Palladium-catalyzed suzuki-miyaura reaction involving a secondary sp 3 carbon: Studies of stereochemistry and scope of the reaction

Article abstract of DOI:10.1002/chem.200601488

Palladium-catalyzed C-C bond formation involving secondary sp ³-hybridized carbon is described. These reactions occur with secondary 1-bromoethyl arylsulfoxides and different arylboronic acids, to produce the corresponding arylated sulfoxides in moderate to high yields and with complete stereospecificity. Despite the presence of β hydrogens in the substrate, the competitive β-hydride elimination is not a significant side reaction when coordinating solvents are used. The reported cross-coupling involves secondary C_sp3-C_sp2 bond formation: this is the first time that a mechanistic study has been carried out with such substrates. The reaction proceeds with inversion of configuration at the stereogenic C _sp3 carbon. The high stereospecificity of the coupling and the mildness of the reaction conditions allow for the preservation of the optical purities of reagents and products and the preparation of useful chiral targets.

Full text of DOI:10.1002/chem.200601488

FULL PAPER
DOI: 10.1002/chem.200601488
Palladium-Catalyzed Suzuki–Miyaura Reaction Involving a Secondary sp3
Carbon: Studies of Stereochemistry and Scope of the Reaction
Nuria Rodríguez, Carmen Ramírez de Arellano, Gregorio Asensio,* and
Mercedes Medio-Simón[a]
À
Abstract: Palladium-catalyzed C C
bond formation involving secondary
sp3-hybridized carbon is described.
These reactions occur with secondary
1-bromoethyl arylsulfoxides and differ-
ent arylboronic acids, to produce the
corresponding arylated sulfoxides in
moderate to high yields and with com-
plete stereospecificity. Despite the
presence of b hydrogens in the sub-
strate, the competitive b-hydride elimi-
nation is not a significant side reaction
when coordinating solvents are used.
The reported cross-coupling involves
substrates. The reaction proceeds with
inversion of configuration at the ste-
reogenic Csp3 carbon. The high stereo-
specificity of the coupling and the
mildness of the reaction conditions
allow for the preservation of the opti-
cal purities of reagents and products
and the preparation of useful chiral tar-
gets.
À
secondary Csp3 Csp2 bond formation:
this is the first time that a mechanistic
study has been carried out with such
Keywords: bromo sulfoxide · cross-
coupling
·
palladium
·
stereochemistry · sulfur
Introduction
compounds are known. Reactions involving primary a-halo
carbonyls have been reported by Suzuki and Miyaura,[7]
Gooßen et al.,[8] and Deng et al.[9] In this context, we recent-
ly reported[10] the first example of this type of reaction with
primary a-halo sulfoxides. A complementary approach con-
sists of the cross-coupling of an aryl halide (electrophile)
and a palladium enolate (nucleophile bearing the function)
generated in situ with base. This procedure has been devel-
oped by Buchwald et al.[11] and Hartwig et al.,[12] while ni-
triles[13] and activated sulfones[14] have also been reported as
suitable substrates for this kind of reaction. Despite ongoing
work in the development of suitable methodologies in the
field of palladium-catalyzed cross-coupling reactions with
functionalized alkyls and the potential synthetic utility of
the described procedures, cross-coupling reactions involving
functionalized secondary halides—and also the stereochemi-
cal course of the cross-coupling when a reaction involve a
stereogenic center—remain unexplored. Although secon-
dary halides are uncommon substrates[5a,15] in transition-
metal cross-coupling reactions, several examples of reactions
of unfunctionalized secondary alkyls have been reported re-
cently.[5a,15] Metals other than palladium (Ni, Fe, Co) have
been used with these substrates, and radical mechanisms
seem to be involved.[5a,15] With regard to studies of the ste-
reochemical courses of palladium-catalyzed reactions at ste-
reogenic carbons, examples are scarce, being practically re-
duced to the pioneering reports by Stille et al.[16] on the
Palladium-catalyzed cross-coupling between organic electro-
philes and organometallic compounds has developed to
À
become a useful methodology for the formation of C C
bonds.[1,2,3] Combinations of aryl halides or pseudohalides
with different organometallic compounds to provide new
Csp2 Csp2 bonds have been extensively reported.[4] In con-
À
trast, reactions between alkyl halides and organometallics to
form Csp3 Csp2 or Csp3 Csp3 bonds are much less usual[5] and
À
À
remain a challenging problem in organic synthesis. In gener-
[6]
À
al, oxidative addition to Csp3 X bonds is slow and the b-
elimination process becomes an important competitive side
reaction. Functionalized primary halo alkyl compounds lack-
ing b hydrogens are therefore suitable substrates for cross-
coupling reactions involving sp3-hybridized carbons since
the undesired b-hydride elimination cannot take place,
while the presence of functional groups allows for synthetic
applications, and in this context a few examples of Suzuki–
Miyaura cross-coupling reaction using functionalized halo
[a]N. Rodríguez, Dr. C. Ramírez de Arellano, Prof. Dr. G. Asensio,
Dr. M. Medio-Simón
Departamento de Química Orgµnica, Universidad de Valencia
Avda. Vícent AndrØs EstellØss/n, 46100-Burjassot-Valencia (Spain)
Fax : (+34)963-544-939
E-mail: gregorio.asensio@uv.es
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4223

mechanism of the oxidative addition of alkyl halides to
zero-valent palladium compounds (Scheme 1A), together
with the recent report by Fu and Netherton[17] on the cou-
Scheme 2. Palladium-catalyzed Suzuki–Miyaura coupling of secondary
bromo sulfoxides 2 with boronic acids 3.
Scheme 1. Palladium-catalyzed reactions at stereogenic carbon centers.
A) 1) [Pd
ACHTREUNG
BBN-Ph (BBN=9-borabicyclo
AHCTREUNG
tained in high yield in two steps. First, the homochiral ethyl-
p-tolyl sulfoxide (R)-1b[18] (Scheme 3) was synthesized from
commercially available (S)-(À)-menthyl-p-toluenesulfinate.
pling of chiral unfunctionalized deuterated primary tosylates
(Scheme 1B). Stille et al.[16] used the insertion of carbon
monoxide in a mechanistic study targeted towards suppres-
sion of the b-elimination process in the oxidative addition
intermediate complex. In the process they found indirect
evidence of inversion of configuration at the carbon atom in
the oxidative addition step, on the assumption that the inser-
tion of carbon monoxide into the palladium-carbon s bond
occurs with retention of configuration (Scheme 1). On the
other hand, Fu et al.[17] deduced the stereochemistry of the
oxidative addition reaction of palladium(0) to deuterated
primary alkyl tosylates from the stereochemistry of the deu-
terated coupling product and the stereochemistry of the ole-
fins obtained by b elimination of hydride from the oxidative
addition complex (Scheme 1).
Scheme 3. Determination of the absolute configuration of (Rs,R)-2b.
Bromination of the chiral sulfoxide was carried out with
Br2/AgNO3/CH3CN/pyridine by a described procedure[19] to
afford the bromo derivative 2b in high diastereomeric
purity. Although it is known from this work that the config-
uration at the sulfur atom is inverted in the bromination re-
action, the configuration of the new chiral center remained
unknown. The bromo sulfoxide 2b was isolated as an oil
and was then converted by oxidation into sulfone 5, which
afforded a crystalline solid (Scheme 3), and the absolute
configuration of sulfone 5 was determined by single-crystal
X-ray diffraction studies (Figure 1). In the crystal structure
the stereocenter shows an R configuration with the p-tolyl
group gauche to both the bromine and the methyl group in
Against this background, we felt it would be interesting to
determine the synthetic scope of palladium-catalyzed Suzuki
reactions of secondary a-bromo sulfoxides and the stereo-
chemical course of the cross-coupling reaction itself.
Results and Discussion
Secondary bromo sulfoxides 2, obtained by bromination of
sulfoxides 1, react with boronic acids 3 with complete ste-
reospecificity and inversion of configuration at the stereo-
genic carbon to give the corresponding arylated product 4’
(we have used X’ to denote that the relative configuration
in the product has changed with respect to the starting ma-
terial) (Scheme 2). Surprisingly we found very remarkable
diastereoselectivity in the coupling reaction. While (Æ)-2a
reacted readily to give the arylated products (Æ)-4’a–g, the
epimer with inverse relative configuration—(Æ)-2’a—was
found to be unreactive under similar reaction conditions.
For an attempt to determine the stereochemical course of
the reaction, the target chiral bromo sulfoxide 2b was ob-
À
À
À
relation to the S1 C1 bond. Intermolecular C(Br) H···O S
hydrogen bonds form infinite molecular chains. In short, the
reaction between sulfoxide (R)-1b and Br2/AgNO3/CH3CN/
pyridine affords enantiomerically pure bromo sulfoxide
(RS,R)-2b.[20]
With the configuration of (RS,R)-2b unequivocally estab-
lished, we examined the palladium-catalyzed reaction be-
tween the bromo sulfoxide (RS,R)-2b and phenylboronic
acid (3a) under standard Suzuki–Miyaura conditions. The
reaction occurred in a stereospecific fashion, with enantio-
merically pure (SS,R)-4’h (Figure 1) being obtained and char-
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Palladium-Catalyzed Suzuki–Miyaura Reaction at Secondary sp3 Carbon
FULL PAPER
oxidative addition step proceeds with an inversion of config-
uration, as it is well documented that reductive elimination
always occurs with a retention[23] of configuration. It is thus
likely that the inversion of configuration observed though
the cross-coupling reaction occurs during the oxidative addi-
tion step. The conclusions reached in our study regarding
the stereochemical outcome of the process should not be
generalized, as the situation might be different for other
classes of organohalides. The reaction between (RS,R)-2b
and a palladium(0) complex reported by us in this work rep-
resents the second example of an oxidative palladium addi-
tion to a secondary sp3 hybridized carbon, after Stilleꢁs pio-
neering report[16] in the seventies. In addition, as far as we
are aware, there are no literature precedents for palladium-
catalyzed cross-coupling reactions involving secondary hal-
ides, so the reactions between secondary a-bromo sulfoxides
and boronic acids constitute the first examples in this area.
Moreover, the high stereoselectivity observed in the reac-
tion of the chiral bromo sulfoxide (RS,R)-2b seems to ex-
clude a radical mechanism, in sharp contrast with the results
reported for reactions with unfunctionalized secondary hal-
ides performed with other metals such as nickel and iron, in
which a radical mechanism has been invoked to explain the
stereochemical outcome of the reactions.[15]
Figure 1. X-ray ellipsoid plot of compounds (R)-5 and (Ss,R)-4’h (50%
probability level).
acterized by X-ray analysis.[20] The absolute structure of a
single crystal, obtained by slow evaporation of a dichloro-
methane/n-hexane solution of (SS,R)-4’h, shows the new ste-
reocenter with an R configuration with both aromatic
Owing to the novelty of the reaction of the secondary
bromo sulfoxide, we decided to study the scope of such
cross-coupling reactions with a series of representative bor-
onic acids (Table 1). The racemic bromo sulfoxide (Æ)-2a
was selected as the benchmark substrate in order to deter-
mine the best conditions and the reaction scope (Table 1).
The required starting material was obtained from racemic
ethyl phenyl sulfoxide (1a) by treatment with Br2/CH3CN/
pyridine, and the reaction behavior of (Æ)-2a under stan-
groups anti in relation to the S1 C1 bond. The 1H NMR
À
data were consistent with those reported in the literature for
racemic 4’h,[21] so the arylation process takes place with an
inversion of configuration, as (RS,R)-2b gave (SS,R)-4’h. It is
noteworthy that no epimerization either of the starting ma-
terial (RS,R)-2b or of the reaction product (SS,R)-4’h occur-
red under our mild reaction conditions, despite the acidic
Table 1. Palladium-catalyzed Suzuki–Miyaura reactions between secon-
dary bromo sulfoxide (Æ)-2a and boronic acids 3a–g.
À
character of the C Ha hydrogen in both compounds.
This result is in good agreement with reports by Stille[16]
and Fu[17] relating to the carbonylation of chiral secondary
benzyl bromides and the oxidative addition process in deu-
terated primary alkyl tosylates, respectively. Inversion of
configuration can in principle occur in the catalytic cycle
either in the additive oxidation or in the reductive elimina-
tion step. All attempts to isolate a crystallized pure sample
of the corresponding oxidative addition complex resulting
Run
3
Ar2
Method[a]
4’
6a
1a
from the reaction between (RS,R)-2b and [Pd(PPh3)4]—to
R
Yield [%]
provide direct evidence of the stereochemical course of the
process—failed because of the lack of complex stability.
However, decomposition products were identified as vinyl
sulfoxide 6b (as 6a but with 4-CH3C6H4 group instead of
Ph) and dibromobis(triphenylphosphine)palladium(II) [Pd-
1
2
3
4
5
6
7
8
a
b
c
b
a
b
d
c
C6H5
A
A
A
B
C
C
C
C
C
C
C
a
b
c
b
a
b
d
c
43
19
17
18
52
33
13
15
31
35
20
20
23
29
4-MeOC6H4
4-BrC6H4
4-MeOC6H4
C6H5
4-MeOC6H4
4-MeC6H4
4-BrC6H4
4-CF3C6H4
2-MeOC6H4
2-MeC6H4
48
46
18
66
87
82
62
10[b]
A
tion analysis.[22] The lack of stability of the oxidative addi-
tion complex has precluded its isolation, and consequently
the direct determination of its stereochemistry by X-ray
analysis.
9
10
11
e
f
g
e
–
–
In this study, the exclusive formation of the cross-coupling
product (SS,R)-4’h from (RS,R)-2b strongly suggests that the
[a]Reaction conditions: A) Na 2CO3 (aq)/MeOH, B) CsF/THF, C) CsF/
tert-amyl alcohol. [b]Determined by NMR analysis.
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G. Asensio et al.
dard Suzuki–Miyaura conditions (aqueous base and metha-
nol as a solvent) was assayed with representative boronic
acids 3a–c, possessing substituents of different electronic
character (Table 1, entries 1–3). Under these conditions, the
corresponding cross-coupled derivative was in each case the
major reaction product, although the conversion was in all
cases only moderate.
Dehalogenation product 1a and b-elimination product 6a
were also isolated as minor side products. To optimize the
yield for the cross-coupling product, we assayed the reac-
tions under the best conditions previously found by us for
Suzuki–Miyaura reactions with unsubstituted sulfoxides as
substrates.[10] Accordingly, CsF was used as an non-aqueous
base in anhydrous THF as a solvent. We reasoned that the
conversion of the oxidative addition intermediate, an inter-
mediate common to the cross-coupling and b-elimination
processes (Scheme 4) should give rise to the transmetallated
the b-hydrogen elimination (Scheme 4). The use of tert-amyl
alcohol, of a non-aqueous base such as CsF, and of degassed
solvents thus allowed the best selectivities towards the for-
mation of the cross-coupling product to be achieved in the
reactions between (Æ)-2a and the parent boronic acid 3a
(Table 1, entry 5), the electron-rich arylboronic acids 3b
(Table 1, entry 6) and 3d (Table 1, entry 7), and the slightly
electron-deficient boronic acid 3c (Table 1, entry 8). In the
case of 3e, in which the aryl group is strongly electron-defi-
cient because of the presence of the p-CF3 substituent, only
a poor yield of the cross-coupling product (Æ)-4’e was ob-
tained (Table 1, entry 9).
The reaction was also sensitive to steric effects. Arylbor-
onic acids 3 f (Table 1, entry 10) and 3g (Table 1, entry 11),
bearing o-substituents, failed in the cross-coupling reaction
and consequently vinyl sulfoxide 6a, resulting from the b-
hydride elimination, was the only product in these cases.
The high selectivity for the cross-coupling process achieved
in the reactions between (Æ)-2a and the parent boronic acid
3a and the nonhindered substituted boronic acids 3b, 3c,
and 3d might be related to the presence of the bulky sulfinyl
moiety. Conformational restrictions could disfavor attain-
ment of the required disposition to allow the b-hydrogen
elimination reaction,[25] and this effect might act together
with the solvent effect, which could minimize the b-hydride
elimination side reaction. If we compare these results with
those previously obtained for the unsubstituted bromometh-
yl phenyl sulfoxide,[10] we can see that the efficiency of the
cross-coupling reaction decreases with the steric hindrance.
This is a general trend in the Suzuki–Miyaura reaction.[2]
We next extended our study to test the reactivity of the
bromo sulfoxide (Æ)-2’a in cross-coupling reactions
(Scheme 5). For this purpose we prepared this bromo sulfox-
ide as a mixture of racemic diastereomers (Æ)-2’a and (Æ)-
2a by treating the racemic sulfinyl anion (Æ)-1a-Li with
Br2. The mixture of diastereomers was separated by column
Scheme 4. Catalytic cycle of the palladium-catalyzed reaction of (Æ)-2a
with boronic acids.
intermediate precursor of the cross-coupled product more
efficiently with use of a fluoride ion as base, while on the
other hand, substitution of methanol for THF as a solvent
should minimize the dehalogenation pathway.[10] Under
these conditions, however, the reaction between (Æ)-2a and
3b indeed took place without dehalogenation, but the for-
mation of vinyl sulfoxide 6a by b elimination became an im-
portant side reaction, probably because of the low coordi-
nating ability of the solvent (Table 1, entry 4). The THF was
therefore substituted by tert-amyl alcohol, which is a non-ox-
idizable solvent capable of occupying vacant sites in the pal-
ladium coordination sphere, favoring the conversion of com-
plex I, the common intermediate for the cross-coupling and
b-elimination reactions, to complex II. Similarly, the rate of
formation of complex III decreases because of the presence
of the coordinating solvent in the coordination sphere of
palladium, which disfavors the occurrence of the agostic pal-
Scheme 5. Palladium-catalyzed cross-coupling reaction of (Æ)-2’a and
(Æ)-2a.
[24]
À
ladium C H bond interaction and consequently hampers
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Palladium-Catalyzed Suzuki–Miyaura Reaction at Secondary sp3 Carbon
FULL PAPER
chromatography. Surprisingly though, bromo sulfoxide (Æ)-
2’a was recovered unchanged when it was subjected to treat-
ment with boronic acids under the same reaction conditions
as previously described for the (Æ)-2a diastereomer. More-
over, when the reaction was carried out with a mixture of
(Æ)-2’a and (Æ)-2a, only (Æ)-4’a, derived from (Æ)-2a, was
formed, while the (Æ)-2’a remained unchanged.
addition step, if it is assumed that the usual reductive elimi-
nation proceeds with retention of configuration. Our results
are in sound agreement with the course of palladium(0)-cat-
alyzed carbonylations of benzyl halides or b eliminations in
unfunctionalized primary tosylates. The complete substrate
selectivity encountered in the palladium cross-coupling reac-
tion with the diastereomeric (Æ)-2’a and (Æ)-2a bromo sulf-
oxides is noteworthy; while the (Æ)-2’a diastereomer does
not react, the (Æ)-2a isomer affords the cross-coupling
product with high stereospecificity in moderate to good
yields. Despite the presence of b hydrogens in the substrate,
the expected b-hydride elimination process can be mini-
mized by using a coordinating solvent. The reaction can be
conducted with chiral substrates without loss of optical
purity, so the palladium-catalyzed Suzuki–Miyaura reaction
with the easily accessible chiral bromo sulfoxide (RS,R)-2b
affords the chiral sulfoxide (SS,R)-4’h in an enantiomerically
pure form.
As far as we are aware, such remarkable differences in
the reactivities of diastereomers have not been reported pre-
viously in cross-coupling reactions with achiral palladium
catalysts. A possible explanation for this unusual behavior
might be that the additive oxidation step takes place in a
complex of Pd0 with the sulfinyl moiety. In such a case, re-
pulsive steric interactions between the gauche methyl and
phenyl groups should disfavor the conformation of bromo-
sulfoxide (Æ)-2’a with the lone electron pair anti to the bro-
mine (Scheme 5). This arrangement is necessary to account
for the inversion of configuration at carbon observed in the
coupling reaction. In the diastereoisomer (Æ)-2a, in con-
trast, the conformation with the lone electron pair anti to
the bromine also has the methyl and phenyl groups in an
anti relationship and should predominate. The difference in
reactivity found for pairs of diastereoisomers opens up the
possibility to explore the potential of the cross-coupling re-
action for kinetic resolution of a diastereomeric racemic
mixture with a chiral catalyst.
With regard to synthetic applications, the described proce-
dure constitutes a convenient method for the synthesis of
the chiral sulfoxide (SS,R)-4’h in enantiomerically pure form.
The chiral sulfoxide (SS,R)-4’h itself, or a direct derivative
such as the corresponding chiral sulfide, might find applica-
tions as, say, chiral ligands. Chiral sulfoxides have been
used, for example, as chiral ligands in the asymmetric allyla-
tion of aldehydes[26] or in the asymmetric Trost reaction.[27]
Sulfides similar to those expected from simple reduction of
(SS,R)-4’h are known to form palladacycles and might find
applications in asymmetric Heck reactions.[28] From the per-
spective of sulfoxide chemistry, our route to (SS,R)-4’h offers
better results than alternative methods such as methylation
of chiral benzyl p-tolyl sulfoxide, which always affords a
mixture of diastereomers that are difficult to separate.[21]
Experimental Section
General: 1H and 13C spectra were recorded with a Bruker AC 300. Chem-
ical shifts are reported in d (ppm) relative to the CHCl3 peak at d=
7.27 ppm (1H) or d=77.0 ppm (13C). High-resolution mass spectra were
recorded on a Fisons VG Autospec instrument. Optical rotations were
determined on a Perkin–Elmer 241 polarimeter at room temperature.
The ee values were determined by HPLC (Chiralcel OD-H). Reactions
were monitored by analytical thin-layer chromatography on commercial
aluminium sheets pre-coated (0.2-mm layer thickness) with silica gel
60 F254 (E. Merck). Product purification by flash chromatography was
performed on silica gel (E. Merck 230–400 mesh). All experiments were
carried out under dry argon. For reactions in degassed solvents, three
freeze-pump-thaw cycles were performed before the reagents were
mixed, in order to exclude atmospheric oxygen from the reaction media.
Preparation of (Æ)-(1-bromoethylsulfinyl)benzene [(Æ)-2a]: This com-
pound was prepared by bromination of ethyl phenyl sulfoxide (1a)[29]
with Br2/pyridine/CH3CN by a described procedure.[19] Yield: 90%; de:
95%; colorless oil; 1H NMR: d=7.63–7.61 (m, 2H), 7.47–7.46 (m, 3H),
4.68 (q, J=6.8 Hz, 1H), 1.74 ppm (d, J=6.8 Hz, 3H); 13C NMR: d=
139.8 (s), 132.4 (d), 129.2 (d), 126.2 (d), 62.8 (d), 18.7 ppm (q); HRMS
(EI+): m/z calcd for C8H9OBrS: 232.9636 [M]+; found: 232.9631.
Synthesis of (RS,R)-1-(1-bromoethylsulfinyl)-4-methylbenzene [(À)2b]:
This compound was prepared by bromination of (R)-ethyl p-tolyl sulfox-
ide ((R)-1b)[18] with Br2/pyridine/CH3CN by a described procedure.[19]
Yield: 86%; ee: 99%; colorless oil; [a]lDit::[19] =À1158 (c=1, acetone),
[a]D =À113.88 (c=1, acetone); 1H NMR: d=7.50 (d, J=8.1 Hz, 2H),
7.25 (d, J=8.1 Hz, 2H), 4.66 (q, J=6.8 Hz, 1H), 2.34 ppm (s, 3H),
1.72 ppm (d, J=6.8 Hz, 3H); 13C NMR: d=142.4 (s), 135.9 (s), 129.4 (d),
125.7 (d), 62.4 (d), 21.4(q), 18.0 ppm (q); HRMS (EI+): m/z calcd for
C9H11OSBr: 245.9714 [M]+; found: 245.9701; HPLC analysis (Chiralce-
l OD-H, 10% propan-2-ol/hexane, 0.8 mLminÀ1).
Conclusion
In summary, we have described for the first time the stereo-
chemical course of a palladium-catalyzed Suzuki–Miyaura
cross-coupling reaction involving a stereogenic sp3-carbon
Synthesis of the diastereomeric mixture of (RS,R)- and (SS,S)-(1-bromo-
AHCTREUNG
atom in a secondary functionalized alkyl halide. The secon-
dary halide used in the stereochemical study is a bromo sulf-
oxide. Secondary halides are uncommon electrophilic part-
ners in transition-metal-catalyzed cross-coupling reactions
and only a few examples with metals other than palladium
have been reported in the literature. The reaction described
here takes place with complete inversion of configuration at
the stereogenic carbon atom. Evidence strongly suggests
that the inversion of configuration occurs in the oxidative
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G. Asensio et al.
sulfoxides (Æ)-2b and (Æ)-2’b (60:40, 82%); colorless oil; 1H NMR: d=
7.74–7.71 (m, 2H), 7.55–7.52 (m, 3H), 4.61 (q, J=6.8 Hz, 1H), 1.90 ppm
(d, J=6.8 Hz, 3H); HRMS (EI+): m/z calcd for C8H9OBrS: 232.9636
[M]+; found: 232.9633.
V=1007.0(4) Š3, Z=4, 1calcd =1.736 gcmÀ3
0.71073 Š, w-scan, diffractometer Nonius Kappa CCD, T=150(2) K,
18033 reflections collected, of which 2897 were independent (Rint
0.069), 2566 observed reflections (I>2sI), absorption correction based
on multi-scans, m=4.253, Tmin 0.205, Tmax 0.304, direct primary solution
and refinement on F2,[32] 120 refined parameters, methyl hydrogen atoms
refined as rigid, others as riding, the absolute structure was determined
by anomalous dispersion effects (Flack parameter 0.001(8),[33]), R1-
, qmax =30.00, MoKa, l=
=
Cross-coupling between bromo sulfoxides 2 and boronic acids 3a–g—
general procedure: The boronic acid
3
(0.8 mmol), [Pd(PPh3)4]
A
(0.04 mmol) and CsF (1.6 mmol) were added to a solution of the appro-
priate a-bromo sulfoxide (Æ)-2a or (À)-2b (0.4 mmol) in degassed tert-
amyl alcohol (8 mL). After having been heated at reflux for an appropri-
ate duration (see Table 1), the reaction mixture was allowed to cool to
room temperature, quenched with water (10 mL) and extracted with di-
ethyl ether (2”15 mL) and dichloromethane (2”15 mL). The combined
organic extracts were dried with Na2SO4 and evaporated under reduced
pressure to yield products 1, 4’ and 6.[30]
A
N
CCDC-616336 and CCDC-616335 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
(Æ)-(1-Phenylethylsulfinyl)benzene ((Æ)-4’a): Yield: 66%; m.p. 67–688C;
1H NMR: d=7.34–6.91 (m, 10H) 3.73 (q, J=7.1 Hz, 1H), 1.63 ppm (d,
J=7.1 Hz, 3H); 13C NMR: d=142.9 (s), 135.9 (s), 131.4 (d), 128.9 (d),
125.3 (d), 67.5 (d), 14.6 ppm (q); HRMS
(FAB+): m/z calcd for C14H14OS
A
Acknowledgements
[M+1]+: 231.0844; found: 231.0842.
Financial support by the Spanish Dirección General de Investigación
Científica y TØcnica (BQU2003–00315), the Generalitat Valenciana
(Grupos 2003–121, 842/2005 and 027/2005) and UVEG (UV-AE-
20050205) is gratefully acknowledged. We also gratefully acknowledge
SCSIE (Universidad de Valencia) for access to instrumental facilities. NR
thanks the Spanish Ministerio de Educación y Ciencia for a fellowship.
(Æ)-1-Methoxy-4-[1-(phenylsulfinyl)ethyl]benzene
((Æ)-4’b):
Yield:
1
87%; m.p. 77–80o C; H NMR: d=7.35–7.16 (m, 5H), 6.84 (d, J=8.8 Hz,
2H), 6.71 (d, J=8.8 Hz, 2H), 3.72 (s, 3H) 3.75–3.69 (m, 1H), 1.59 ppm
(d, J=7.2 Hz, 3H); 13C NMR: d=159.9 (s), 142.4 (s), 131.3 (d), 130.2 (d),
128.8 (d), 127.7 (s), 125.4 (d), 114.2 (d), 66.7 (d), 55.8 (q), 14.7 ppm (q);
HRMS
(FAB+): m/z calcd for C15H17O2S [M+1]+: 261.0949; found:
N
261.0959.
(Æ)-1-Bromo-4-[1-(phenylsulfinyl)ethyl]benzene ((Æ)-4’c): Yield: 62%;
m.p. 137–138o C; 1H NMR: d=7.39–7.28 (m, 5H), 7.25 (d, J=8.3 Hz,
2H), 6.87 (d, J=8.3 Hz, 2H), 3.80 (q, J=7.1 Hz, 1H), 1.63 ppm (d, J=
7.1 Hz, 3H); 13C NMR: d=141.5 (s), 134.4 (s), 131.5 (d), 131.2 (d), 130.2
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Bolm), Wiley-VCH, Weinheim, 2004.
(d), 128.6 (d), 124.9 (d), 122.4 (s), 66.1 (d), 13.7 ppm (q); HRMS
(EI+):
G
m/z calcd for C14H13OBrS: 307.9867 [M]+; found: 307.9873.
(Æ)-1-Methyl-4-[1-(phenylsulfinyl)ethyl]benzene ((Æ)-4’d): Yield: 82%;
m.p. 77–80o C; 1H NMR: d=7.34–7.17 (m, 5H), 6.98 (d, J=7.9 Hz, 2H),
6.81 (d, J=7.9 Hz, 2H), 3.69 (q, J=7.1 Hz, 1H), 2.25 (s, 3H), 1.59 ppm
(d, J=7.1 Hz, 3H); 13C NMR: d=142.1 (s), 138.1 (s), 132.4 (s), 130.9 (d),
129.1 (d), 128.5 (d), 128.4 (d), 124.9 (d), 66.7 (d), 21.1 (q), 13.9 ppm (q);
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HRMS
A
ACHTREUNG
1
65%; m.p. 83–86o C; H NMR: d=7.19–6.92 (m, 9H), 3.71 (q, J=7.1 Hz,
1H), 2.29 (s, 3H), 1.63 ppm (d, J=7.1 Hz, 3H); 13C NMR: d=141.4 (s),
138.7 (s), 135.6 (s), 129.2 (d), 128.7 (d), 128.4 (d), 128.2 (d), 124.9 (d),
67.0 (d), 21.4(q), 14.6 ppm (q); HRMS (EI+): m/z calcd for C15H16OS:
244.0918 [M]+; found: 244.0921. HPLC analysis (Chiralcel OD-H, 10%
propan-2-ol/hexane, 0.8 mLminÀ1).
(R)-1-(1-Bromoethylsulfonyl)-4-methylbenzene ((À)-5): This compound
was prepared by oxidation of (RS,R)-2a with m-CPBA by a described
procedure.[19] Yield: 80%; ee: 80% ; m.p. 93–968C; [a]Dlit::[31]: À11.98 (c=1,
acetone); [a]D: À14.98 (c=1, acetone); 1H NMR: d=7.78 (d, J=8.3 Hz,
2H), 7.32 (d, J=8.3 Hz, 2H), 4.77 (q, J=6.9 Hz, 1H), 2.41 (s, 3H),
1.90 ppm (d, J=6.9 Hz, 3H); 13C NMR: d=146.2 (s), 132.0 (s), 130.5 (d),
130.1 (d), 59.6 (d), 22.1 (q), 19.9 ppm (q); HRMS
(EI+): m/z calcd for
A
C9H11O2SBr: 261.9663 [M]+; found: 261.9623; HPLC analysis (Chiralce-
l OD-H, 5% propan-2-ol/hexane, 0.8 mLminÀ1).
Single-crystal X-ray diffraction
X-ray data for compound (SS,R)-4’h: Colorless needle, 0.48”0.10”
0.08 mm size, orthorhombic, P212121, a=5.8007(12), b=7.4505(15), c=
29.585(6) Š, V=1278.6(5) Š3, Z=4, 1calcd =1.269 gcmÀ3
, qmax =27.88,
MoKa, l=0.71073 Š, w-scan, diffractometer Nonius Kappa CCD, T=
150(2) K, 9384 reflections collected, of which 3027 were independent
(Rint =0.050), 2473 observed reflections (I>2sI), direct primary solution
and refinement on F2,[32] 156 refined parameters, methyl hydrogen atoms
refined as rigid, others as riding, the absolute structure was determined
from anomalous dispersion effects (Flack parameter 0.10(8),[33]), R1-
A
N
X-ray data for compound (À)-5: Colorless prism, 0.38”0.36”0.28 mm
size, orthorhombic, P212121, a=6.9382(14), b=10.725(2), c=13.532(3) Š,
4228
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 4223 – 4229

Palladium-Catalyzed Suzuki–Miyaura Reaction at Secondary sp3 Carbon
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Received: October 19, 2006
Revised: January 9, 2007
Published online: March 1, 2007
Chem. Eur. J. 2007, 13, 4223 – 4229
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4229