4), 1.28 (dd, J = 2.9, 14.0 Hz, 1 H, 4Ј), 0.87 (s, 9 H,
4), 0.71 (s, 9 H, 4Ј) ppm. 13C NMR: δ = 199.2, 142.0, 141.7, 141.5,
141.2, 141.0, 141.0, 139.9, 138.8, 136.5, 133.3, 132.9, 131.9, 131.5,
130.1, 130.0, 129.1, 128.9, 128.8, 128.7, 128.4, 128.3, 128.3, 128.2,
127.4, 127.0, 126.3, 126.2, 48.0, 47.6, 44.6, 43.8, 31.9, 31.6, 30.2,
30.0, 21.4, 21.3 ppm. MS (FAB): m/z (%) = 405 (100) [M + 1]+.
HRMS calcd. for C26H29O2S [M + 1]+ 405.1888; found 405.1890.
General Procedure for Reduction: A solution of the ketone
(0.14 mmol) and Yb(OTf)3 (0.15 mmol) in THF/CH2Cl2 (1:1,
0.05 m) was stirred at room temp. for 30 min under an argon atmo-
sphere. The mixture was cooled to –78 °C, and then a solution of
DIBALH (0.2 mmol, 1 m in heptane) was added. After 6 h and
three more additions of DIBALH (3ϫ 0.20 mmol), the reaction
was quenched with HCl (10% aqueous). The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2 (3ϫ
10 mL). The combined organic extracts were washed with brine
(2ϫ 10 mL) and dried (MgSO4), and the solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography. The eluent is indicated in each case.
(S)-4,4-Dimethyl-2-{2-[(S)-p-tolylsulfinyl]phenyl}pentanal (5a):
Compound 5a was obtained as the major diastereomer from alde-
hyde 2 (27 mg, 0.1 mmol) and tert-butyl iodide (3a). Compound 5a
could not be isolated as pure compound. Chromatography: n-hex-
1
ane/EtOAc, 4:1, yield 30%; colourless oil; H NMR: δ = 9.01 (d,
J = 1.5 Hz, 1 H), 8.08–8.03 (m, 1 H), 7.52–7.43 (m, 4 H), 7.24–
7.15 (m, 3 H), 4.19–4.11 (m, 1 H), 2.36 (s, 3 H), 2.24 (dd, J = 14.2,
5.9 Hz, 1 H), 1.67–1.57 (m, 1 H), 0.89 (s, 9 H) ppm.
General Procedure for Conjugate Radical Addition and Aldehyde
Allylation of (S)-2-[2-(p-Tolylsulfinyl)phenyl]propenal: A solution of
aldehyde 2 (0.15 mmol) and Yb(OTf)3 (0.16 mmol) in THF/CH2Cl2 (4S,5S)-7,7-Dimethyl-5-{2-[(S)-p-tolylsulfinyl]phenyl}octan-4-ol (9):
(1:1, 0.05 m) was stirred at room temp. for 30 min under an argon
atmosphere. The mixture was cooled to 0 °C, and then the alkyl
Compound 9 was obtained as the minor diastereomer from 4Ba
(52 mg, 0.14 mmol). Chromatography: n-hexane/EtOAc, 4:1, yield
1802
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1796–1804

The Sulfinyl Group as a Remote Chiral Auxiliary
28%; white solid. [α]2D0 = –31.4 (c = 0.5, CHCl3). 1H NMR: δ =
ee [HPLC analysis of the product: Daicel CHIRALPAK AD col-
umn; solvent system: 1% iPrOH in hexanes; 1.0 mL/min; retention
8.05–8.03 (m, 1 H), 7.51–7.42 (m, 5 H), 7.25–7.22 (m, 2 H), 3.15–
3.12 (m, 1 H), 2.86 (m, 1 H), 2.36 (s, 3 H), 1.83–1.65 (m, 2 H), times: 22.9 min (major), 29.8 min (minor)]; colourless oil. [α]2D0
=
1.18–1.01 (m, 2 H), 1.00–0.80 (m, 2 H), 0.79 (s, 9 H), 0.73 (t, J = –36.7 (c = 0.5, CHCl3). 1H NMR: δ = 7.41–7.22 (m, 10 H), 3.70
7.3 Hz, 3 H) ppm. 13C NMR: δ = 143.9, 142.1, 141.7, 130.8, 130.1,
128.5, 127.3, 127.2, 125.6, 75.3, 43.7, 42.0, 37.0, 31.1, 30.1, 21.4,
19.7, 13.8 ppm.
(dd, J = 8.7, 3.9 Hz, 1 H), 2.01 (dd, J = 14.1, 4.0 Hz, 1 H), 1.60
(dd, J = 14.1, 8.7 Hz, 1 H), 1.02 (s, 9 H) ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra for all new starting materials and
(2R,3S)-3-{2-[(S)-p-Tolylsulfinyl]phenyl}hexan-2-ol (12): Com-
pound 12 was obtained as the major diastereomer from 4Ae
(44 mg, 0.14 mmol). Chromatography: n-hexane/EtOAc, 2:1, yield
final products.
1
63%; colourless oil; H NMR: δ = 7.84–7.81 (m, 1 H), 7.52–7.47
Acknowledgments
(m, 3 H), 7.43–7.35 (m, 2 H), 7.25–7.23 (m, 2 H), 3.77–3.66 (m, 1
H), 3.29–3.21 (m, 1 H), 2.36 (s, 3 H), 2.14 (br. s, 1 H), 1.65–1.43
(m, 2 H), 1.19 (d, J = 6.2 Hz, 3 H), 0.89–0.76 (m, 2 H), 0.75–0.69
(m, 3 H) ppm. 13C NMR: δ = 144.5, 143.4, 141.7, 141.1, 132.0,
129.8, 127.7, 127.3, 127.2, 125.5, 71.7, 47.8, 34.9, 21.9, 21.3, 20.2,
14.3 ppm.
Financial support of this work by the Spanish Government (grant
CTQ2012-35957) and Comunidad Autónoma de Madrid (CCG08-
UAM/PPQ-4151 and AVANCAT S2009/PPQ1634) is gratefully ac-
knowledged. J. A. F.-S. thanks Comunidad Autónoma de Madrid
(AVANCAT S2009/PPQ1634) for a predoctoral contract.
(SS,5S)-5-[2-(p-Tolylsulfinyl)phenyl]oct-1-en-4-one (10): PCC
(31 mg, 0.142 mmol) was added to a solution of a diastereoisomeric
mixture of 6e and 7e (34 mg, 0.1 mmol) in CH2Cl2 (2 mL). After
3 h, the solvent was evaporated under reduced pressure. Compound
10 was obtained as a single diastereoisomer. Chromatography: n-
[1] For recent reviews, see: a) J. L. Garcia Ruano, J. Aleman, M. B.
Cid, M. A. Fernandez-Ibañez, M. C. Maestro, R. Martin,
A. M. Martín Castro (pp. 55–159) and A. Volonterio, M.
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Tetrahedron 2006, 62, 5559–5601.
1
hexane/EtOAc, 4:1, yield 80%; colourless oil; H NMR: δ = 8.01
(dd, J = 7.1, 2.1 Hz, 1 H), 7.48–7.45 (m, 4 H), 7.29–7.20 (m, 3 H),
5.68–5.62 (m, 1 H), 4.99 (d, J = 10.2 Hz, 1 H), 4.76 (d, J = 17.2 Hz,
1 H), 4.16 (t, J = 7.0 Hz, 1 H), 2.59 (d, J = 6.8 Hz, 2 H), 2.37 (s,
3 H), 1.99–1.88 (m, 1 H), 1.36–1.20 (m, 2 H), 1.09–1.01 (m, 1 H),
0.81 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR: δ = 207.0, 142.7, 142.2,
141.6, 137.7, 131.8, 130.2, 130.2, 128.8, 128.1, 126.6, 126.5, 118.3,
52.2, 46.4, 35.5, 21.4, 20.8, 14.0 ppm.
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T. Kobatake, S. Yoshida, H. Yorimitsu, K. Oshima, Org. Lett.
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707–708; k) T. Kimura, M. Hagiwara, T. Nakata, Tetrahedron
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General Desulfinylation Procedure: tert-BuLi (1.7 m in pentane,
0.4 mmol) was added dropwise to a solution of the corresponding
sulfoxide (0.12 mmol) in dry THF (2 mL) at –78 °C. When the reac-
tion was complete (30 min), the mixture was quenched with H2O
(1 mL), and then extracted with EtOAc (3ϫ 10 mL). The combined
organic extracts were washed with brine (10 mL) and dried
(MgSO4), and the solvent was removed under reduced pressure.
(2S,3S)-7,7-Dimethyl-5-phenyloct-1-en-4-ol (11): Compound 11 was
obtained as a single diastereomer from sulfoxide 6a (44 mg,
0.12 mmol). Chromatography: n-hexane/EtOAc, 2:1, yield 70 %;
colourless oil. [α]2D0 = +2.2 (c = 1.1, CHCl3). H NMR: δ = 7.33–
1
7.27 (m, 2 H), 7.23–7.18 (m, 3 H), 5.85–5.70 (m, 1 H), 5.13–5.03
(m, 2 H), 3.65–3.55 (m, 1 H), 2.76–2.68 (m, 1 H), 2.15–2.09 (m, 1
H), 1.97–1.85 (m, 2 H), 1.77–1.68 (m, 1 H), 0.76 (s, 9 H) ppm. 13C
NMR: δ = 144.1, 135.3, 128.8, 128.2, 126.3, 118.2, 75.1, 48.6, 44.5,
39.3, 31.1, 30.1 ppm. MS (ESI): m/z (%) = 255 (60) [M + Na]+, 173
(100). HRMS calcd. for C16H24ONa [M + Na]+ 255.1719; found
255.1726.
(2R,3S)-3-Phenylhexan-2-ol (14): Compound 14 was obtained as a
single diastereomer from sulfoxide 12 (38 mg, 0.12 mmol).
Chromatography: n-hexane/EtOAc, 2:1, yield 86%; colourless oil.
[α]2D0 = +9.6 (c = 0.5, CHCl3). H NMR: δ = 7.36–7.31 (m, 2 H),
1
7.24–7.20 (m, 3 H), 3.95–3.86 (m, 1 H), 2.55–2.48 (m, 1 H), 1.71–
1.60 (m, 2 H), 1.20 (d, J = 6.25 Hz, 3 H), 1.17–1.08 (m, 2 H), 0.85
(t, J = 7.2 Hz, 3 H) ppm. 13C NMR: δ = 141.6, 128.9, 128.5, 126.7,
71.3, 53.9, 34.1, 21.2, 20.7, 14.1 ppm. MS (ESI): m/z (%) = 201
(34) [M + Na]+, 161 (30), 149 (49), 105 (100). HRMS calcd. for
C12H18ONa [M + Na]+ 201.1249; found 201.1240.
4,4-Dimethyl-1,2-diphenylpentan-1-one (15): Compound 15 was ob-
tained from a 73:27 mixture of 4Da + 4ЈDa (50 mg, 0.12 mmol).
Chromatography: n-hexane/EtOAc, 25:1. ColourYield: 50%; 46%
Eur. J. Org. Chem. 2013, 1796–1804
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1803

M. C. Maestro, M. M. R.-Fernández, J. L. G.-Ruano et al.
FULL PAPER
[4]
to generate it at a rate higher than the rate of addition of the
ethyl radical to starting enone 1A.
[15] C. Chatgilialoglu, in: Radicals in Organic Synthesis (Eds.: P.
Renaud, M. P. Sibi), Wiley-VCH, Weinheim, Germany, 2001,
vol. 1, pp. 28–49.
[16] Double bond reduction with low diastereoselectivity was ob-
served at room temp. under the standard conditions [in a 1:1
mixture of THF and CH2Cl2 and Yb(OTf)3 as Lewis acid],
using Bu3SnH as radical chain carrier and triethylborane/oxy-
gen as radical initiator. Also, a diastereomeric mixture of tert-
butyl adducts (4Aa and 4ЈAa) was obtained in low yield (43%)
and dr (56:44), when the reaction was performed at –78 °C (see
SI for experimental details).
[17] For a review on tin-free radical reactions mediated by or-
ganoboron compounds, see: V. Darmecy, P. Renaud, Top. Curr.
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[18] a) A 55:45 diasteromeric mixture of 4Aa and 4ЈAa was ob-
tained in an unselective control reaction without a Lewis acid;
b) We observed a similar diastereoselectivity using either acetic
acid or trifluoracetic acid as proton source (both gave dr 92:8).
In contrast, when NaH2PO4 was used as the protonation agent,
a lower diastereoselectivity was obtained (see Supporting Infor-
mation for additional data).
[19] Starting from cyclohexyl iodide (3d), a slow addition of
Bu3SnH by syringe pump was tested, to avoid side-reactions
such as ethyl transfer. Nevertheless, cyclohexyl adduct 4Ad was
not formed, and the double-bond-reduction product was the
only observed product (see Supporting Information for experi-
mental details).
[20] The lower reactivity of the stabilized primary radicals (allyl and
benzyl) could also play some role in this behaviour.
[21] H. C. Aspinall, J. S. Bissett, N. Greeves, D. Levin, Tetrahedron
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an example with 1,1-bis-p-tolylsulfoxides, see: d) F. Brevion, M.
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Asymmetry 2003, 14, 2889–2896.
For a review on asymmetric conjugate additions with α-sulf-
inyl-α,β-unsaturated enones as polar acceptors, see: a) G. H.
Posner, in: The Chemistry of Sulfones and Sulfoxides (Eds.: S.
Patai, Z. Rappoport, C. J. M. Stirling), Wiley, New York, 1988,
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Asymmetric conjugate additions with α-sulfinyl α,β-unsatu-
rated enones as radical acceptors have been reported: a) N.
Mase, Y. Watanabe, T. Toru, J. Org. Chem. 1998, 63, 3899–
3904; b) see ref.[7]
a) N. Mase, Y. Watanabe, Y. Ueno, T. Toru, J. Org. Chem. 1997,
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Watanabe, T. Toru, Bull. Chem. Soc. Jpn. 1998, 71, 2957–2965.
For a review, see: a) J. L. García Ruano, A. M. Martín-Castro,
Heteroat. Chem. 2007, 18, 537 (and references cited therein).
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[5]
[6]
[7]
[8]
[23] Asymmetric allylations of sulfinyl-substituted furfural and
thiophenecarbaldehyde have been reported: a) Y. Arai, A. Ma-
suda, Y. Masaki, T. Koizumi, Heterocycles 1994, 38, 1751–
1756; b) Y. Arai, A. Suzuki, T. Masuda, Y. Masaki, M. Shiro,
J. Chem. Soc. Perkin Trans. 1 1995, 2913–2917. For a review
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[9] a) J. L. García Ruano, A. M. Martín-Castro, F. Tato, E. Tor-
rente, G. Tocco, V. Capriati, Tetrahedron 2010, 66, 1581–1585;
b) J. L. García Ruano, M. A. Fernández-Ibáñez, J. A.
Fernández-Salas, M. C. Maestro, P. Márquez-López, M. M.
Rodríguez-Fernández, J. Org. Chem. 2009, 74, 1200–1204; c)
J. L. García Ruano, M. A. Fernández-Ibáñez, M. C. Maestro, [24] CCDC-907864 contains the supplementary crystallographic
M. M. Rodríguez-Fernández, Tetrahedron 2006, 62, 1245–1252;
d) J. L. García Ruano, M. A. Fernández-Ibáñez, M. C. Mae-
stro, Tetrahedron 2006, 62, 12297–12305.
data for compound 9. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[10] Asymmetric carbonyl group reduction of these enones has been
[25] CCDC-907865 contains the supplementary crystallographic
data for compound 6a. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[26] a) J. Clayden, D. Mitjans, L. H. Youssef, J. Am. Chem. Soc.
2002, 124, 5266–5267; b) J. L. García Ruano, M. A.
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[27] The formation of boron enolates as intermediate species in rad-
ical conjugate addition to unsaturated carbonyl compounds
has been reported: a) see ref.[13a]; b) S. Chandrasekhar, C. Nar-
sihmulu, R. N. Ramakrishna, R. Srinivasa, Tetrahedron Lett.
2003, 44, 2583–2585; c) V. Beraud, Y. Gnanou, J. C. Walton,
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[28] F. F. Fleming, B. C. Shook, T. Jiang, O. W. Steward, Tetrahe-
dron 2003, 59, 737–745.
reported by us, see ref.[9b]
[11] Remote sulfinyl induction in nucleophilic conjugate additions
has been reported: a) Y. Arai, M. Kasai, Y. Masaki, Chem.
Pharm. Bull. 2004, 52, 733–738 and references cited therein b)
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[12] J. L. García Ruano, J. Alemán, M. T. Aranda, M. A.
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1991, 64, 403–409; b) C. Ollivier, P. Renaud, Chem. Rev. 2001,
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[14] All the trials performed with tert-butyl bromide gave adduct
4Ae exclusively. This compound results from the addition of
the ethyl radical generated from Et3B and O2. This fact indi-
cates that the ethyl radical is not able to generate the tert-butyl
radical from the starting bromide, or at least, that it is not able
Received: December 5, 2012
Published Online: February 7, 2013
1804
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1796–1804