The first stereoselective Pd-catalyzed addition of boronic acids onto aldehydes

Article abstract of DOI:10.1016/j.tetasy.2007.06.031

The coupling reaction between 2-p-tolylsulfinyl benzaldehyde and substituted boronic acids catalyzed by Pd₂(dba)₃·CHCl₃ proceeds in a stereoselective manner, demonstrating the efficiency of the sulfinyl group as a chiral i

Full text of DOI:10.1016/j.tetasy.2007.06.031

Tetrahedron: Asymmetry 18 (2007) 1628–1634
The first stereoselective Pd-catalyzed addition of boronic acids
onto aldehydes
*
`
`
`
´ ´
Alexandra Novodomska, Maria Dudicˇova, Frederic R. Leroux and Franc¸oise Colobert
Laboratoire de Ste´re´ochimie (UMR CNRS 7509), Universite´ Louis Pasteur (ECPM), 25 rue Becquerel,
F-67087 Strasbourg Cedex 2, France
Received 19 June 2007; accepted 25 June 2007
Abstract—The coupling reaction between 2-p-tolylsulfinyl benzaldehyde and substituted boronic acids catalyzed by Pd2(dba)3ÆCHCl3
proceeds in a stereoselective manner, demonstrating the efficiency of the sulfinyl group as a chiral inductor. Enantiopure secondary diaryl
alcohols become easily accessible by subsequent sulfoxide–lithium exchange.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the reduction methodology requires the presence of an
ortho-substituent on one of the aryls or electronically very
different aryl groups. In the catalyzed additions to alde-
hydes, only phenyl transfer reactions have been developed
to a satisfying level to afford arylphenylmethanols with
high enantioselectivities. Other protocols employing aryl-
boronic acids,2,3 arylstannanes,9 or arylsilanes10 are either
non-asymmetric or lead to products with low enantiomeric
excess.11
The addition of a metal–carbon bond to the carbon–het-
eroatom double bond is a very popular reaction in main
group metal reagents of lithium and magnesium, but less
attention has been paid to the corresponding reaction of
transition-metal compounds.1 Recent results have de-
scribed the addition of arylboronic acids to aldehydes in
the presence of catalytic amounts of rhodium and phos-
phine additives2 or N-heterocyclic carbenes.3 In spite of
the rare activity of Pd-catalysts for the 1,2-addition of aryl-
boronic acids to aromatic aldehydes, two examples4 have
been reported but no application to asymmetric synthesis
has been developed in order to obtain pure chiral carbinols.
We previously demonstrated the efficient atropo-diastereo-
selective Suzuki–Miyaura coupling reaction by means of a
stereogenic benzylic carbinol bearing a chiral sulfoxide at
the b-position.5
Herein, we report a new approach toward optically active
diaryl methanols, which employs readily accessible,
commercially available arylboronic acids as aryl source.
Recently, Ito and Ohta reported on the palladium-cata-
lyzed reaction of arylboronic acids with aldehydes4 and
observed that general palladium complexes have no cata-
lytic activity without chloroform meaning chloroform is
essential for this reaction.
Chiral diaryl methanols are important intermediates for the
synthesis of biologically active compounds.6 Two general
approaches exist for their catalytic enantioselective synthe-
sis. They can be obtained either by reduction of the corre-
sponding unsymmetrical diaryl ketones7 or are accessible
by enantioselective aryl transfer reactions to aldehydes.8
However, both methods have severe limitations and only
work well for a limited range of substrates. For example,
Therefore we planned to apply this procedure to a diaste-
reoselective coupling. Using an inexpensive metal instead
of rhodium, catalysis with Pd2(dba)3ÆCHCl3 is easy to
12
perform and yields a broad range of products by the dia-
stereoselective 1,2-addition of aromatic aldehydes with
arylboronic acids in the presence of an enantiopure 2-p-tol-
ylsulfinyl group as a traceless chiral auxiliary.13 Sulfoxides
as chiral auxiliaries have several features which make them
highly useful for this purpose: firstly, they can be con-
structed in enantiomerically pure form by any of a number
of methods, the most important for our purposes being the
Andersen substitution of (2)-menthyl sulfinate.14 Secondly,
*
Corresponding author. Tel.: +33 3 90 24 27 44; fax: +33 3 90 24 27 42;
e-mail: fcolober@chimie.u-strasbg.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.031

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A. Novodomska et al. / Tetrahedron: Asymmetry 18 (2007) 1628–1634
1629
Table 1. Pd2(dba)3ÆCHCl3-catalyzed diastereoselective 1,2-addition of
they have electronic properties, which exaggerate the con-
trast between the physical properties of the two stereo-
isomers, mainly because of dipole orientation.15 And
thirdly, they are very useful as traceless resolving agents,
as they can undergo sulfoxide–lithium exchange16 to afford
new organometallic intermediates, which can subsequently
be trapped by various electrophiles.17
aromatic aldehydes with arylboronic acidsa
p-Tol
p-Tol
OH
S
O
S
H
O
Pd2(dba)3.CHCl3 (5 mol%)
PPh3 (10 mol%),
CHO
C
Ar
Cs2CO3 (1 eq)
Ar-B(OR)2 (2 eq)
toluene, reflux, 2 h
(R,(S)S)-2a-p
(S)(S)-1
2. Results and discussion
Entry
ArB(OR)2
Selectivity
[R,(S)S]:[S,(S)S]
Yieldb [%]
Enantiomerically pure (S)-2-p-tolylsulfinylbenzaldehyde 1
was prepared in high overall yield over a two-step sequence
starting from commercially available 2-bromobenzalde-
hyde diethyl acetal. Sulfinylation and subsequent hydroly-
sis of the acetal function afforded our target molecule
(Scheme 1).18
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5B(OH)2
62:38
86:14
74:26
71:29
75:25
61:39
61:39
100:0
57:43
80:20
nrd
67 (2a)
51 (2b)
65 (2b)c
43 (2b)d
89 (2b)e
56 (2c)
62 (2d)
61 (2e)
59 (2f)
50 (2g)
<1 (2h)
<1 (2k)
<1 (2l)
<1 (2m)
2-H3COC6H4B(OH)2
2-H3COC6H4B(OH)2
2-H3COC6H4B(OH)2
2-H3COC6H4B(OH)2
3-H3COC6H4B(OH)2
4-H3COC6H4B(OH)2
2,6-(H3CO)2C6H3B(OH)2
2-H3CC6H4B(OH)2
2-H3CO-5-H3C-C6H3
2-(H3C)2NC6H4B(OH)2
3-O2NC6H4B(OH)2
2-NCC6H4B(OH)2
p-Tol
S
Br OC2H5
OC2H5
O
1) BuLi, -75 °C, THF
2) (S)-TolS(O)-OMent
3) PyOTs
CHO
nr
nr
nr
4) Acetone/H2O
69%
4-F3CC6H4B(OH)2
(S)(S)-1
O
O
B
15
96:4
55 (2p)
Scheme 1.
OCH3
The palladium-catalyzed addition of phenylboronic acid
and different substituted derivatives thereof are presented
in Table 1.
a The reaction was carried out using 2-p-tolylsulfinylbenzaldehyde
(1.0 mmol), the corresponding aryl boronic acid (2.0 equiv), Cs2CO3
(1.0 equiv), Pd2(dba)3ÆCHCl3 (5 mol %), and PPh3 (10 mol %) in 2.0 mL
of toluene at 120 ꢁC. The reaction was followed by TLC analysis.
b Yield of product isolated by silica gel column chromatography.
c Reaction conducted in THF.
As can be seen in entries 1–14, a remarkably high influence
of electronic effects in the arylboronic acids can be
observed. The yields vary only in a small range between
50% and 89% with electron-rich arylboronic acids. In the
coupling reaction with 2-methoxyphenyl boronic acid,
changing the solvent from toluene to either THF, CH3CN,
or dioxane decreased the diastereomeric excess but
increased the yield in the case of dioxane (entries 2–5).
However, electron-deficient arylboronic acids showed no
reaction at all (entries 12–14). Ito and Ohta have reported
similar results. In their case, arylation with electron-
deficient arylboronic acids in the presence of Pd–CHCl3
proceeded only very sluggishly.4 Changing from an aryl-
boronic acid to an arylester does not significantly influence
the yields (entry 15). Although in our case the aldehyde is
bearing the highly sterically demanding 2-p-tolylsulfinyl
group as a chiral inductor, our yields are only slightly infe-
rior to those of Ito and Ohta. However in terms of selectiv-
ity, Table 1 clearly shows the need for a coordinating
substituent in the ortho-position. The selectivity increases
from phenylboronic acid (62:38, entry 1) over 2-methoxy-
phenylboronic acid (86:14, entry 2) to 2,6-dimethoxy-
phenylboronic acid (100:0, entry 8). Unfortunately,
2-dimethylaminophenylboronic acid did not react under
these conditions (entry 11). In all cases, the diastereoiso-
mers could easily be separated either by column chroma-
tography or by crystallization.
d Reaction conducted in CH3CN.
e Reaction conducted in dioxane.
The (R)-absolute configuration of the stereogenic center
formed in the major diastereomer was determined by
analysis of the carbinol 2b by X-ray crystallography
(Fig. 1).19,20
In order to investigate the scope and limitations of this cou-
pling procedure, we decided to modify as well the substitu-
ent pattern of the aldehyde. Several groups observed an
increased regioselectivity of the addition of aluminum
and magnesium reagents onto aldehydes,21 as well as the
hydrocyanation of d-ketosulfoxides22 and benzaldehydes23
in the presence of a remote 2-p-tolylsulfinyl group and
coordinating methoxy substituents. Therefore we decided,
to introduce a methoxy substituent next to the aldehyde
(compound 3, Scheme 2).
The coupling between derivative 3 and phenylboronic acid
was conducted as described above. However, probably due
to steric reasons, we were unable to observe any coupling
reaction. Increasing the amount of palladium (15 mol %)
did not change the situation.

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A. Novodomska et al. / Tetrahedron: Asymmetry 18 (2007) 1628–1634
p-Tol
MeO
MeO
H
S
R
H
1) 4 eq. BuLi, -75 °C,
THF, 10 min
O
C
C
Ar
Ar
2) H2O or H3CI
Ar = 2,6-(H3CO)2C6H4
(S)-6a (86%)
(S)-6b (57%)
R = H:
R = CH3:
(R,(S)S)-5
86%
Scheme 4.
The 1H NMR spectrum of (S)-6a using the chiral shift
reagent Eu(hfc)3 showed that no racemization took place
during the sulfoxide–lithium exchange. Only one signal
assignable to the protons of the non-aromatic methoxy
Figure 1. X-ray crystal structure of 2b.
1
group appeared in the H NMR spectrum, while two sig-
p-Tol
nals of the methoxy protons were separately observed in
a similar NMR experiment of the corresponding racemic
mixture (obtained by addition of 2,6-dimethoxyphenyl-
lithium to benzaldehyde followed by conversion of the
benzyl alcohol into the methyl ether).
S
Br
O
1) BuLi, -75 °C, THF
2) (S)-TolS(O)-OMent
CHO
OCH3
3) LDA, -75 °C, THF, 2h
OCH3
4) DMF
56%
(S)(S)-3
3. Conclusion
Scheme 2.
In conclusion, arylboronic acids having electron-donor
functions react with 2-p-tolylsulfinyl benzaldehyde in the
presence of base and a catalytic amount of Pd2(dba)3Æ
CHCl3, to afford the corresponding secondary alcohols in
good yields and high diastereoselectivity when donor-sub-
stituents are present at the ortho-position. The chiral sulf-
oxide auxiliary can be easily removed by means of
sulfoxide–lithium exchange affording the enantiopure sec-
ondary alcohols in high yields.
Next, we wanted to investigate, whether this addition is
restricted to just aldehydes or if ketones are also suitable
substrates giving rise to substituted benzyl alcohols. Thus,
we prepared the 2-p-tolylsulfinyl substituted ketone 4
depicted in Scheme 3. However again, the substrate under-
went no coupling reaction with phenylboronic acid.
p-Tol
4. Experimental
4.1. General
S
O
Br
O
O
1) p-TsOH, HO(CH2)2OH
2) BuLi, -75 °C, THF
3) TMEDA, (S)-TolS(O)-OMent
4) p-TsOH, acetone/H2O
Starting materials, if commercial, were purchased and used
as such, provided that adequate checks (melting ranges,
refractive indices, and gas chromatography) had confirmed
the claimed purity. When known compounds had to be
prepared according to literature procedures, pertinent ref-
erences are given. Air- and moisture-sensitive materials
were stored in Schlenk tubes or Schlenk buret. They were
protected by and handled under an atmosphere of argon,
using appropriate glassware. Diethyl ether and tetrahydro-
furan were dried by distillation from sodium after the
characteristic blue color of sodium diphenyl ketyl (benzo-
phenone–sodium ‘radical–anion’) had been found to
persist. Ether or other organic extracts were dried by wash-
ing with brine and then by storage over sodium sulfate. If
no reduced pressure is specified, boiling ranges (bp) refer to
ordinary atmospheric conditions (725 25 Torr). Melting
ranges (mp) given were found to be reproducible after reso-
lidification, unless stated otherwise (‘decomp.’), and were
corrected using a calibration curve established with authen-
tic standards. The temperature of dry ice/acetone baths is
(S)(S)-4
33%
Scheme 3.
As enantiopure diaryl carbinols are important starting
materials for the total synthesis of natural products,5 we
were interested to see, if the 2-p-tolylsulfinyl group could
be removed without any loss of chirality by sulfoxide–lith-
ium exchange. As a model compound we took the methyl
ether 5 generated from 2e by treatment with NaH/MeI
with the 2,6-dimethoxyphenyl unit. Its precursor, alcohol
2e was obtained diastereomerically pure. The sulfoxide–
lithium exchange proceeded smoothly with butyllithium
without any loss of chirality at ꢀ78 ꢁC giving rise to the
corresponding diaryl compound 6a in high yield. Analo-
gously, alkylation of the intermediate aryllithium species
with iodomethane afforded derivative 6b in a yield of
57% (Scheme 4).

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A. Novodomska et al. / Tetrahedron: Asymmetry 18 (2007) 1628–1634
1631
consistently indicated as ꢀ75 ꢁC and ‘room temperature’
(22–26 ꢁC) as 25 ꢁC. Silica gel (Merck Silica Gel Si60, 40–
63 lm) particle size was used for column chromatography.
The solid support was suspended in cyclohexane and, when
all air bubbles had escaped, was washed into the column.
When the level of the liquid was still 3–5 cm above the sup-
port layer, the dry powder, obtained by adsorption of the
crude mixture to some 25 mL of silica and subsequent
evaporation of the solvent, was poured on top of the col-
mixture was canulated into a 0 ꢁC cold solution of
(1R,2S,5R)-(ꢀ)-menthyl-(S)-p-toluenesulfinate (7.35 g,
25 mmol) in diethyl ether (50 mL). After stirring for 3 h,
the reaction mixture was quenched with saturated aqueous
ammonium chloride (100 mL) and extracted with dichloro-
methane (3 · 100 mL). The combined organic layers were
washed with brine (100 mL), dried, and evaporated. The
residue was purified by column chromatography on silica
gel (EtOAC/cHex = 1:4) to afford (S)-1-methoxy-3-(p-tolyl-
sulfinyl)benzene, which crystallizes from EtOAC/hexanes
as colorless cubes; 5.35 g (87%). [a]D = +49.8 (c 1, ace-
tone). 1H NMR (CDCl3, 300 MHz): d = 7.55 (d,
J = 8.21 Hz, 2H), 7.35 (t, J = 7.94, 7.94 Hz, 1H), 7.30–
7.23 (m, 3H), 7.15 (ddd, J = 7.65, 1.49, 0.98 Hz, 1H),
6.96 (ddd, J = 8.22, 2.57, 0.92 Hz, 1H), 3.83 (s, 3H), 2.38
(s, 3H). 13C NMR (CDCl3, 75 MHz): d = 160.3, 147.1,
142.4, 141.6, 130.1, 130.0, 125.0, 117.2, 116.8, 109.0, 55.5,
21.4. Anal. Calcd for C14H14O2S (246.32): C, 68.26; H,
5.73. Found: C, 68.13; H, 5.76.
1
umn. H and (1H decoupled) 13C nuclear magnetic reso-
nance (NMR) spectra were recorded at 300 and 75 MHz,
respectively. Chemical shifts are reported in d units, parts
per million (ppm) and were measured relative to the signals
for residual chloroform (7.27 ppm). Coupling constants J
are given in Hz. Coupling patterns are abbreviated as, for
example, s (singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublets), td (triplet of doublets), and m
(multiplet).
4.2. Starting materials
4.2.2.2. (S)-2-Methoxy-6-(p-tolylsulfinyl)benzaldehyde 3.
Diisopropylamine (3.5 mL, 2.5 g, 25 mmol) and (S)-1-
methoxy-3-(p-tolylsulfinyl)benzene (5.67 g, 23 mmol) from
Section 4.2.2.1 were consecutively added to a solution of
butyllithium (25 mmol) in tetrahydrofuran (50 mL) and
hexanes (15.6 mL) at ꢀ75 ꢁC. After 2 h at ꢀ75 ꢁC, N-form-
ylmorpholine (3.02 mL, 3.45 g, 30 mmol) was added. The
reaction mixture was quenched with saturated aqueous
NH4Cl (100 mL) and extracted with CH2Cl2 (3 ·
100 mL). The combined organic layers were washed with
brine (100 mL), dried, and evaporated. The residue was
purified by column chromatography on silica gel
(EtOAC/cHex = 1:4) to afford 3, which crystallizes from
EtOAC/hexanes as colorless cubes; 4.04 g (64%); [a]D =
ꢀ368 (c 1, acetone). 1H NMR (CDCl3, 300 MHz):
d = 10.31 (s, 1H), 8.05 (d, J = 7.88 Hz, 1H), 7.75 (t,
J = 8.14, 8.14 Hz, 1H), 7.54 (d, J = 8.25 Hz, 2H), 7.07 (t,
J = 8.79, 3H), 3.87 (s, 3H), 2.23 (s, 3H). 13C NMR (CDCl3,
75 MHz): d = 188.8, 162.9, 150.3, 143.3, 141.2, 136.0,
129.5, 126.8, 121.1, 116.3, 113.5, 56.3, 21.4. Anal. Calcd
for C15H14O3S (274.33): C, 65.67; H, 5.14. Found: C,
65.81; H, 5.23.
4.2.1. (S)-2-(p-Tolylsulfinyl)benzaldehyde 1
4.2.1.1. 2-(S)-(p-Tolylsulfinyl)benzaldehyde diethyl ace-
tal. At ꢀ78 ꢁC, butyllithium (25 mmol) in hexanes
(15.6 mL) was added dropwise to a solution of 2-bromo-
benzaldehyde acetal (5.00 mL, 6.48 g, 25 mmol) in tetra-
hydrofuran (125 mL). After 40 min N,N,N0,N0-tetra-
methylethylenediamine (3.73 mL, 25 mmol) and (1R,2S,
5R)-(ꢀ)-menthyl-(S)-p-toluenesulfinate (6.47 g, 22 mmol)
was added. After 3 h, saturated aqueous NH4Cl (100 mL)
was added, followed by extraction with diethylether
(3 · 100 mL). The combined organic layers were dried, fil-
tered, and evaporated. The yellow oil was purified by chro-
matography on silica gel (DEE/cHex 1:1) to afford 2-(S)-
(p-tolylsulfinyl)benzaldehyde diethyl acetal; 6.68 g (84%)
1
as a colorless oil. H NMR (CDCl3, 300 MHz): d = 7.95
(dd, J = 6.9, 2.1 Hz, 1H), 7.64 (dd, J = 7.0, 2.1 Hz, 1H),
7.55 (d, J = 8.3 Hz, 2H), 7.50–7.43 (m, 2H), 7.22 (d,
J = 7.9 Hz, 2H), 5.74 (s, 1H), 3.71–3.45 (m, 4H), 2.35 (s,
3H), 1.26 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H).
4.2.1.2. (S)-2-(p-Tolylsulfinyl)benzaldehyde 1. A mix-
ture of pyridinium p-toluensulfonate (3.00 g, 11.94 mmol)
and 2-(S)-(p-tolylsulfinyl)benzaldehyde diethyl acetal from
Section 4.2.1.1 (5.00 g, 15.72 mmol) was dissolved in a mix-
ture of water (30 mL) and acetone (450 mL). The solution
was heated under reflux. After 4 h, the solution was evap-
orated and more water (100 mL) was added, followed by
extraction with EtOAc (3 · 200 mL). The combined organ-
ic layers were dried and evaporated. The yellow solid was
purified by crystallization from hexanes, which afforded
1; 3.15 g (82%) as yellow solid. Mp 87–91 ꢁC,
4.2.3. (S)-1-(2-(p-Tolylsulfinyl)phenyl)ethanone 4
4.2.3.1. 2-(2-Bromophenyl)-2-methyl-1,3-dioxolane.
A
mixture of 1-(2-bromophenyl)ethanone (16.97 mL, 25.05 g,
125.80 mmol), p-TSOH (1.20 g, 6.29 mmol) and ethane-
1,2-diol (10.52 mL, 11.72 g, 188.76 mmol) was dissolved in
benzene (300 mL). The solution was heated at reflux for
2 h. Water (200 mL) was added followed by extraction with
EtOAc (3 · 200 mL). The combined organic layers were
dried and evaporated to afford 2-(2-bromophenyl)-2-
methyl-1,3-dioxolane; 28.48 g (93%). 1H NMR (CDCl3,
300 MHz): d = 7.53 (d, J = 7.9 Hz, 1H), 7.44 (d, J =
7.7 Hz, 1H), 7.14 (t, J = 6.4 Hz, 1H), 6.99 (t, J = 7.2 Hz,
1H), 3.90 (s, 2H), 3.60 (s, 2H), 1.67 (s, 3H).
1
[a]D = ꢀ278 (c 1, acetone). H NMR (CDCl3, 300 MHz):
d = 10.00 (s, 1H), 8.52 (d, J = 8.3 Hz, 1H), 7.92–7.86 (m,
2H), 7.68 (ddd, J = 7.5, 7.4, 1.1 Hz, 1H), 7.59 (d,
J = 8.3 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 2.31 (s, 3H).
4.2.2. (S)-2-Methoxy-6-(p-tolylsulfinyl)benzaldehyde 3
4.2.2.1. (S)-1-Methoxy-3-(p-tolylsulfinyl)benzene. At
ꢀ75 ꢁC, butyllithium (25 mmol) in hexanes (15.6 mL) was
added to a solution of 3-bromoanisole (3.17 mL, 4.68 g,
25 mmol) in diethyl ether (50 mL). After 30 min, the
4.2.3.2.
(S)-2-Methyl-2-(2-(p-tolylsulfinyl)phenyl)-1,3-
dioxolane. At ꢀ78 ꢁC, butyllithium (25 mmol) in hexanes
(15.6 mL) was added dropwise to a solution of 2-(2-bromo-
phenyl)-2-methyl-1,3-dioxolane from Section 4.2.3.1
(6.08 g, 25 mmol) in tetrahydrofuran (125 mL). After

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A. Novodomska et al. / Tetrahedron: Asymmetry 18 (2007) 1628–1634
1632
40 min N,N,N0,N0-tetramethylethylenediamine (3.73 mL,
25 mmol) and (1R,2S,5R)-(ꢀ)-menthyl-(S)-p-toluenesulfi-
nate (6.47 g, 22 mmol) was added. After 3 h, saturated
aqueous solution of ammonium chloride (100 mL) was
added, followed by extraction with diethylether (3 ·
100 mL). The combined organic layers were dried and
evaporated. The oily residue was purified by chromatogra-
phy on silica gel (DEE/cHex 1:1) to afford (S)-2-methyl-2-
d = 7.93–7.80 (m, 1H), 7.51–7.39 (m, 3H), 7.28–7.19 (m,
3H), 7.04 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 8.1 Hz, 1H),
6.78–6.72 (m, 2H), 6.52 (d, J = 4.2 Hz, 1H), 3.81 (s, 3H),
3.30 (d, J = 4.2 Hz, 1H), 2.28 (s, 3H). 13C NMR (CDCl3,
75 MHz): d = 156.7, 143.7, 141.5, 141.1, 140.8, 130.9,
130.1, 129.5, 129.0, 128.9, 128.5, 127.8, 125.8, 125.2,
120.6, 110.5, 68.2, 55.4, 21.3. Anal. Calcd for C21H20O3S
(352.45): C, 71.56; H, 5.72. Found: C, 71.13; H, 5.64.
1
(2-(p-tolylsulfinyl)phenyl)-1,3-dioxolane; 4.47 g (59%). H
NMR (CDCl3, 300 MHz): d = 9.33 (dd, J = 7.9, 1.1 Hz,
1H), 7.58–7.41 (m, 5H), 7.18 (d, J = 7.9 Hz, 2H), 4.02–
3.93 (m, 1H), 3.73 (symm. m, 2H), 3.16–3.02 (m, 1H),
2.32 (s, 3H), 1.48 (s, 3H). 13C NMR (CDCl3, 75 MHz):
d = 143.5, 142.4, 141.1, 130.6, 129.5, 129.2, 127.0, 126.6,
125.1, 108.9, 64.2, 63.9, 27.3, 21.3. Anal. Calcd for
C17H18O3S (302.39): C, 67.52; H, 6.00. Found: C, 67.70;
H, 6.08.
4.3.3. (R)-(4-Methoxyphenyl)(2-((S)-p-tolylsulfinyl)phenyl)-
20
methanol 2d. 0.22 g (62%); mp 127–131 ꢁC, ½aꢁD ¼ ꢀ108
(c 0.3, CHCl3). 1H NMR (CDCl3, 300 MHz): d = 7.79
(dd, J = 7.4, 1.7 Hz, 1H), 7.60 (dd, J = 7.4, 1.5 Hz, 1H),
7.51–7.40 (m, 2H), 7.14–7.06 (m, 6H), 6.76 (d, J =
8.7 Hz, 2H), 6.38 (s, 1H), 3.77 (s, 3H), 2.68 (br s, 1H),
2.31 (s, 3H). 13C NMR (CDCl3, 75 MHz): d = 159.3,
143.0, 142.6, 141.2, 134.5, 131.5, 129.7, 128.9, 128.7,
127.6, 126.0, 125.6, 113.9, 71.7, 55.3, 21.3. Anal. Calcd
for C21H20O3S (382.12): C, 71.56; H, 5.72. Found: C,
71.34; H, 5.66.
4.2.3.3. (S)-1-(2-(p-Tolylsulfinyl)phenyl)ethanone 4. (S)-
2-Methyl-2-(2-(p-tolylsulfinyl)phenyl)-1,3-dioxolane (6.94 g,
23 mmol) from Section 4.2.3.2 and PTSA (2.62 g,
13.77 mmol) was dissolved in a mixture of acetone (0.5 L)
and water (33 mL). After 3 h, more PTSA was added and
the solution was heated at reflux for 4 h. Water (200 mL)
was added followed by extraction with EtOAc
(3 · 200 mL). The combined organic layers were dried and
evaporated. The solid was washed with ethyl acetate to
afford 4 as a colorless solid; 3.47 g (57%); mp 136–140 ꢁC.
1H NMR (CDCl3, 300 MHz): d = 8.59 (dd, J = 7.9,
0.9 Hz, 1H), 7.91 (dd, J = 7.7, 1.1 Hz, 1H), 7.86 (td,
J = 7.5, 1.3 Hz, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.59 (s,
1H), 7.18 (d, J = 7.9 Hz, 2H), 2.56 (s, 3H), 2.31 (s, 3H).
13C NMR (CDCl3, 75 MHz): d = 197.5, 148.6, 143.7,
140.9, 133.9, 133.8, 130.6, 130.2, 129.5, 126.7, 125.2, 21.3.
Anal. Calcd for C15H14O2S (258.07): C, 69.74; H, 5.46.
Found: C, 69.76; H, 5.65.
4.3.4. (R)-(2,6-Dimethoxyphenyl)(2-((S)-p-tolylsulfinyl)phen-
20
yl)methanol 2e. 0.23 g (61%); mp 163–166 ꢁC, ½aꢁD
¼
ꢀ128 (c 0.3, CHCl3). 1H NMR (CDCl3, 300 MHz):
d = 8.15 (dd, J = 7.9, 1.3 Hz, 1H), 7.53 (d, J = 8.1 Hz,
2H), 7.42 (ddd, J = 8.1, 0.8 Hz, 1H), 7.28–7.19 (m, 4H),
6.91 (d, J = 7.7 Hz, 1H), 6.57 (d, J = 8.3 Hz, 2H), 6.23
(d, J = 11.5 Hz, 1H), 4.34 (d, J = 11.5 Hz, 1H), 3.70 (s,
6H), 2.36 (s, 3H). 13C NMR (CDCl3, 75 MHz):
d = 157.8, 144.5, 142.6, 141.6, 140.8, 130.0, 129.6, 128.0,
126.6, 126.3, 124.9, 117.6, 104.5, 67.2, 55.8, 21.3. Anal.
Calcd for C22H22O4S (382.47): C, 69.09; H, 5.80. Found:
C, 69.29; H, 5.81.
4.3.5.
(R)-o-Tolyl(2-((S)-p-tolylsulfinyl)phenyl)methanol
20
2f. 0.20 g (59%); mp 165–170 ꢁC, ½aꢁD ¼ ꢀ216 (c 0.5,
1
CHCl3). H NMR (CDCl3, 300 MHz): d = 7.72–7.69 (m,
4.3. General procedure for the coupling
1H), 7.46–7.39 (m, 3H), 7.32–7.06 (m, 7H), 6.58 (d,
J = 4.3 Hz, 1H), 2.75 (d, J = 4.5 Hz, 1H), 2.32 (s, 3H),
2.24 (s, 3H). 13C NMR (CDCl3, 75 MHz): d = 143.3,
142.0, 141.6, 140.3, 139.7, 135.9, 131.3, 130.7, 129.8,
128.8, 128.0, 127.7 (d, J = 2.2), 126.2, 125.9, 125.7, 69.1,
21.3, 19.0. Anal. Calcd for C21H20O2S (336.45): C, 74.97;
H, 5.99. Found: C, 74.62; H, 5.99.
A mixture of 2-p-(tolylsulfinyl)benzaldehyde 1 (0.244 g,
1.00 mmol), Pd2(dba)3ÆCHCl3 (0.052 g, 5 mol %), tri-
phenylphosphine (0.026 g, 10 mol %), boronic acid
(2.00 mmol, 2 equiv) and cesium carbonate (0.326 g,
1.00 mmol) was dissolved in toluene (2 mL) and stirred
under argon. 15 min later, the mixture was heated at
120 ꢁC. After 2 h, water (5 mL) was added, followed by
extraction with ethyl acetate (3 · 10 mL). The combined
organic layers were dried and evaporated. The compound
was purified by chromatography on silica gel (EtOAc/
cHex = 3:2) and crystallized from hexanes.
4.3.6. (R)-(2-Methoxy-5-methylphenyl)(2-((S)-p-tolylsulfin-
yl)phenyl)methanol 2g. 0.18 g (50%); mp 154–158 ꢁC,
20
½aꢁD ¼ ꢀ59:6 (c 0.5, CHCl3). 1H NMR (CDCl3,
300 MHz): d = 7.97 (d, J = 6.4 Hz, 1H), 7.53–7.43 (m,
3H), 7.24 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H),
6.98 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 8.3 Hz, 1H), 6.46
(d, J = 4.1 Hz, 1H), 6.38 (d, J = 1.7 Hz, 1H), 3.80 (s,
3H), 3.37 (br s, 1H), 2.27 (s, 3H), 2.06 (s, 3H). 13C NMR
(CDCl3, 75 MHz): d = 154.7, 143.5, 141.1, 140.6, 130.9,
129.7, 129.4, 129.2, 129.1, 128.8, 127.8, 125.9, 124.9,
110.4, 68.2, 55.5, 30.9, 21.2, 20.3. Anal. Calcd for
C22H22O3S (366.13): C, 72.10; H, 6.05. Found: C, 71.52;
H, 6.42.
4.3.1.
(R)-Phenyl(2-((S)-p-tolylsulfinyl)phenyl)methanol
2a. 0.22 g, (67%). 1H NMR (CDCl3, 300 MHz): d =
7.76 (dd, J = 7.50, 1.68 Hz, 1H), 7.60–7.04 (m, 13H), 6.43
(s, 1H), 2.33 (s, 3H). 13C NMR (CDCl3, 75 MHz):
d = 142.5, 142.2, 141.3, 131.4, 129.7, 128.9, 128.5, 127.9,
127.7, 127.3, 125.5, 71.7, 21.3. Anal. Calcd for C20H18O2S
(322.10): C, 74.50; H, 5.63. Found: C, 74.71; H, 5.46.
4.3.2. (R)-(2-Methoxyphenyl)(2-((S)-p-tolylsulfinyl)phenyl)-
¼
4.3.7. (R)-(2-Methoxynaphthalen-1-yl)(2-((S)-p-tolylsulfin-
yl)phenyl)methanol 2p. 0.22 g (55%); mp 178–182 ꢁC,
20
methanol 2b. 0.18 g, (51%); mp 173–176 ꢁC; ½aꢁD
20
ꢀ127:6 (c 0.5, CHCl3). 1H NMR (CDCl3, 300 MHz):
½aꢁD ¼ þ5:2 (c 0.5, CHCl3). H NMR (CDCl3, 300 MHz):
1

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A. Novodomska et al. / Tetrahedron: Asymmetry 18 (2007) 1628–1634
1633
d = 8.26 (dd, J = 7.9, 1.3 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H),
7.78 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.4 Hz, 2H), 7.39 (d,
J = 8.5 Hz, 1H), 7.34–7.20 (m, 7H), 6.82 (d, J = 7.7 Hz,
1H), 6.40 (s, 1H), 4.41 (br s, 1H), 3.87 (s, 3H), 2.42 (s,
3H). 13C NMR (CDCl3, 75 MHz): d = 155.2, 144.1, 141.7,
141.6, 141.1, 131.9, 130.6, 130.2, 129.8, 129.3, 128.6,
128.2, 127.3, 127.1, 127.0, 125.2, 123.8, 122.7, 121.8,
113.4. Anal. Calcd for C25H22O3S (402.13): C, 74.60; H,
5.51. Found: C, 74.95; H, 5.71.
nol 6b was obtained after chromatography on silica gel
(EtOAc/cHex = 1:4) followed by crystallization from
EtOAc/hexanes. Colorless needles. 46.5 mg (57%); mp
89–91 ꢁC; [a]D = ꢀ116.7 (c 0.8, CDCl3). 1H NMR (CDCl3,
300 MHz): d = 7.75 (d, J = 7.6 Hz, 1H), 7.43–7.39 (m, 2H),
7.26–7.21 (m, 2H), 6.56 (d, J = 7.1 Hz, 2H), 6.03 (s, 1H),
3.71 (s, 6H), 3.44 (s, 3H), 2.12 (s, 3H). 13C NMR (CDCl3,
75 MHz): d = 159.2, 142.8, 139.9, 135.1, 129.7, 129.4,
127.5, 126.1, 125.9, 124.6, 116.5, 104.8, 74.2, 57.1, 55.9,
19.0. Anal. Calcd for C17H20O3 (272.34): C, 74.97; H,
7.40. Found: C, 75.11; H, 7.51.
4.4. Sulfoxide–lithium exchange
4.4.1. Preparation of 1,3-dimethoxy-2-((R)-methoxy(2-((S)-
p-tolylsulfinyl)phenyl)methyl)benzene 5. Sodium hydride
(0.11 g, 2.87 mmol) was added to the carbinol 2e (0.91 g,
2.39 mmol) in tetrahydrofuran (6.41 mL) at 0 ꢁC. After
10 min, methyl iodide (0.3 mL, 0.68 g, 4.78 mmol) was
added and the reaction mixture then allowed to reach
25 ꢁC. After 1 h, the same amount of sodium hydride and
methyl iodide was added and the reaction stirred for an-
other 1 h. Water (5 mL) was carefully added, followed by
extraction with diethyl ether (3 · 10 mL). The combined
organic layers were dried and evaporated. The residue
was purified by chromatography on silica gel (EtOAc/
cHex = 1:1) and crystallization from hexanes afforded 5
as colorless needles; 0.61 g (64%); mp 148–151 ꢁC,
[a]D = ꢀ316 (c 0.5, CHCl3). 1H NMR (CDCl3,
300 MHz): d = 7.76 (dd, J = 7.54, 1.32 Hz, 1H), 7.68 (d,
J = 7.54 Hz, 1H), 7.42–7.30 (m, 2H), 7.20 (t, J = 7.98 Hz,
1H), 7.03 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.28 Hz, 2H),
6.45 (d, J = 8.28 Hz, 2H), 6.38 (s, 1H), 3.62 (s, 6H), 3.37
(s, 3H), 2.28 (s, 3H). 13C NMR (CDCl3, 75 MHz):
d = 159.0, 142.6, 142.4, 141.4, 140.2, 130.2, 129.8, 129.3,
127.7, 125.4, 125.0, 117.1, 104.6, 73.5, 57.0, 55.7, 21.1.
Anal. Calcd for C23H24O4S (396.14): C, 69.67; H, 6.10.
Found: C, 69.83; H, 6.22.
Acknowledgments
`
We are grateful to the CNRS and Ministere de la Recher-
che. A.N. and M.D. are grateful for a SOCRATES/ERAS-
MUS fellowship.
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10 min, iodomethane (0.09 mL, 0.212 g, 1.50 mmol) was
added. At 25 ꢁC, water (10 mL) was added followed by
extraction with diethyl ether (3 · 10 mL). The combined
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A. Novodomska et al. / Tetrahedron: Asymmetry 18 (2007) 1628–1634
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´
19. We thank Dr Andre DeCian for his assistance with the
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