Meta- and para-difunctionalization of arenes via an ortho-magnesiation and a subsequent sulfoxide-magnesium exchange

Article abstract of DOI:10.1055/s-0028-1087984

Highly functionalized 1,2,4-trisubstituted arenes can be prepared on large scale by a two-step sequence, triggered by an aryl sulfoxide group. In the first step, the sulfoxide moiety acts as a metalation directing group, allowing a smooth magnesiation wit

Full text of DOI:10.1055/s-0028-1087984

PRACTICAL SYNTHETIC PROCEDURES
1041
Meta- and Para-Difunctionalization of Arenes via an Ortho-Magnesiation and
a Subsequent Sulfoxide–Magnesium Exchange
Synthesis of
H
ig
a
hly Functi
u
onalized 1,2,
r
4-Trisub
i
stitute
d
n
A
renes Melzig, Christian B. Rauhut, Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München,
Butenandtstraße 5–13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
PSP
Received 29 September 2008; revised 29 October 2008
No152
Abstract: Highly functionalized 1,2,4-trisubstituted arenes can be prepared on large scale by a two-step sequence, triggered by an aryl
sulfoxide group. In the first step, the sulfoxide moiety acts as a metalation directing group, allowing a smooth magnesiation with tmp-
MgCl·LiCl. After a quenching reaction with an electrophile, the resulting sulfoxide is converted with i-PrMgCl·LiCl into a second magne-
sium reagent (sulfoxide–magnesium exchange), which can be trapped with various electrophiles. The highly chemoselective tmpMgCl·LiCl
and i-PrMgCl·LiCl are compatible with a broad range of functional groups (FG = F, Cl, CF3, CN, CO2t-Bu, alkynyl).
Key words: metalation, ortho-magnesiation, sulfoxide–magnesium exchange, polyfunctional Grignard reagents
Procedure 1:
Ar1
Cl
Cl
O
Ar1
O
Br
S
1) tmpMgCl•LiCl (1)
THF, –30 °C, 20 min
2) ZnCl2
S
CHO
CF3
1) iPrMgCl•LiCl (2)
1) iPrMgCl•LiCl (2)
2-Me-THF, –50 °C
THF, 25 °C, 16 h
Ar1SOCl
2)
3) Pd(dba)2, tfp cat
2) DMF
–20 °C to 25 °C
79%
(100 mmol scale)
83%
(25 mmol scale)
CF3
CF3
CF3
5a: Ar1 = 4-MeOC6H4
Cl
I
3a: Ar1 = 4-MeOC6H4
8a
75%
(35 mmol scale)
CO2Et
Procedure 2:
O
Ar1
O
Ar1
1) iPrMgCl•LiCl (2)
2-Me-THF, –50 °C
2) ZnCl2
1) tmpMgCl•LiCl (1)
THF, –30 °C, 20 min
2) I2
MgBr
S
F
S
F
TMS
TMS
Ar1SOCl, THF
–20 °C to 25 °C
3) Pd(dba)2, tfp cat
EtO2C
3) Pd(dba)2, tfp cat
TMS ZnCl
91%
(100 mmol scale)
F
F
I
86%
(40 mmol scale)
86%
(34 mmol scale)
3b: Ar1 = 4-MeOC6H4
5b: Ar1 = 4-MeOC6H4
8b
Scheme 1
source of a carbon–metal bond by performing a sulf-
Introduction
oxide–magnesium exchange using i-PrMgCl·LiCl4b (2).
Highly functionalized arenes have found numerous appli- Both reagents tmpMgCl·LiCl (1) and i-PrMgCl·LiCl (2)
cations in the preparation of pharmaceuticals and in mate- have found to be compatible with a broad range of func-
rials science.1 Arylorganometallic intermediates are tional groups (FG = F, Cl, CF3, CN, CO2t-Bu, alkynyl,
especially versatile reagents for the functionalization of etc).
aromatics. They can be prepared by a directed ortho-met-
The sulfoxide–metal exchange has already been used in
alation,2 a metal insertion,3 a halogen–metal exchange,4 or
synthetic organic chemistry for performing a ligand ex-
a sulfoxide–metal exchange.5–7 In this last approach the
change on pyridyl or quinolyl systems,5 for generating
sulfoxide function may serve two purposes: (i) it may act
various carbenoids starting from a-chlorosulfoxides or a-
as an ortho-directing group8 using tmpMgCl·LiCl (1)9 for
thiosulfoxides6 and for racemic resolution.7 Recently, we
ensuring a smooth magnesiation, and (ii) it may be the
reported an efficient two-step synthesis for the generation
of 1,2,4-trisubstituted arenes, starting from sulfoxides of
type 3 (Scheme 2).10
SYNTHESIS 2009, No. 6, pp 1041–1048
x
x
.
x
x
.2
0
0
9
Advanced online publication: 02.03.2009
DOI: 10.1055/s-0028-1087984; Art ID: T16908SS
© Georg Thieme Verlag Stuttgart · New York

1042
step 1
L. Melzig et al.
PRACTICAL SYNTHETIC PROCEDURES
According to these expedient procedures the sulfoxides
5e,f were prepared in 79–81% yield.
Ar1
O
Ar1
O
Ar1
S
O
S
S
The third step of the synthetic sequence (Scheme 1), that
is, the sulfoxide–magnesium exchange was >95% regi-
oselective, providing only the desired functionalized
aromatic magnesium reagents, and not the 4-methoxy-
phenylmagnesium chloride or 4-(dimethylamino)phenyl-
magnesium chloride.
MgCl
E1
E1
tmpMgCl•LiCl (1)
THF, –30 °C,
20 min
FG
FG
FG
3
4
5
step 2
Ar1
S
O
Thus, sulfoxide 5a (25 mmol) was treated with i-PrMgCl·LiCl
(2; 1.1 equiv, –50 °C, 1.5 h) leading to the corresponding
functionalized magnesium reagent, which reacted
smoothly with DMF (0.8 equiv, –50 to 25 °C, 30 min)
giving the aldehyde 8a in 83% yield (Table 1, entry 1).
The alkynyl substituted sulfoxide 5b (34 mmol) displayed
a higher reactivity, allowing to perform the sulfoxide–
magnesium exchange within 5 minutes at –50 °C. The re-
sulting magnesium compound provided after Negishi
cross-coupling the biphenyl 8b in 86% yield (entry 2).
This high reactivity of the ortho-alkynated sulfoxides
allows to perform the sulfoxide–magnesium exchange
with the ester-functionalized sulfoxide 5c, which after a
subsequent reaction with DMF gave the aldehyde 9c in
78% yield (entry 3). The cyano-substituted sulfoxide 5d
underwent a rapid sulfoxide–magnesium exchange (–50 °C,
5 min), leading to the aldehyde 8d in 72% yield (entry 4).
The bis-alkynylated sulfoxide 5e led after a sulfoxide–
magnesium exchange (–50 °C, 5 min) and after an addi-
tion to 3,4-dichlorobenzaldehyde to the alcohol 8e in 72%
yield (entry 5). In contrast, the sterically hindered sulfox-
ide 5f required seven hours at –50 °C for completing the
sulfoxide–magnesium exchange. Reaction with ethyl 2-
(bromomethyl)acrylate12 furnished the acrylate 8f in 60%
yield (entry 6).
MgCl
E2
iPrMgCl•LiCl (2),
2-Me-THF, –50 °C
E1
E1
E1
E2
O
–
(6)
S
Ar1
iPr
FG
FG
FG
5
7
8
Ar1 = 4-MeOC6H4 or 4-Me2NC6H4
tmp = 2,2,6,6-tetramethylpiperidyl
Scheme 2
Herein, we report an extension of this reaction sequence
as well as its scale-up allowing a convenient synthesis of
1,2,4-trisubstituted arenes. Thus, by treating a diaryl
sulfoxide of type 3 with tmpMgCl·LiCl (1; 1.1 equiv) at
–30 °C for 20 minutes, a smooth ortho-magnesiation oc-
curred and the intermediate magnesium reagent 4 was
formed. Its quenching with an electrophile (E1) led to
functionalized sulfoxides of type 5. Performing the sulf-
oxide–magnesium exchange with i-PrMgCl·LiCl (2; 1.1
equiv) at –50 °C for five minutes to seven hours furnished
the magnesium reagent 7. Remarkably, a selective cleav-
age of the carbon–sulfoxide bond occurs giving only
(>95%) 7 and not Ar1MgCl. This may be explained by the
presence of the donor substituent (OMe or NMe2) of Ar1,
which destabilizes Ar1MgCl compared to the arylmagne-
sium compound 7. The addition of a second electrophile
(E2) to the magnesium reagent 7 led to various polyfunc-
tionalized arenes of type 8 (Table 1).
Preparation of the Starting Sulfoxides
The starting functionalized diaryl sulfoxides 3a–f were
prepared by convenient one- or two-step syntheses. The
reaction of arylmagnesium reagents, obtained by
insertion3 or halogen–magnesium exchange4 with 4-meth-
oxybenzenesulfinyl chloride13 was performed on 15–
100 mmol scale leading to the sulfoxides 3a–e in 70–98%
yield. Alternatively, the sulfoxide 3f was prepared by the
reaction of 4-(dimethylamino)phenyl thiocyanate14 (9)
with 4-chlorophenylmagnesium bromide (10). Subse-
quent oxidation of the resulting crude sulfide performed
on large scale (100 mmol) provided the sulfoxide 3f in
64% yield (Scheme 3).
Scope and Limitations
In all cases, the sulfoxides 3a–f were metalated with tmp-
MgCl·LiCl (1, 1.1 equiv, –30 °C, 20 min) and functional-
ized by Negishi11 cross-couplings. Thus, the
trifluoromethyl-substituted sulfoxide 3a (35 mmol scale)
was deprotonated (–30 °C, 20 min) and after addition of
zinc chloride coupled with 4-chloro-1-iodobenzene (1.2
equiv) in the presence of Pd(dba)2 (1 mol%) and tfp (2
mol%; 7 h, 50 °C), furnishing the biphenyl 5a in 75%
yield (Table 1). The fluorinated sulfoxide 3b (40 mmol
scale) was metalated, trapped with iodine and reacted in
situ with 2-(trimethylsilyl)ethynylzinc chloride11c in the
presence of Pd(PPh3)4 (2 mol%; 2 h, 50 °C) giving the sul-
foxide 5b in 86% yield. The ester 3c was deprotonated
and underwent a similar Negishi cross-coupling, leading
to the sulfoxide 5c in 68% yield. Magnesiation of 3d,
transmetalation with zinc chloride and cross-coupling
with 4-bromo-N,N-dimethylaniline gave 5d in 84% yield.
NMe2
1)
Me2N
SCN (9)
MgBr
O
S
THF, –20 °C to 25 °C
2) m-CPBA, CH2Cl2, –20 °C
Cl
Cl
64%
10
(100 mmol scale)
3f
Scheme 3
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Conclusion
Synthesis of Highly Functionalized 1,2,4-Trisubstituted Arenes
1043
The use of tmpMgCl·LiCl (1) and i-PrMgCl·LiCl (2) al-
lows a compatibility with a wide range of functional
In summary, we have developed an efficient protocol, on groups (FG = F, Cl, CF3 CN, CO2t-Bu, alkynyl). Further
a multigram scale, for the preparation of polyfunctional- extensions of this method are underway in our laborato-
ized diaryl sulfoxides and the consecutive sulfoxide–mag- ries.
nesium exchange leading to 1,2,4-trisubstituted arenes.
Table 1 Functionalization of Diaryl Sulfoxides and Sulfoxide–Magnesium Exchange Followed by Reaction with an Electrophile
Sulfoxide
E1
Sulfoxide, yield (%)a
E2
Product, yield (%)a
Cl
Cl
I
O
S
O
3a
5a
DMF
8a
CHO
S
F3C
OMe
Cl
F3C
OMe
F3C
75b,c,d
83e
TMS
TMS
I
O
S
CO2Et
O
i) I2
ii)
3b
5b
8b
8c
S
TMS
ZnCl
F
OMe
CO2Et
F
86b,c
OMe
F
86d,e
TMS
TMS
O
S
O
i) I2
ii)
3c
5c
DMF
DMF
S
CHO
TMS
ZnCl
t-BuO2C
OMe
t-BuO2C
OMe
t-BuO2C
68
78
F
F
F
I
O
S
O
3d
5d
8d
8e
8f
CHO
S
NC
OMe
NC
NC
71d
TMS
OMe
72
TMS
CHO
O
S
O
S
OH
i) I2
ii)
Cl
Cl
3e
5e
TMS
ZnCl
OMe
Cl
OMe
TMS
Cl
TMS
81
TMS
72
CO2t-Bu
CO2t-Bu
I
O
Br
S
O
3f
5f
S
CO2Et
CO2Et
Cl
NMe2
CO2t-Bu
Cl
NMe2
Cl
60f
79b,d
a Yield of analytically pure product.
b The starting material of type 1 was prepared on a 100 mmol scale.
c This functionalization was performed on a >35 mmol scale.
d A transmetalation using ZnCl2 (1.0 M in THF) was performed.
e The sulfoxide–magnesium exchange was performed on a >25 mmol scale.
f CuCN·2LiCl (5 mol%, 1.0 M in THF) was used as catalyst.
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York

1044
L. Melzig et al.
PRACTICAL SYNTHETIC PROCEDURES
Procedures
type 5 (1.00 mmol) in 2-methyltetrahydrofuran (2 mL). The reac-
tion mixture was cooled to –50 °C and i-PrMgCl·LiCl (920 mL, 1.10
mmol, 1.20 M in THF) was added dropwise. After stirring at –50 °C
until GC analysis showed full conversion of the sulfoxide, the de-
sired electrophile (0.8 mmol) was added and the mixture was stirred
at the given temperature until GC analysis showed full conversion
of the electrophile. The mixture was quenched with a sat. aq NH4Cl
(5 mL) and extracted with EtOAc (3 × 10 mL). The combined or-
ganic layers were dried (MgSO4) and after filtration, the solvent was
removed under reduced pressure. Flash chromatographic purifica-
tion yielded the products of type 8.
All reactions were carried out under argon in dried glassware. All
starting materials were purchased from commercial suppliers and
used without further purification, unless otherwise stated. THF was
continuously refluxed and freshly distilled from sodium benzophe-
none ketyl under N2. Yields refer to isolated compounds estimated
to be >95% pure as determined by 1H NMR and capillary GC anal-
ysis.
Sulfoxides of Type 3a–e; General Procedure (GP 1)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with a solution (approx. 0.5 M,
10.0 mmol) of the appropriate magnesium reagent and cooled to
–20 °C. 4-Methoxybenzenesulfinyl chloride (2.48 g, 13.0 mmol)
was added slowly and the reaction mixture was allowed to warm to
25 °C. The mixture was quenched with sat. aq NH4Cl (50 mL) and
extracted with EtOAc (3 × 50 mL). The combined organic layers
were dried (MgSO4) and after filtration, the solvent was removed
under reduced pressure. Flash chromatographic purification yielded
the products 3a–e.
Procedure 1
4-Methoxyphenyl 4-(Trifluoromethyl)phenyl Sulfoxide (3a)
According to GP 1, sulfoxide 3a was prepared from 4-trifluoro-
methylphenylmagnesium bromide (100 mL, 100 mmol, 1.00 M in
THF) and 4-methoxybenzenesulfinyl chloride (24.8 g, 130 mmol)
and purified by flash chromatography (silica gel, pentane–
Et2O, 1:1), furnishing 3a as a colorless solid; yield: 23.7 g (79%);
mp 92–94 °C.
IR (ATR): 1592 (s), 1575 (m), 1491 (s), 1398 (m), 1319 (s), 1305
(s), 1245 (vs), 1183 (s), 1172 (s), 1167 (s), 1141 (s), 1128 cm–1 (vs).
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 3 H), 6.93–6.95 (m, 2 H),
7.54–7.57 (m, 2 H), 7.67–7.71 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.4 (CH3), 115.0 (CH), 123.4 (q,
J = 274.3 Hz, CF3), 124.7 (CH), 126.1 (q, J = 3.8 Hz, CH), 127.3
(CH), 132.4 (q, J = 32.6 Hz), 135.9, 150.2, 162.4.
Deprotonation of Sulfoxides and Negishi-Type Cross-Coupling;
General Procedure (GP 2)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with a sulfoxide of type 3 (1.00
mmol) dissolved in THF (2 mL). The reaction mixture was cooled
to –30 °C and tmpMgCl·LiCl (920 mL, 1.1 mmol, 1.20 M in THF)
was added dropwise. After stirring for 20 min at –30 °C, ZnCl2
(1.00 mL, 1.00 mmol, 1.00 M in THF) was added, and the mixture
was allowed to warm to 25 °C. A Pd catalyst and an electrophile
were added and the mixture was stirred between 25 and 50 °C de-
pending upon the substrate. The mixture was quenched with sat. aq
NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were dried (MgSO4) and after filtration, the
solvent was removed under reduced pressure. Flash chromato-
graphic purification yielded the products of type 5.
MS (EI, 70 eV): m/z (%) = 300 (24), 284 (11), 253 (16), 252 (100),
237 (12), 155 (95), 139 (29), 123 (59), 92 (10).
HRMS (EI): m/z calcd for C14H11F3O232S: 300.0432; found:
300.0427.
4¢-Chloro-5-(trifluoromethyl)biphenyl-2-yl 4-Methoxyphenyl
Sulfoxide (5a)
According to GP 2, sulfoxide 5a was prepared starting from sulfox-
ide 3a (35.0 mmol, 10.5 g), using Pd(dba)2 (201 mg, 350 mmol), tri-
2-furylphosphine (tfp, 162 mg, 700 mmol) and 4-chloro-1-iodoben-
zene (10.02 g, 42.0 mmol) for the cross-coupling. The reaction mix-
ture was stirred for 7 h at 50 °C. Flash chromatographic purification
(silica gel, pentane–Et2O, 1:1) afforded a colorless solid; yield: 10.8
g (75%); mp 113–115 °C.
Functionalization of Sulfoxides with Alkynyl Substrates; Gen-
eral Procedure (GP 3)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with a sulfoxide of type 3 (10.0
mmol) dissolved in THF (20 mL). The reaction mixture was cooled
to –30 °C and tmpMgCl·LiCl (9.20 mL, 11.0 mmol, 1.20 M in THF)
was added dropwise. After stirring for 20 min at –30 °C, I2 (3.05 g,
12.0 mmol) was added and the mixture was allowed to warm to
25 °C. The mixture was then diluted with EtOAc (200 mL) and
washed with sat. aq Na2S2O3 (100 mL). The organic layer was dried
(MgSO4) and after filtration, the solvent was removed under re-
duced pressure. The crude product was dried in high vacuum for 3
h and then dissolved in THF (20 mL). In a second dry and argon
flushed Schlenk flask, equipped with a magnetic stirrer and a sep-
tum, the desired alkyne (11.0 mmol) was added slowly to i-
PrMgCl·LiCl (8.80 mL, 10.5 mmol, 1.20 M in THF). After cessa-
tion of gas evolution, the mixture was heated to 60 °C for 5 min. Af-
ter cooling to 25 °C, a ZnCl2 solution (11.0 mL, 11.0 mmol, 1.0 M
in THF) was added slowly. The resulting zinc reagent was trans-
ferred to the previously prepared crude sulfoxide and a Pd catalyst
was added. The mixture was stirred at the given temperature and
quenched with sat. aq NH4Cl (50 mL) and extracted with EtOAc (3
× 50 mL). The combined organic layers were dried (MgSO4) and af-
ter filtration, the solvent was removed under reduced pressure.
Flash chromatographic purification yielded the products of type 5.
IR (ATR): 1594 (m), 1578 (w), 1412 (m), 1327 (s), 1307 (m), 1292
(m), 1253 (s), 1240 (m), 1174 (s), 1135 (vs), 1089 (s), 1075 (s),
1044 (s), 1023 (s), 1012 cm–1 (s).
1H NMR (600 MHz, CDCl3): d = 3.74 (s, 3 H), 6.71 (d, J = 8.6 Hz,
2 H), 6.95 (d, J = 8.6 Hz, 2 H), 7.05 (d, J = 8.6 Hz, 2 H), 7.34 (d,
J = 8.6 Hz, 2 H), 7.41 (s, 1 H), 7.86–7.87 (m, 1 H), 8.37 (d, J = 8.11
Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 55.4 (CH3), 114.5 (CH), 123.5 (q,
J = 272.9 Hz, CF3), 124.6 (CH), 125.4 (q, J = 3.9 Hz, CH), 127.1
(q, J = 3.7 Hz, CH), 128.1 (CH), 128.8 (CH), 130.6 (CH), 132.6 (q,
J = 32.9 Hz), 134.7, 135.0, 135.2, 139.7, 148.2, 162.1.
MS (EI, 70 eV): m/z (%) = 412 (9), 410 (23), 394 (7), 362 (9), 251
(6), 157 (5), 156 (8), 155 (100), 139 (20), 124 (30), 123 (28).
HRMS (EI): m/z calcd for C20H1435ClF3O232S: 410.0355; found:
410.0355.
4¢-Chloro-5-(trifluoromethyl)biphenyl-2-carbaldehyde (8a)
According to GP 4, the sulfoxide 5a (10.3 g, 25.0 mmol) was treat-
ed with i-PrMgCl·LiCl (2; 17.3 mL, 27.5 mmol, 1.59 M in THF) at
–50 °C for 30 min. DMF (1.47 g, 1.56 mL, 20.0 mmol) was then
added and the reaction mixture was allowed to warm to 25 °C and
stirred for an additional 4 h. Flash chromatographic purification
Sulfoxide–Magnesium Exchange Leading to Arenes of Type 8;
General Procedure (GP 4)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with a solution of sulfoxide of
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Highly Functionalized 1,2,4-Trisubstituted Arenes
1045
(silica gel, pentane– Et2O, 17:1) gave a colorless solid; yield: 4.74
g (83%); mp 58–60 °C.
Ethyl 4¢-Fluoro-2¢-[(trimethylsilyl)ethynyl]biphenyl-4-carboxy-
late (8b)
According to GP 4, the sulfoxide 5b (11.7 g, 34.0 mmol) was treat-
ed with i-PrMgCl·LiCl (2; 33.7 mL, 37.4 mmol, 1.11 M in THF) at
–50 °C for 5 min. ZnCl2 (37.4 mL, 37.4 mmol, 1.00 M in THF) was
then added and the reaction mixture was allowed to warm to 25 °C.
Ethyl 4-iodobenzoate (7.51 g, 4.52 mL, 27.2 mmol) and Pd(PPh3)4
(750 mg, 680 mmol) were added and the mixture was stirred for an
additional 4 h. Flash chromatographic purification (silica gel, pen-
tane–Et2O, 50:1) gave a yellow oil; yield: 8.09 g (86%).
IR (ATR): 2860 (w), 1696 (s), 1484 (m), 1418 (m), 1390 (m), 1332
(s), 1298 (m), 1278 (m), 1246 (s), 1200 (m), 1168 (s), 1120 (vs),
1106 (s), 1092 (s), 1074 cm–1 (vs).
1H NMR (300 MHz CDCl3): d = 7.31–7.35 (m, 2 H), 7.47–7.51 (m,
2 H), 7.68 (s, 1 H), 7.74–7.77 (m, 1 H), 8.12 (d, J = 8.2 Hz, 1 H),
9.99 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 123.3 (q, J = 272.0 Hz, CF3),
124.9 (q, J = 3.6 Hz, CH), 127.7 (q, J = 3.7 Hz, CH), 128.7 (CH),
129.1 (CH), 131.2 (CH), 134.8, 134.9 (q, J = 32.9 Hz), 135.4,
136.0, 144.8, 190.7 (CH).
IR (ATR): 2898 (w), 1475 (m), 1367 (w), 1269 (vs), 1250 (s), 1180
(m), 1156 (m), 1099 (s), 1026 (m), 959 (s), 840 (vs), 775 (s), 758
(s), 704 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 0.11 (s, 9 H), 1.38 (t, J = 7.1 Hz,
3 H), 4.38 (q, J = 7.1 Hz, 2 H), 7.00–7.07 (m, 1 H), 7.22–7.30 (m, 2
H), 7.57–7.61 (m, 2 H), 8.03–8.07 (m, 2 H).
MS (EI, 70 eV): m/z (%) = 286 (22), 285 (21), 284 (67), 283 (41),
249 (100), 220 (23), 201 (29), 152 (32).
HRMS (EI): m/z calcd for C14H835ClF3O: 284.0216; found:
13C NMR (75 MHz, CDCl3): d = –0.56 (SiCH3), 14.3 (CH3), 60.9
(CH2), 99.3, 102.8, 116.1 (d, J = 21.4 Hz, CH), 119.7 (d, J = 22.7
Hz, CH), 123.1 (d, J = 9.54 Hz, CH), 129.0 (CH), 129.2 (CH),
129.4, 130.9 (d, J = 8.8 Hz), 139.2 (d, J = 3.4 Hz), 143.8, 161.6 (d,
J = 248.2 Hz, CF), 166.3.
284.0212.
Procedure 2
4-Fluorophenyl 4-Methoxyphenyl Sulfoxide (3b)
According to GP 1, sulfoxide 3b was prepared from 4-fluorophe-
nylmagnesium bromide (100 mL, 100 mmol, 1.00 M in THF), and
4-methoxybenzenesulfinyl chloride (24.8 g, 130 mmol) and recrys-
tallized from pentane furnishing 3b as a colorless solid; yield: 22.9
g (91%); mp 83–84 °C.
MS (EI, 70 eV): m/z (%) = 341 (16), 340 (61), 325 (37), 297 (28),
295 (19), 282 (24), 280 (100), 189 (16), 140 (28), 75 (17).
HRMS (EI): m/z calcd for C20H21FO228Si: 340.1295; found:
340.1295.
IR (ATR): = 2836 (w), 1592 (s), 1577 (s), 1496 (s), 1436 (m), 1410
(m), 1311 (m), 1303 (m), 1254 (s), 1215 (s), 1154 (m), 1089 (s),
1076 (s), 1035 (s), 855 (s), 828 cm–1 (vs).
tert-Butyl 4-[(4-Methoxyphenyl)sulfinyl]benzoate (3c)
According to GP 1, sulfoxide 3c was prepared from 4-(tert-butoxy-
carbonyl)phenylmagnesium chloride (33.7 mL, 30.0 mmol, 0.89 M
in THF) and 4-methoxybenzenesulfinyl chloride (6.27 g, 33.0
mmol), and purified by flash chromatography (silica gel, pentane–
Et2O, 1:1) to give 3c as a colorless solid; yield: 9.01 g (90%); mp
73–75 °C.
1H NMR (300 MHz, CDCl3): d = 3.79 (s, 3 H), 6.92–6.95 (m, 2 H),
7.09–7.15 (m, 2 H), 7.51–7.60 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 55.4 (CH3), 114.8 (CH), 116.4 (d,
J = 22.67 Hz, CH), 126.9 (d, J = 8.85 Hz, CH), 127.0 (CH), 136.5,
141.4 (d, J = 3.04 Hz), 162.1, 164.0 (d, J = 251.2 Hz, CF).
IR (ATR): 2978 (m), 1705 (vs), 1594 (s), 1576 (m), 1366 (s), 1301
(s), 1290 (s), 1246 (vs), 1167 (s), 1121 (s), 1087 (s), 1040 (s), 1023
(s), 1011 (s), 827 cm–1 (m).
1H NMR (300 MHz, CDCl3): d = 1.36 (s, 9 H), 3.55 (s, 3 H), 6.73
(d, J = 9.0 Hz, 2 H), 7.38 (d, J = 9.0 Hz, 2 H), 7.48 (d, J = 8.8 Hz, 2
H), 7.86 (d, J = 8.8 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 27.5 (CH3), 54.9 (CH3), 80.9,
114.4 (CH), 123.5 (CH), 126 (CH), 129.6 (CH), 133.4, 135.8,
150.0, 161.7, 163.9.
MS (EI, 70 eV): m/z (%) = 251 (8), 250 (49), 233 (8), 203 (13), 202
(100), 187 (17), 154 (43), 139 (23), 123 (60), 101 (8).
HRMS (EI): m/z calcd for C13H11FO232S: 250.0464; found:
250.0470.
({5-Fluoro-2-[(4-methoxyphenyl)sulfinyl]phenyl}ethynyl)(tri-
methyl)silane (5b)
According to GP 3, sulfoxide 5b was prepared starting from sulfox-
ide 3b (10.0 g, 40.0 mmol), using Pd(PPh3)4 (880 mg, 800 mmol)
and trimethylethynylsilane (5.88 g, 8.52 mL, 60.0 mmol) for the
cross-coupling. The reaction mixture was stirred for 2 h at 50 °C.
Flash chromatographic purification (silica gel, pentane– Et2O, 1:1)
afforded a colorless solid; yield: 12.0 g (86%); mp 83–85 °C.
MS (EI, 70 eV): m/z (%) = 332 (11), 284 (30), 260 (7), 259 (6), 229
(13), 228 (100), 155 (34), 139 (45), 123 (59), 57 (7).
HRMS (EI): m/z calcd for C18H20O432S: 332.1082; found: 322.1066.
IR (ATR): 2956 (w), 1738 (m), 1591 (m), 1576 (m), 1495 (m), 1457
(s), 1249 (vs), 1217 (m), 1148 (m), 1083 (s), 1058 (s), 1037 (s), 952
(s), 846 (vs), 833 (vs), 821 cm–1 (vs).
1H NMR (300 MHz, CDCl3): d = 0.26 (s, 9 H), 3.80 (s, 3 H), 6.89–
6.92 (m, 2 H), 7.13 (dd, J = 8.8, 2.4 Hz, 1 H), 7.20–7.24 (m, 1 H),
7.59–7.63 (m, 2 H), 8.02 (dd, J = 8.8, 5.7 Hz, 1 H).
4-[(4-Methoxyphenyl)sulfinyl]benzonitrile (3d)
According to GP 1, sulfoxide 3d was prepared from 4-cyanophe-
nylmagnesium bromide (51.0 mL, 50.0 mmol, 0.98 M in THF) and
4-methoxybenzenesulfinyl chloride (10.5 g, 55.0 mmol), and puri-
fied by flash chromatography (silica gel, Et2O), furnishing 3d as a
colorless solid; yield: 9.01 g (70%); mp 121–123 °C.
13C NMR (75 MHz, CDCl3): d = –0.42 (SiCH3), 55.4 (CH3), 99.9
(d, J = 2.7 Hz), 104.9, 114.5 (CH), 117.0 (d, J = 22.2 Hz, CH),
120.0 (d, J = 24.1 Hz, CH), 122.2 (d, J = 10.3 Hz, CH), 125.8 (d,
J = 9.3 Hz), 127.8 (CH), 136.3 (d, J = 1.2 Hz), 143.1 (d, J = 3.1 Hz),
162.0, 163.3 (d, J = 251.4 Hz, CF).
IR (ATR): 2228 (s), 1590 (s), 1575 (s), 1495 (s), 1258 (s), 1184 (w),
1174 (m), 1086 (s), 1039 (vs), 1024 (s), 1013 (s), 828 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 3.80 (s, 3 H), 6.93–6.98 (m, 2 H),
6.52–6.57 (m, 2 H), 7.67–7.76 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 55.5 (CH3), 114.3, 115.2 (CH),
117.7, 124.9 (CH), 127.4 (CH), 132.8 (CH), 135.5, 151.5, 162.6.
MS (EI, 70 eV): m/z (%) = 346 (40), 332 (24), 331 (100), 330 (14),
316 (14), 245 (13), 155 (14), 139 (14), 123 (15), 73 (88).
MS (EI, 70 eV): m/z (%) = 257 (15), 210 (14), 209 (56), 194 (10),
166 (7), 154 (100), 139 (21), 123 (40), 92 (7), 64 (7).
HRMS (EI): m/z calcd for C14H11NO232S: 257.0510; found:
HRMS (EI): m/z calcd for C18H19FO232S28Si: 346.0859; found:
346.0863.
257.0500.
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York

1046
L. Melzig et al.
PRACTICAL SYNTHETIC PROCEDURES
({4-[(4-Methoxyphenyl)sulfinyl]phenyl}ethynyl)(trimethyl)si-
lane (3e)
tert-Butyl 4-[(4-Methoxyphenyl)sulfinyl]-3-[(trimethyl-
silyl)ethynyl]benzoate (5c)
A dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, was charged with ethynyl(trimethyl)silane
(1.96 g, 2.84 mL, 20.0 mmol), and i-PrMgCl·LiCl (15.2 mL, 19.0
mmol, 1.25 M in THF) was added at 25 °C. After cessation of gas
evolution, the reaction mixture was heated to 60 °C for 5 min. After
cooling to 25 °C, a ZnCl2 solution (20.0 mL, 20.0 mmol, 1.00 M in
THF) was slowly added. The resulting mixture was stirred for 30
min at 25 °C, then 4-iodophenyl-4¢-methoxyphenyl sulfoxide10
(15.0 mmol, 5.37 g), Pd(dba)2 (173 mg, 300 mmol), and tri-2-fu-
rylphosphine (139 mg, 600 mol) were added and the mixture was
stirred for 14 h at 25 °C. The mixture was quenched with sat. aq
NH4Cl (50 mL) and extracted with EtOAc (3 × 50 mL). The com-
bined organic layers were dried (MgSO4) and after filtration, the
solvents were removed under reduced pressure. Flash chromato-
graphic purification (silica gel, pentane–EtOAc, 2:1) afforded 3e as
a colorless solid; yield: 4.85 g (98%); mp 122–124 °C.
According to GP 3, sulfoxide 5c was prepared starting from sulfox-
ide 3c (3.32 g, 10.0 mmol), using Pd(PPh3)4 (0.22 g, 0.20 mmol) and
trimethylethynylsilane (1.47 g, 2.13 mL, 15.0 mmol) for the cross-
coupling. The reaction mixture was stirred for 2 h at 50 °C. Flash
chromatographic purification (silica gel, pentane–Et2O, 1:1) afford-
ed a colorless solid; yield: 2.91 g (68%); mp 134–135 °C.
IR (ATR): 1713 (vs), 1590 (m), 1495 (m), 1457 (m), 1368 (m),
1300 (s), 1250 (vs), 1160 (s), 1036 (s), 841 (vs), 833 (vs), 762 cm–1
(s).
1H NMR (300 MHz, CDCl3): d = 0.23 (s, 9 H), 1.53 (s, 9 H), 3.74
(s, 3 H), 6.86 (d, J = 8.8 Hz, 2 H), 7.59 (d, J = 8.6 Hz, 2 H), 7.96–
7.99 (m, 1 H), 8.08–8.12 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = –0.5 (SiCH3), 27.9 (CH3), 55.3
(CH3), 81.8, 99.4, 104.4, 114.4 (CH), 120.0, 123.1 (CH), 128.1
(CH), 129.9 (CH), 133.8, 134.1 (CH), 135.7, 151.4, 162.0, 163.9.
IR (ATR): 1591 (s), 1576 (m), 1491 (s), 1245 (vs), 1187 (m), 1171
(m), 1086 (s), 845 (m), 835 (s), 829 (s), 816 cm–1 (s).
MS (EI, 70 eV): m/z (%) = 412 (16), 373 (20), 372 (60), 358 (27),
357 (98), 356 (35), 254 (50), 139 (21), 73 (100), 43 (24).
1H NMR (600 MHz, CDCl3): d = 0.21 (9 H), 3.78 (3 H), 6.90–6.93
(m, 2 H), 7.49–7.52 (m, 6 H).
HRMS (EI): m/z calcd for C23H28O4SSi: 428.1478; found:
428.1468.
13C NMR (150 MHz, CDCl3): d = –0.3 (SiCH3), 55.4 (CH3), 96.7,
103.6, 114.8 (CH), 124.3 (CH), 125.6, 127.3 (CH), 132.5 (CH),
136.4, 145.7, 162.2.
4¢-Fluoro-6-[(4-methoxyphenyl)sulfinyl]biphenyl-3-carbo-
nitrile (5d)
According to GP 2, sulfoxide 5d was prepared starting from sulfox-
ide 3d (1.29 g, 5.00 mmol), using Pd(PPh3)4 (110 mg, 100 mmol)
and 1-fluoro-4-iodobenzene (1.33 g, 6.00 mmol) for the cross-cou-
pling. The reaction mixture was stirred for 2 h at 50 °C. Flash chro-
matographic purification (silica gel, pentane–Et2O, 3:7) gave a
colorless solid; yield: 1.25 g (71%); mp 121–122 °C.
MS (EI, 70 eV): m/z (%) = 328 (12), 313 (17), 312 (18), 297 (26),
281 (20), 280 (100), 266 (17), 265 (84), 158 (23), 155 (16), 143
(12), 139 (50), 123 (25).
HRMS (EI): m/z calcd for C18H20O232S28Si: 328.0953; found:
328.0945.
IR (ATR): 1591 (vs), 1577 (m), 1509 (vs), 1494 (vs), 1460 (s), 1249
(vs), 1220 (s), 1159 (m), 1083 (s), 1042 (vs), 1026 (vs), 825 cm–1
(vs).
1H NMR (300 MHz, CDCl3): d = 3.75 (s, 3 H), 6.68–6.72 (m, 2 H),
6.88–6.93 (m, 2 H), 7.05–7.08 (m, 4 H), 7.44 (dd, J = 1.7, 0.5 Hz, 1
H), 7.89 (d, J = 8.1, 1.7 Hz, 1 H), 8.38 (dd, J = 8.11, 0.48 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.3 (CH3), 114.3, 114.4 (CH),
115.7 (d, J = 21.72 Hz, CH), 117.5, 124.5 (CH), 127.9 (CH), 130.8
(d, J = 8.48 Hz, CH), 131.8 (CH), 131.9 (d, J = 2.39 Hz), 133.3
(CH), 134.1, 140.1, 149.6, 162.0, 162.8 (d, J = 249.8 Hz, CF).
{4-[(4-Chlorophenyl)sulfinyl]phenyl}dimethylamine (3f)
In a dry and argon-flushed Schlenk flask, equipped with a magnetic
stirrer and a septum, 4-(dimethylamino)phenyl thiocyanate (17.8 g
100 mmol) was dissolved in THF (100 mL) and cooled to –20 °C.
A solution of 4-chlorophenylmagnesium bromide (125 mL, 110
mmol, 0.88 M in THF) was added and the reaction mixture was al-
lowed to warm to 25 °C. The mixture was quenched with sat. aq
NH4Cl (100 mL) and extracted with EtOAc (3 × 200 mL). The com-
bined organic layers were dried (MgSO4) and after filtration, the
solvent was removed under reduced pressure. The crude sulfide was
dissolved in CH2Cl2 (100 mL) and cooled to –20 °C. MCPBA (27.0
g, 110 mmol, 70% in H2O) dissolved in CH2Cl2 (100 mL) was add-
ed slowly. After stirring for 1 h at –20 °C, the mixture was quenched
with sat. aq Na2S2O3 (50 mL) and extracted with EtOAc (3 × 200
mL). The combined organic layers were dried (MgSO4) and after
filtration, the solvent was removed under reduced pressure. Flash
chromatographic purification (silica gel, pentane–EtOAc, 1:1) fur-
nished 3f as a colorless solid; yield: 17.9 g (64%); mp 128–129 °C.
MS (EI, 70 eV): m/z (%) = 352 (25), 351 (9), 303 (14), 156 (10), 155
(100), 139 (20), 124 (26), 123 (36), 114 (12), 44 (7).
HRMS (EI): m/z calcd for C20H14FNO232S: 351.0729; found:
351.0717.
[{4-[(4-Methoxyphenyl)sulfinyl]-1,3-phenylene}bis(ethyne-2,1-
diyl)]bis(trimethylsilane) (5e)
According to GP 3, sulfoxide 5e was prepared starting from sulfox-
ide 3e (657 mg, 2.00 mmol), using Pd(dba)2 (23.0 mg, 40.0 mmol),
tri-2-furylphosphine (19.0 mg, 80.0 mmol) and trimethylethynylsi-
lane (393 mg, 4.00 mmol) for the cross-coupling. The reaction mix-
ture was stirred for 2 h at 50 °C. Flash chromatographic purification
(silica gel, pentane–EtOAc, 9:2) gave 5e as a yellow oil; yield: 610
mg (72%).
IR (ATR): 1596 (s), 1509 (m), 1091 (s), 1083 (s), 1060 (m), 1045
(vs), 1010 (s), 826 (s), 807 (s), 738 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.99 (s, 6 H), 6.65–6.70 (m, 2 H),
7.38–7.46 (m, 4 H), 7.49–7.54 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 40.1 (CH3), 112.0 (CH), 126.0
(CH), 127.7 (CH), 129.2 (CH), 130.3, 136.3, 144.8, 152.5.
IR (ATR): 2958 (m), 2151 (m), 1738 (w), 1592 (m), 1578 (m),
1495 (m), 1460 (m), 1378 (w), 1302 (m), 1248 (s), 1036 (m), 950
(m), 836 (vs), 825 cm–1 (vs).
1H NMR (600 MHz, CDCl3): d = 0.22 (s, 9 H), 0.25 (s, 9 H), 3.80
(s, 3 H), 6.89–6.90 (m, 2 H), 7.53 (s, 1 H), 7.59–7.61 (m, 3 H), 8.00
(d, J = 8.4 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 279 (19), 263 (34), 233 (25), 232 (23),
231 (80), 230 (30), 168 (100), 152 (25), 136 (30), 44 (19).
HRMS (EI): m/z calcd for C14H1435ClNO32S: 279.0485; found:
279.0479.
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of Highly Functionalized 1,2,4-Trisubstituted Arenes
1047
13C NMR (150 MHz, CDCl3): d = –0.4 (Si CH3), –0.3 (SiCH3), 55.5
(CH3), 97.3, 99.3, 102.9, 104.2, 114.5 (CH), 120.3, 123.4 (CH),
125.5, 128.2 (CH), 132.6 (CH), 136.1, 136.4 (CH), 147.1, 162.1.
IR (ATR): 1691 (vs), 1602 (s), 1507 (s), 1415 (m), 1390 (m), 1259
(m), 1226 (s), 1197 (s), 832 cm–1 (vs).
1H NMR (300 MHz, CDCl3): d = 7.21–7.29 (m, 2 H), 7.36–7.42 (m,
2 H), 7.77–7.78 (m, 1 H), 7.79–7.82 (m, 1 H), 8.12 (dd, J = 8.0, 0.5
Hz, 1 H), 10.01 (d, J = 0.7 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 425 (17), 424 (51), 411 (11), 410 (33),
409 (100), 408 (13), 381 (7), 336 (8), 323 (9), 287 (9), 273 (6).
HRMS (EI): m/z calcd for C23H28O232S28Si2: 424.1349; found:
424.1336.
13C NMR (75 MHz, CDCl3): d = 116.1 (d, J = 22.01 Hz, CH),
116.9, 117.6, 128.6 (CH), 131.1 (CH), 131.5 (d, J = 3.4 Hz, CH),
131.6 (d, J = 8.5 Hz, CH), 134.5 (d, J = 1.0 Hz), 136.2, 145.0, 163.3
(d, J = 250 Hz, CF), 190.4 (CH).
tert-Butyl 5¢-Chloro-2¢-{[4-(dimethylamino)phenyl]sulfinyl}bi-
phenyl-4-carboxylate (5f)
MS (EI, 70 eV): m/z (%) = 226 (10), 225 (93), 224 (100), 197 (20),
196 (26), 195 (19), 170 (7), 169 (15), 168 (6), 129 (8).
According to GP 2, sulfoxide 5f was prepared starting from sulfox-
ide 3f (2.80 g, 10.0 mmol), using Pd(dba)2 (120 mg, 200 mmol), tri-
2-furylphosphine (93.0 mg, 400 mmol), and tert-butyl 4-iodoben-
zoate (3.65 g 12.0 mmol) for the cross-coupling. The reaction mix-
ture was stirred for 15 min at 50 °C. Flash chromatographic
purification (silica gel, pentane–EtOAc, 1:1) furnished 5f as a col-
orless solid; yield: 3.61 g (79%); mp 137–139 °C.
HRMS (EI): m/z calcd for C14H8FNO: 225.0590; found: 225.0585.
{2,4-Bis[(trimethylsilyl)ethynyl]phenyl}(3,4-dichlorophe-
nyl)methanol (8e)
According to GP 4, the sulfoxide 5e (425 mg, 1.00 mmol) was treat-
ed with i-PrMgCl·LiCl (2; 920 mL, 1.10 mmol, 1.20 M in THF) at
–50 °C for 5 min. 3,4-Dichlorobenzaldehyde (140 mg, 800 mmol)
was then added and the reaction mixture was allowed to warm to
25 °C. Flash chromatographic purification (silica gel, pentane–
Et2O, 4:1) gave a colorless oil; yield: 257 mg (72%).
IR (ATR): 1712 (vs), 1592 (vs), 1516 (s), 1366 (vs), 1294 (vs), 1282
(s), 1170 (s), 1120 (s), 1092 (s), 1086 (s), 1066 (s), 1040 (vs), 1024
(s), 1012 (s), 802 cm–1 (vs).
1H NMR (300 MHz, CDCl3): d = 1.62 (s, 9 H), 2.92 (s, 6 H), 6.40–
6.45 (m, 2 H), 6.85–6.90 (m, 2 H), 7.14–7.18 (m, 3 H), 7.57 (dd,
J = 8.4, 2.21 Hz, 1 H), 7.91–7.95 (m, 2 H), 8.18 (d, J = 8.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 28.2 (CH3), 40.1 (CH3), 81.4,
111.6 (CH), 125.6 (CH), 127.8 (CH), 128.7 (CH), 129.2 (CH),
129.3, 129.4 (CH), 130.0 (CH), 131.8, 136.3, 140.9, 141.1, 142.9,
152.1, 165.3.
IR (ATR): 2150 (m), 1483 (w), 1469 (m), 1389 (m), 1248 (s), 1186
(m), 1031 (m), 956 (m), 836 (vs), 797 (m), 757 cm–1 (s).
1H NMR (200 MHz, CDCl3): d = 0.24 (s, 18 H), 2.60 (s, 1 H), 6.17
(s, 1 H), 7.20 (dd, J = 8.3, 2.1 Hz, 1 H), 7.37 (d, J = 8.7 Hz, 1 H),
7.41 (s, 1 H), 7.42 (s, 1 H), 7.53 (d, J = 1.8 Hz, 1 H), 7.57–7.58 (m,
1 H).
MS (EI, 70 eV): m/z (%) = 457 (22), 456 (17), 455 (67), 384 (20),
383 (42), 382 (27), 351 (28), 170 (19), 169 (40), 168 (100), 152
(31), 136 (83), 119 (15).
HRMS (EI): m/z calcd for C25H2635ClNO332S: 455.1322; found:
13C NMR (75 MHz, CDCl3): d = –0.3 (SiCH3), –0.1 (SiCH3), 72.6
(CH), 95.5, 101.4, 110.8, 103.5, 121.2, 122.9, 125.9 (CH), 126.1
(CH), 128.1 (CH), 130.3 (CH), 131.5, 132.3 (CH), 132.4, 136.3
(CH), 142.8, 144.8.
455.1319.
MS (EI, 70 eV): m/z (%) = 446 (11), 444 (14), 429 (19), 409 (16),
375 (15), 374 (17), 373 (73), 372 (25), 371 (100), 358 (26), 357
(15), 356 (38), 336 (16), 75 (12).
HRMS (EI): m/z calcd for C23H2635ClO28Si2: 444.0899; found:
tert-Butyl 4-Formyl-3-[(trimethylsilyl)ethynyl]benzoate (8c)
According to GP 4, the sulfoxide 5c (429 mg, 1.00 mmol) was treat-
ed with i-PrMgCl·LiCl (2; 920 mL, 1.10 mmol, 1.20 M in THF) at
–50 °C for 15 min. DMF (62.0 mL, 800 mmol) was then added and
the reaction mixture was allowed to warm to 25 °C. Flash chro-
matographic purification (silica gel, pentane–Et2O, 20:1) afforded a
colorless solid; yield. 189 mg (78%); mp 116–118 °C.
444.0887.
tert-Butyl 5¢-Chloro-2¢-[2-(ethoxycarbonyl)prop-2-en-1-yl]bi-
phenyl-4-carboxylate (8f)
According to GP 4, the sulfoxide 5f (456 mg, 1.00 mmol) was treat-
ed with i-PrMgCl·LiCl (2; 850 mL, 1.10 mmol, 1.30 M in THF)
at –50 °C for 7 h. CuCN·2LiCl (50.0 mL, 5.00 mol%, 1.00 M in
THF) and ethyl 2-(bromomethyl)acrylate (154 mg, 800 mmol) were
then added and the reaction mixture was allowed to warm to 25 °C.
Flash chromatographic purification (silica gel, pentane–Et2O, 12:1)
furnished a colorless liquid; yield: 193 mg (60%).
IR (ATR): 2977 (w), 1716 (s), 1693 (s), 1600 (w), 1390 (m), 1087
(w), 941 (w), 842 (vs), 758 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 0.27 (s, 9 H), 1.59 (s, 9 H), 7.91
(dd, J = 8.2, 0.7 Hz, 1 H), 7.98 (ddd, J = 8.2, 1.7, 0.8 Hz, 1 H), 8.13
(dd, J = 1.7, 0.7 Hz, 1 H), 10.56 (d, J = 0.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = –0.3 (SiCH3), 28.1 (CH3), 82.3,
99.3, 103.3, 126.6, 126.8 (CH), 129.3 (CH), 134.5 (CH), 136.4,
138.3, 164.0, 191.3 (CH).
IR (ATR): 1709 (vs), 1367 (m), 1308 (m), 1293 (s), 1252 (m), 1162
(m), 1142 (m), 1115 (s), 1099 (m), 846 cm–1 (m).
MS (EI, 70 eV): m/z (%) = 246 (57), 233 (21), 232 (100), 231 (24),
229 (83), 201 (93), 186 (19), 107 (26), 73 (23), 57 (49).
HRMS (EI): m/z calcd for C17H22O328Si: 302.1338; found:
302.1344.
1H NMR (300 MHz, CDCl3): d = 1.21 (t, J = 7.17 Hz, 3 H), 1.60 (s,
9 H), 3.52 (s, 2 H), 4.12 (q, J = 7.2 Hz, CH2), 5.19 (s, 1 H), 6.19 (s,
1 H), 7.18 (d, J = 8.3 Hz, 1 H), 7.22 (d, J = 2.2 Hz, 1 H), 7.28 (d,
J = 2.2 Hz, 1 H), 7.30–7.33 (m, 2 H), 7.98–8.02 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 28.2 (CH3), 34.7
(CH2), 60.8 (CH2), 81.1, 126.5 (CH2), 127.9 (CH), 128.8 (CH),
129.4 (CH), 129.7 (CH), 131.2, 131.4 (CH), 132.2, 134.4, 139.9,
143.1, 144.3, 165.5, 166.5.
4¢-Fluoro-6-formylbiphenyl-3-carbonitrile (8d)
According to GP 4, the sulfoxide 5d (351 mg, 1.00 mmol) was
treated with i-PrMgCl·LiCl (2; 920 mL, 1.10 mmol, 1.20 M in THF)
at –50 °C for 15 min. DMF (62.0 mL, 800 mmol) was then added and
the reaction mixture was allowed to warm to 25 °C. Flash chro-
matographic purification (silica gel, pentane–Et2O, 10:1) furnished
a colorless solid; yield: 0.129 g (72%); mp 116–118 °C.
MS (EI, 70 eV): m/z (%) = 400 (0.5), 344 (31), 328 (42), 327 (71),
326 (100), 300 (38), 299 (34), 298 (91), 270 (39), 253 (28),
HRMS (EI): m/z calcd for C23H2535ClO4: 400.1441; found:
400.1442.
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York

1048
L. Melzig et al.
PRACTICAL SYNTHETIC PROCEDURES
(5) (a) Oae, S.; Kawai, T.; Furukawa, N. Tetrahedron Lett.
1984, 25, 69. (b) Kawai, T.; Furukawa, N. Tetrahedron Lett.
1984, 25, 2549. (c) Furukawa, N.; Shibutani, T.; Fujihara,
H. Tetrahedron Lett. 1989, 30, 7091. (d) Shibutani, T.;
Fujihara, H.; Furukawa, N. Tetrahedron Lett. 1991, 32,
2943. (e) Uenishi, J.; Yamamoto, A.; Takeda, T.;
Wakabayashi, S.; Oae, S. Heteroat. Chem. 1992, 3, 73.
(6) (a) Hoffmann, R. W.; Hölzer, B.; Knopff, O.; Harms, K.
Angew. Chem. Int. Ed. 2000, 39, 3072. (b) Satoh, T.; Akita,
K. Chem. Pharm. Bull. 2003, 51, 181. (c) Sugiyama, S.;
Shimizu, H.; Satoh, T. Tetrahedron Lett. 2006, 47, 8771.
(d) Ferber, B.; Kagan, H. B. Adv. Synth. Catal. 2007, 349,
493. (e) Brebion, F.; Goddard, J.-P.; Fensterbank, L.;
Malacria, M. Org. Lett. 2008, 10, 1917.
(7) (a) Guillaneux, D.; Kagan, H. B. J. Org. Chem. 1995, 60,
2502. (b) Kloetzing, R. J.; Knochel, P. Tetrahedron:
Asymmetry 2006, 17, 116. (c) Thaler, T.; Geittner, F.;
Knochel, P. Synlett 2007, 2655.
(8) Quesnelle, C.; Iihama, T.; Aubert, T.; Terrier, H.; Snieckus,
V. Tetrahedron Lett. 1992, 33, 2625.
Acknowledgment
We thank the Fonds der Chemischen Industrie and the DFG for fi-
nancial support. We thank Chemetall GmbH (Frankfurt), W. C.
Heraeus GmbH (Hanau), and BASF AG (Ludwigshafen) for the ge-
nerous gift of chemicals.
References
(1) (a) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances; Georg Thieme Verlag:
Stuttgart, 2001. (b) Valeur, B. Molecular Fluorescence;
Wiley-VCH: Weinheim, 2002. (c) Hartung, C. G.;
Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.;
Wiley-VCH: Weinheim, 2002, 330. (d) Schlosser, M.
Organometallics in Synthesis: A Manual; Schlosser, M.,
Ed.; Wiley: Chichester, 2002, 1. (e) Knochel, P. Handbook
of Functionalized Organometallics; Knochel, P., Ed.;
Wiley-VCH: Weinheim, 2005.
(2) (a) Eaton, P. E.; Lee, C. H.; Xiong, Y. J. Am. Chem. Soc.
1989, 111, 8016. (b) Clososki, G. C.; Rohbogner, C. J.;
Knochel, P. Angew. Chem. Int. Ed. 2007, 46, 7681.
(3) (a) Rieke, R. D. Science 1989, 246, 1260. (b) Rieke, R. D.;
Hanson, M. V. Tetrahedron 1997, 53, 1925. (c) Lee, J.;
Velarde-Ortiz, R.; Guijarro, A.; Wurst, J. R.; Rieke, R. D.
J. Org. Chem. 2000, 65, 5428. (d) Krasovskiy, A.;
Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem.
Int. Ed. 2006, 45, 6040. (e) Piller, F. M.; Appukkuttan, P.;
Gavryushin, A.; Helm, M.; Knochel, P. Angew. Chem. Int.
Ed. 2008, 47, 6802.
(4) (a) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.
F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V.-V. Angew.
Chem. Int. Ed. 2003, 42, 4302. (b) Krasovskiy, A.;
Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333. (c)Ren,
H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215.
(d) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun.
2005, 543. (e) Kopp, F.; Knochel, P. Org. Lett. 2007, 9,
1639. (f) Kopp, F.; Wunderlich, S.; Knochel, P. Chem.
Commun. 2007, 2075.
(9) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew.
Chem. Int. Ed. 2006, 45, 2958. (b) Lin, W.; Baron, O.;
Knochel, P. Org. Lett. 2006, 8, 5673. (c) Rohbogner, C. J.;
Clososki, G. C.; Knochel, P. Angew. Chem. Int. Ed. 2007,
46, 7681.
(10) Rauhut, C. B.; Melzig, L.; Knochel, P. Org. Lett. 2008, 10,
3891.
(11) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem.
Soc. 1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982,
15, 340. (c) Negishi, E.; Quian, M.; Zeng, F.; Anastasia, L.;
Babinski, D. Org. Lett. 2003, 5, 1597. (d) Zeng, X.; Quian,
M.; Hu, Q.; Negishi, E. Angew. Chem. Int. Ed. 2004, 43,
2259.
(12) (a) Villieras, J.; Rambaud, M. Synthesis 1982, 924.
(b) Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(13) Peyronneau, M.; Roques, N.; Mazieres, S.; Le Roux, C.
Synlett 2003, 631.
(14) (a) Brewster, R. Q.; Schroeder, W. Org. Synth. 1943, 19, 79.
(b) Jendralla, H.; Chen, L. Synthesis 1990, 827.
Synthesis 2009, No. 6, 1041–1048 © Thieme Stuttgart · New York