A ligand-free palladium-catalyzed cross-coupling of aryl sulfinates with aryl bromides

Article abstract of DOI:10.1055/s-0033-1339279

A ligand-free Pd-catalyzed cross-coupling of aryl sulfinates with aryl bromides has been developed. A variety of aryl bromides and aryl sulfinates undergo this transformation to yield the desired biaryl in a practical and economical manner. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339279

LETTER
▌1715
lAetteLr igand-Free Palladium-Catalyzed Cross-Coupling of Aryl Sulfinates with
Aryl Bromides
Ligand-Free Palladium-Catalyzed Cross-Couplings of Aryl Sulfinates
Dirk H. Ortgies,a,b Pat Forgione*a,b
a
Concordia University, Department of Chemistry and Biochemistry, 7141 Rue Sherbrooke O., Montréal, QC, H4B 1R6, Canada
Fax +1(514)8482868; E-mail: pat.forgione@concordia.ca
b
Centre in Green Chemistry and Catalysis, Montréal, QC, H3C 3J7, Canada
Received: 28.03.2013; Accepted after revision: 24.05.2013
Although direct C–H activation is a valuable route to a
Abstract: A ligand-free Pd-catalyzed cross-coupling of aryl sul-
range of biaryls, in some cases the reactions are not regi-
finates with aryl bromides has been developed. A variety of aryl
oselective, or not selective for the desired C–H group. To
bromides and aryl sulfinates undergo this transformation to yield
overcome these issues while still minimizing the produc-
tion of unwanted salt byproducts, functional groups that
release gases upon generation of an organopalladium
species have been exploited. Decarboxylative cross-
couplings are examples of this type of reaction that have
emerged over the past decade.7,8 Organosulfur com-
pounds have also attracted interest in transition-metal-
catalyzed reactions.9 Analogous to the decarboxylative
coupling reactions, a range of desulfinylative processes
has been developed that have demonstrated an energetic
advantage.10 The reactivity of sulfonyl chlorides in cross-
coupling reactions was demonstrated by Kasahara11 and
Miura12 for the first time in Mizoroki–Heck-type reac-
tions. Vogel and co-workers expanded on this work
(Mizoroki–Heck),13 and subsequently demonstrated their
versatility as the electrophilic coupling partner in Stille,14
Suzuki–Miyaura,15 Sonogashira–Hagihara,16 Negishi,17
and both palladium- and iron-catalyzed variants of the
Kumada–Corriu cross-coupling reactions.18 Sulfonyl
chlorides have also found applications in a solid-phase
Suzuki-type transformation,19 in a homocoupling reac-
tion,20 a copper-catalyzed coupling with arylalkynes,21
and in the C–H activation of oxazoles.22 Arylsulfonyl hy-
drazides recently demonstrated related reactivity in the di-
rect arylation of N-heteroarenes23 and in an oxidative
Mizoroki–Heck-type reaction.24
the desired biaryl in a practical and economical manner.
Key words: palladium, sulfur, cross-coupling, catalysis, biaryls
The development of palladium-catalyzed reactions for the
formation of carbon–carbon bonds was seminal for the
widespread synthesis of biaryls,1 which are present as
privileged structures in a diverse range of applications, in-
cluding pharmaceuticals,2 ligands,3 agrochemicals,4 and
novel materials5 (Figure 1). More recent developments in
this area have been aimed at eliminating the need for stoi-
chiometric amounts of organometallic coupling partners,
which lead to large amounts of unwanted byproducts. Di-
rect C–H activation of an aryl carbon–hydrogen bond has
proven to be a simple and elegant solution in many cases
by circumventing additional steps and functional group
manipulations necessary to obtain the organometallic
coupling partner.6
CN
N
C5H11
N
N
N
HN
N
Cl
Losartan (1)
AT1 antagonist
5CB (2)
liquid crystal
HO
Aryl sulfinates have recently attracted attention in metal-
catalyzed coupling reactions expanding on early work by
Garves25 and Selke and Thiele26 using stoichiometric
amounts of palladium(II) to achieve homocouplings and
Mizoroki–Heck-type additions to double bonds and ni-
triles. Aryl sulfinates are convenient coupling partners
due to their ease of handling and the fact that they are
bench-stable, as opposed to sulfinic acids that are known
to undergo radical autoxidation processes.27 Recently,
Rao et al. published a palladium-mediated homocoupling
reaction of aryl sulfinates employing catalytic Cu2O with
O2 as the reoxidant.28 The reactivity of aryl sulfinates as
the electrophilic coupling partner in a catalytic cross-cou-
pling with Grignard reagents had been demonstrated for
the first time using nickel.29 A rhodium-catalyzed addition
to aldehydes30 and palladium-mediated reactions with
nitriles31 were disclosed with extraordinary work by the
group of Deng in the latter area. The Deng group also de-
Cl
CF3
O
H
N
HN
NH
O
N
O
Cl
N
CF3
Lomitapide (3)
MTP inhibitor
Boscalide (4)
fungicide
Figure 1 Important structures containing the biphenyl motif
SYNLETT 2013, 24, 1715–1721
Advanced online publication: 18.07.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339279; Art ID: ST-2013-S0280-L
© Georg Thieme Verlag Stuttgart · New York

1716
D. H. Ortgies, P. Forgione
LETTER
scribed the use of aryl sulfinates as the electrophilic cou- Original reports on the coupling of sulfinates employed a
pling partner in
palladium-catalyzed oxidative phosphine-based ligand and a palladium(II) precatalyst.38–44
a
Mizoroki–Heck reaction,32 in a conjugate addition,33 and Ligand-free, palladium-mediated couplings47 are becom-
in C–H activations of indoles and azoles.34 Independently, ing increasingly important in order to render these trans-
Miao disclosed a Heck-type reaction using sulfinic acids35 formations more cost-efficient. Phosphine-based ligands
and most recently the group of Qi described an oxidative are often bulky and therefore high in molecular weight.
Heck-type coupling under air.36 Additionally, the groups Although the phosphine ligand is implicated as the reduc-
of You and Wang reported C–H arylations of heteroarenes tant for palladium(II) precatalysts, it is not necessary if
employing sulfinates.37
other potential reductants (reactants with lone pairs on N-,
O- or S-atoms, any type of double bond) are present.48
Hence, the overall efficiency of a transformation will be
improved in the event that the phosphine can be avoided.
The recently disclosed desulfinylative homocoupling by
Rao et al.,28 the tandem cyclization–arylation reaction by
the group of Wang40 and the Heck-type coupling by the
group of Qi36 do not require a ligand, but to the best of our
knowledge, no examples of the palladium(0)-mediated
cross-coupling of aryl sulfinates and aryl halides exist
without the use of a ligand.
The utilization of aryl sulfinates as the nucleophilic cou-
pling partner, as a replacement for the stoichiometric
amounts of organometallic reagents required in classic
cross-coupling reactions, had until very recently only
been disclosed in a patent.38 The group of Duan demon-
strated a palladium-catalyzed cross-coupling reaction be-
tween aryl sulfinates and aryltriflates,39 and Chen et al.
explored an approach to benzofurans and benzothio-
phenes via a tandem cyclization–arylation reaction em-
ploying stoichiometric amounts of copper as the reoxidant
for palladium.40 Most recently benzylchlorides were ex- During the course of our studies on the palladium(0)-cat-
plored as coupling partners by the group of Deng,41 and alyzed reaction of aryl sulfinate 5a with aryl bromide 6a,44
Colomb and Billard demonstrated a coupling with bromo- we discovered that the transformation proceeds in excel-
quinolines.42 Our group disclosed the cross-couplings of lent yields in the absence of a phosphine ligand (Table 1,
heteroaromatic sulfinates43 and aryl sulfinates44 with aryl entry 1). However, the phosphine-free reaction is greatly
bromides. Increasing the scope of aryl sulfinates as nu- affected by both the palladium source and the solvent.
cleophilic coupling partners is an ongoing challenge Changing from PdCl2 (entry 1) to Pd(OAc)2 (entry 2) or
(Scheme 1).
Pd(acac)2 (entry 3) resulted in significant reduction in
yield, as did the employment of Pd(η3-1-PhC3H4)(η5-C5H5)
(Petey; entry 4). Pd(dba)2 and PdI2 also provided the de-
sired product in excellent yields. The use of the heteroge-
neous Pd/C catalyst yielded product 7a in moderate yield
and generated a significant amount of byproducts (entry
7). PdCl2 was employed for all further screenings since it
was the most cost-efficient palladium source. Changing
the solvent from the polar aprotic DMF (entries 1–7) to
apolar solvents such as toluene (entry 8) and mesitylene
(entry 9) led to significant reduction in yields. Meanwhile,
other polar aprotic solvents such as DMA (entry 10) and
NMP (entry 11) could be employed with only minor re-
ductions in yield.
aryl sulfinates as electrophiles:
R1
R1
R2
Y
R2
R1
PdX2, ligand
+
O
Y
R2
N
NaO2S
R2
R1
Y
Z
H
R2
Z
R2
Y = CH2 or O
In order to ensure that this transformation was indeed a
palladium-mediated process, a reaction had been conduct-
ed previously in the absence of the palladium source in a
vial that was rigorously washed to ensure no leached pal-
ladium was present.44 Interestingly, a trace amount of the
cross-coupling product was observed; however, the major
product was the SNAr reaction of the sulfinate 5 with the
aryl bromide 6a to yield the corresponding sulfone 8a in
very good yield (Scheme 2). Although sulfinates have
demonstrated this type of reactivity previously, this is the
first example with a relatively poor SNAr electrophile
such as the bromotrifluoromethylbenzene (6a).
aryl sulfinates as nucleophiles:
R2
SO2Na
+
PdX2, ligand
R2
R1
X
R1
5
6
7
Scheme 1 Electrophilic and nucleophilic cross-couplings of aryl sul-
finates
The cross-coupling of aryl sulfinates is an attractive route
since it does not require the use of a stoichiometric metal-
based coupling partner and the main byproduct, namely
SO2, can be captured and recycled easily on an industrial
scale.45 Additionally, sulfur and organosulfur compounds
are an underutilized byproduct of the oil industry and
therefore readily available.46
Subsequently, the scope of aryl bromides 6 that could be
employed in the cross-coupling reaction was evaluated
(Table 2). As demonstrated above, 4-bromobenzotrifluo-
ride (6a) gave an excellent yield of 82% (entry 1). Shifting
the trifluoromethyl group to the meta position (6b) yield-
Synlett 2013, 24, 1715–1721
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ligand-Free Palladium-Catalyzed Cross-Couplings of Aryl Sulfinates
1717
Table 1 Screening of Reaction Conditionsa
withdrawing esters 6g and 6h (entries 7 and 8) proved
more challenging, and the desired coupling products
could be isolated in reasonable to good yields; however,
the catalyst loading needed to be increased as well as the
reaction time. Other electron-withdrawing groups at the
4-position (F 6i, entry 9 and CN 6j, entry 10) provided the
product in excellent yields. The best results were obtained
with para- (entry 10) and meta-substituted (entry 11)
bromobenzonitriles (6j,k). The yield is only reduced when
the more sterically hindered 2-bromobenzonitrile 6l (en-
try 12) was employed. The limitations of the ligand-free
coupling are demonstrated in entries 13 and 14. Nitro-
group-bearing substrate 6n did not yield any of the desired
product; instead, it was observed that some reduction to
the corresponding amine had occurred. This is likely due
to the reducing environment caused by the release of SO2
during the course of the reaction, although further studies
are required to confirm this hypothesis. Overall, a range of
bromides 6 can be employed to provide the cross-coupling
products 7 in moderate to excellent yields.
SO2Na
Pd source (5 mol%)
Cs2CO3 (1.5 equiv)
CF3
5a
solvent
+
185 °C, 20 h
CF3
7a
Br
6a
Entry
Pd source
Solvent
Yield (%)b
1
2
PdCl2
DMF
82
30
36
43
84
81
43c
15
10
66
66
Pd(OAc)2
Pd(acac)2
Petey
DMF
3
DMF
4
DMF
5
Pd(dba)2
PdI2
DMF
6
DMF
Preliminary investigations were conducted to study why
the 4- and 3-bromobenzonitriles 6j and 6k provided the
best yields for the aryl bromide scope and, importantly,
better yields than our previously disclosed cross-coupling
reaction conditions employing dppf as a ligand.44 Al-
though electron-deficient aryl bromides are known to un-
dergo oxidative addition more readily than electron-rich
aryl bromides,49 this observation does not explain why the
yield without the ligand was higher for 4-bromobenzoni-
trile while remaining unchanged for 4-bromobenzotriflu-
oride (Scheme 3).
7
10% Pd/C
PdCl2
DMF
8
toluene
mesitylene
DMA
NMP
9
PdCl2
10
11
PdCl2
PdCl2
a Reaction conditions: sodium p-toluenesulfinate (5a, 2 mmol, 4
equiv), 4-bromobenzotrifluoride (6a, 0.5 mmol, 1 equiv), Pd source
(5 mol%), Cs2CO3 (0.75 mmol, 1.5 equiv), solvent (4 mL), 185 °C, 20
h.
b Isolated yields.
If this observation were related to electron-deficient sub-
stituents, a decrease in yield upon switching from p- (6j)
to m-bromobenzonitrile (6k) should be observed, similar
to the diminished yield obtained in the analogous change
of the substitution pattern of the electron-withdrawing tri-
fluoromethyl group in substrates 6a to 6b or the ester
group from 6g to 6h. Therefore we considered a stabiliz-
ing ligand effect by the cyano group.50 To investigate this
c Side-products observed in GC.
ed the product in 57% (entry 2), whereas the sterically
more demanding 2-bromobenzotrifluoride (6c) gave a
similarly good yield of 58% (entry 3). The use of electron-
rich aryl bromides 6d–f provided the product 7 in slightly
reduced but still useful yields (entries 4–6). The electron-
CF3
O
O
CF3
S
no Pd
+
+
ArSO2Na
Br
CF3
5a
6a
7a
8a
3%
78%
Scheme 2 Reaction under palladium- and ligand-free conditions. Reagents and conditions: sodium p-toluenesulfinate (5a; 2 mmol, 4 equiv),
4-bromobenzotrifluoride (6a; 0.5 mmol, 1 equiv), Cs2CO3 (0.75 mmol, 1.5 equiv), DMF (4 mL), 185 °C, 20 h.
R
R
R
ArSO2Na
with dppf
ArSO2Na
no ligand
Br
7a 82% R = CF3
7j 74% R = CN
6a R = CF3
6i R = CN
7a 82% R = CF3
7j 83% R = CN
Scheme 3 Comparison of reactions with and without ligand. Reagents and conditions: sodium p-toluenesulfinate (5a, 2 mmol, 4 equiv), aryl
bromide 6 (0.5 mmol, 1 equiv), PdCl2 (5 mol%), Cs2CO3 (0.75 mmol, 1.5 equiv), DMF (4 mL), 185 °C, 20 h, dppf (5 mol%).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1715–1721

1718
D. H. Ortgies, P. Forgione
LETTER
Table 2 Scope of the Aryl Bromidea (continued)
possibility, we evaluated the effect of 4-cyano-4′-methyl-
biphenyl (7j), the product of the reaction with bromoben-
zonitrile (6j), on a coupling reaction without a nitrile
present in the substrate (Table 3, entry 1). The initial in-
vestigation included 5 mol% of 7j (1:1 ratio of Pd/RCN);
however, a slightly reduced yield was observed (entry 2).
Subsequently, 20 mol% cyanobiphenyl 7j (1:4 ratio
Pd/RCN), which could fill all coordination sites on palla-
dium, were investigated, but the yield decreased further
(entry 3). Lastly, an excess with respect to palladium of 7j
was explored (entry 4) that increased the yield compared
to entry 3 but it was lower than without the nitrile present
(entry 1). Therefore, all these preliminary experiments
seemed to show no positive effect for the labile ligand 4-
cyano-4′-methylbiphenyl (7j) on the reaction, although an
interesting variation in yield was observed. Further stud-
ies involving other nitrile ligands are required to fully elu-
cidate the potential role of the cyano group in the reaction
mechanism.
SO2Na
PdCl2 (5 mol%)
Cs2CO3 (1.5 equiv)
R
5a
+
DMF, 185 °C, 20 h
R
7
Br
Entry
9
6
Aryl bromide
Yield (%)b
63
F
6i
6j
Br
CN
CN
10
83
Br
11
12
13
14
6k
6l
83
54
–
Table 2 Scope of the Aryl Bromidea
Br
NC
SO2Na
PdCl2 (5 mol%)
Cs2CO3 (1.5 equiv)
Br
Br
R
5a
NMe2
NO2
+
DMF, 185 °C, 20 h
6m
6n
R
7
Br
6
–
Br
Entry
Aryl bromide
Yield (%)b
82
a Reaction conditions: sodium p-toluenesulfinate (5a, 2 mmol, 4
equiv), aryl bromide 6 (0.5 mmol, 1 equiv), PdCl2 (5 mol%), Cs2CO3
(0.75 mmol, 1.5 equiv), DMF (4 mL), 185 °C, 20 h.
b Isolated yields.
CF3
1
2
6a
6b
Br
c PdCl2 (10 mol%).
57
58
Table 3 Effect of 4-Cyano-4′-methylbiphenyl as Additivea
Br
Br
CF3
SO2Na
PdCl2 (5 mol%)
Cs2CO3 (1.5 equiv)
3
6c
5a
CF3
7j (additive)
OMe
+
MeO
Br
DMF, 185 °C, 20 h
4
5
6
6d
6e
6f
50
55
55
7e
Br
OMe
6e
Entry
Amount 7j (mol%)
Yield (%)b
Br
Br
OMe
OMe
c
1
2
3
4
–
55
47
34
42
2
20
40
CO2Et
CO2Et
7c
8c
6g
6h
68
45
Br
Br
Synlett 2013, 24, 1715–1721
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ligand-Free Palladium-Catalyzed Cross-Couplings of Aryl Sulfinates
1719
Table 3 Effect of 4-Cyano-4′-methylbiphenyl as Additivea
Table 4 Scope of the Aryl Sulfinatea
SO2Na
SO2Na
PdCl2 (5 mol%)
Cs2CO3 (1.5 equiv)
CN
PdCl2 (5 mol%)
Cs2CO3 (1.5 equiv)
R
5a
5
+
7j (additive)
OMe
+
DMF, 185 °C, 20 h
DMF, 185 °C, 20 h
CN
R
7e
7
Br
OMe
Br
6e
6j
Entry
Amount 7j (mol%)
Yield (%)b
Entry
Aryl sulfinate
Yield (%)b
45
a Conditions: sodium toluenesulfinate (5a, 2 mmol, 4 equiv), 3-bro-
moanisole (6e, 0.5 mmol, 1 equiv), PdCl2 (5 mol%), 4-cyano-4′-meth-
ylbiphenyl (7j), Cs2CO3 (0.75 mmol, 1.5 equiv), DMF (4 mL),
185 °C, 20 h.
SO2Na
6
5f
Cl
SO2Na
SO2Na
b Isolated yields.
c See Table 2, entry 5.
7
5g
80
52
MeO
MeO
An investigation into the sulfinates 5 employed in the
cross-coupling (Table 4) began with the investigation of
the p- (5a) vs. m-toluenesulfinate (5b; entry 1 vs. 2),
which interestingly reduced the yield drastically. Chang-
ing to the ortho-toluenesulfinate 5c (entry 3) decreased
the yield even further, which likely is due to increased ste-
ric hindrance. The tert-butyl substituent on 5d gave a
moderate yield (entry 4) as did the reaction with benzene-
sulfinate 5e (entry 5). 4-Chloro-substituted 5f did not im-
prove the yield (entry 6). An excellent yield was observed
for the electron-rich 4-methoxybenzenesulfinate 5g (entry
7), but the less activated meta position in 5h gave only a
moderate yield (entry 8).
8c
5h
a Conditions: sodium aryl sulfinate 5 (2 mmol, 4 equiv), aryl bromide
6j (0.5 mmol, 1 equiv), PdCl2 (5 mol%), Cs2CO3 (0.75 mmol, 1.5
equiv), DMF (4 mL), 185 °C, 20 h.
b Isolated yields.
c 4-Bromobenzotrifluoride (6a) instead of 4-bromobenzonitrile (6j)
Overall, an efficient ligand-free, palladium-mediated
cross-coupling between aryl bromides and aryl sulfinates
has been developed. A range of substrates can be em-
ployed that yield the product in moderate to excellent
yields. Although the reaction is likely a palladium(0)-cat-
alyzed transformation, further mechanistic studies are re-
quired to better understand the reaction and will provide
insights to aid in further improvements.
Table 4 Scope of the Aryl Sulfinatea
SO2Na
CN
PdCl2 (5 mol%)
Cs2CO3 (1.5 equiv)
R
5
All reactions, unless more specific conditions are stated, were per-
formed in an oven-dried (110 °C) microwave vial under an argon at-
mosphere containing a Teflon-coated stirrer bar and dry septum.
Chemicals were purchased from Aldrich and Alfa Aesar and used
without further purification. All solvents were purchased as ACS
grade from Fisher Scientific or JT Baker and were dried over acti-
vated MS 3 Å, distilled water was obtained from an in-house water
distillery prior to use. Column chromatography was performed us-
ing silica gel (Zeoprep 60 Eco, 40–63 μm, Zeochem AG).
1H NMR and 13C NMR spectra were recorded on a Varian VNMRS-
500 NMR (1H NMR: 500 MHz; 13C NMR: 125 MHz). Tetrameth-
ylsilane was used as a reference for the 1H NMR and 13C NMR spec-
tra. The molecular masses of the compounds were obtained on a
GC–MS system [GC: Agilent 7890A, column HP 140915-433A,
MS: Agilent 5975C VL MSD (EI, 70 eV)].
+
DMF, 185 °C, 20 h
CN
R
7
Br
6j
Entry
Aryl sulfinate
Yield (%)b
83
SO2Na
1
5a
SO2Na
2
3
5b
5c
17
12
SO2Na
General Procedure
Aryl sulfinate (2 mmol), bromoarene (0.5 mmol), PdCl2 (0.05
mmol), and anhyd Cs2CO3 (244 mg, 0.75 mmol) were added to a
vial under an argon atmosphere followed by the addition of anhyd
DMF (4 mL). The vial was sealed with a PTFE septum and heated
for 20 h at 185 °C. The mixture was allowed to cool to 23 °C, fil-
tered over Celite®, and the vial and the Celite® pad were successive-
ly washed with EtOAc (20 mL) and H2O (15 mL). After separating
the layers the aqueous layer was extracted with EtOAc (20 mL), and
the combined organic phases were washed with brine (2 ×15 mL),
SO2Na
4c
5
5d
5e
66
60
t-Bu
SO2Na
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1715–1721

1720
D. H. Ortgies, P. Forgione
LETTER
followed by sat. NaHCO3 solution (2 × 15 mL), and lastly brine (2
× 15 mL). The combined organic phases were dried over anhyd
Na2SO4, and the solvent was removed under reduced pressure. The
crude, colored product was purified by column chromatography to
yield a colorless solid.
Vicente, R.; Kapdi, A. R. Angew. Chem. Int. Ed. 2009, 48,
9792. (c) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2009, 48, 5094. (d) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(e) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36,
1173.
Representative Example: 4-Cyano-4′-methyl-1,1′-biphenyl (7j)
[CAS Reg. No.: 50670-50-3]
(7) For selected examples, see: (a) Lange, P. P.; Goossen, L. J.;
Podmore, P.; Underwood, T.; Sciammetta, N. Chem.
Commun. 2011, 47, 3628. (b) Goossen, L. J.; Rodríguez, N.;
Lange, P. P.; Linder, C. Angew. Chem. Int. Ed. 2010, 49,
1111. (c) Goossen, L. J.; Rodríguez, N.; Linder, C.; Lange,
P. P.; Fromm, A. ChemCatChem 2010, 2, 430. (d) Goossen,
L. J.; Linder, C.; Rodríguez, N.; Lange, P. P. Chem. Eur. J.
2009, 15, 9336. (e) Goossen, L. J.; Manjolinho, F.; Khan, B.
A.; Rodriguez, N. J. Org. Chem. 2009, 74, 2620.
Compound 7j was prepared from 4-bromobenzonitrile (6j; 91 mg,
0.5 mmol) and sodium p-toluenesulfinate (5a; 356 mg, 2 mmol).
Purification by column chromatography (5–10% Et2O–hexanes)
gave a colorless solid (80 mg, 0.41 mmol, 83%); mp 103–105 °C.
The spectroscopic data (NMR, GC–MS) matched those reported in
the literature for 4-cyano-4′-methyl-1,1′-biphenyl.
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 7.29 (dm, 2 H,
3
3J = 8 Hz, H-3′/H-5′), 7.49 (dm, 2 H, J = 8 Hz, H-2′/H-6′), 7.67
(f) Goossen, L. J.; Linder, C.; Rodríguez, N.; Lange, P. P.;
Fromm, A. Chem. Commun. 2009, 7173. (g) Goossen, L. J.;
Zimmermann, B.; Knauber, T. Angew. Chem. Int. Ed. 2008,
47, 7103. (h) Goossen, L. J.; Knauber, T. J. Org. Chem.
2008, 73, 8631. (i) Goossen, L. J.; Rodríguez, N.; Melzer,
B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc.
2007, 129, 4824. (j) Goossen, L. J.; Deng, G.; Levy, L. M.
Science 2006, 313, 662. (k) Tanaka, D.; Romeril, S. P.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323. (l) Myers,
A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002,
124, 11250. (m) Becht, J.-M.; Le Drian, C. Org. Lett. 2008,
10, 3161. (n) Becht, J.-M.; Le Drian, C.; Catala, C.; Wagner,
A. Org. Lett. 2007, 9, 1781. (o) Cornella, J.; Lahlali, H.;
Larrosa, I. Chem. Commun. 2010, 46, 8276. (p) Mitchell, D.;
Coppert, D. M.; Moynihan, H. A.; Lorenz, K. T.; Kissane,
M.; McNamaraO, A.; Maguire, A. R. Org. Process Res. Dev.
2011, 15, 981. (q) Wong, N. W. Y.; Forgione, P. Org. Lett.
2012, 14, 2738. (r) Bilodeau, F.; Brochu, M.-C.; Guimond,
N.; Thesen, K. H.; Forgione, P. J. Org. Chem. 2010, 75,
1550. (s) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen,
K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006,
128, 11350.
(dm, 2 H, 3J = 9 Hz, H-3/H-5), 7.71 (dm, 2 H, 3J = 9 Hz, H-2/H-6).
13C NMR (125 MHz, CDCl3): δ = 21.2 (CH3), 110.5, 119.0, 127.0,
127.4, 129.8, 132.5, 136.3, 138.7, 145.6. MS (EI, 70 eV): m/z (%) =
165.1 (20), 193.1 (100) [M]+.
Acknowledgment
This work was funded by the Natural Sciences and Engineering Re-
search Council (NSERC) of Canada and Le Fonds de Recherche du
Québec, Nature et Technologies (FQRNT). Support was also kindly
provided by Boehringer Ingelheim, Wyeth, Merck Frosst, and Con-
cordia University. We thank Simon Woo (Concordia University)
for helpful discussions of the manuscript. Dirk Ortgies is grateful to
the Centre in Green Chemistry and Catalysis and Concordia Univer-
sity for scholarships.
References
(1) For recent reviews, see: (a) Hassan, J.; Sévignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
(b) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41,
1461. (c) Ackermann, L. Modern Arylation Methods;
Wiley-VCH: Weinheim, 2009. (d) Johansson Seechurn, C.
C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew.
Chem. Int. Ed. 2012, 51, 5062.
(8) For selected reviews, see: (a) Dzik, W. I.; Lange, P. P.;
Gooßen, L. J. Chem. Sci. 2012, 3, 2671. (b) Cornella, J.;
Larrosa, I. Synthesis 2012, 44, 653. (c) Satoh, T.; Miura, M.
Synthesis 2010, 3395. (d) Rodríguez, N.; Gooßen, L. J.
Chem. Soc. Rev. 2011, 40, 5030.
(2) (a) Hadjuk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J.
Med. Chem. 2000, 43, 3443. (b) Nicolaou, K. C.; Boddy, C.
N. C.; Bräse, S.; Winssinger, N. Angew. Chem Int. Ed. 1999,
38, 2096. (c) The Merck Index: An Encyclopedia of
Chemicals, Drugs, and Biologicals; Merck & Co. Inc:
Whitehouse Station, 2006. (d) Wallace, J. L. Physiol. Rev.
2008, 88, 1547. (e) Wetterau, J. R.; Gregg, R. E.; Harrity, T.
W.; Arbeeny, C.; Cap, M.; Connolly, F.; Chu, C.-H.;
George, R. J.; Gordon, D. A.; Jamil, H.; Jolibois, K. G.;
Kunselman, L. K.; Lan, S.-H.; Maccagnan, T. J.; Ricci, B.;
Yan, M.; Young, D.; Chen, Y.; Fryszman, O. M.; Logan, J.
V. H.; Musial, C. L.; Poss, M. A.; Robl, J. A.; Simpkins, L.
M.; Slusarchyk, W. A.; Sulsky, R.; Taunk, P.; Magnin, D.
R.; Tino, J. A.; Lawrence, R. M.; Dickson, J. K. Jr.; Biller,
S. A. Science 1998, 282, 751.
(9) For reviews, see (a) Dubbaka, S. R.; Vogel, P. Angew.
Chem. Int. Ed. 2005, 44, 7674. (b) Wang, L.; He, W.; Yu, Z.
Chem. Soc. Rev. 2012, 599.
(10) O’Connor Sraj, L.; Khairallah, G. N.; da Silva, G.; O’Hair,
R. A. J. Organometallics 2012, 31, 1801.
(11) (a) Kasahara, A.; Izumi, T.; Kudou, N.; Azami, H.;
Yamamato, S. Chem. Ind. 1988, 51. (b) Kasahara, A.; Izumi,
T.; Miyamoto, K.; Sakai, T. Chem. Ind. 1989, 192.
(12) (a) Miura, M.; Hashimoto, H.; Itoh, K.; Nomura, M.
Tetrahedron Lett. 1989, 30, 975. (b) Miura, M.; Hashimoto,
H.; Itoh, K.; Nomura, M. J. Chem. Soc., Perkin Trans. 1
1990, 8, 2207.
(13) (a) Reddy Dubbaka, S.; Zhao, D.; Fei, Z.; Rao Volla, C.;
Dyson, P.; Vogel, P. Synlett 2006, 3155. (b) Dubbaka, S.;
Vogel, P. Chem. Eur. J. 2005, 11, 2633.
(3) (a) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41,
1461. (b) Pu, L. Chem. Rev. 1998, 98, 2405. (c) Noyori, R.
Chem. Soc. Rev. 1989, 18, 187.
(14) (a) Dubbaka, S.; Steunenberg, P.; Vogel, P. Synlett 2004,
1235. (b) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003,
125, 15292.
(4) Matheron, M. E.; Porchas, M. Plant Dis. 2004, 88, 665.
(5) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem.
Int. Ed. 2009, 48, 9792. (b) Picken, S. J.; van Gunsteren, W.
F.; van Duijnen, P. T.; de Jeu, W. H. Liquid Crystals 2006,
33, 1363.
(15) Dubbaka, S. R.; Vogel, P. Org. Lett. 2004, 6, 95.
(16) Dubbaka, S.; Vogel, P. Adv. Synth. Catal. 2004, 346, 1793.
(17) Dubbaka, S. R.; Vogel, P. Tetrahedron Lett. 2006, 47, 3345.
(18) (a) Rao Volla, C. M.; Dubbaka, S. R.; Vogel, P. Tetrahedron
2009, 65, 504. (b) Volla, C. M. R.; Markovic, D.; Dubbaka,
S. R.; Vogel, P. Eur. J. Org. Chem. 2009, 6281. (c) Rao
(6) For selected reviews, see: (a) Newhouse, T.; Baran, P. S.
Angew. Chem. Int. Ed. 2011, 50, 3362. (b) Ackermann, L.;
Synlett 2013, 24, 1715–1721
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ligand-Free Palladium-Catalyzed Cross-Couplings of Aryl Sulfinates
1721
Volla, C. M.; Vogel, P. Angew. Chem. Int. Ed. 2008, 47,
1305.
(19) Zhang, S.; Zeng, X.; Wei, Z.; Zhao, D.; Kang, T.; Zhang, W.;
Yan, M.; Luo, M. Synlett 2006, 1891.
(20) Kashiwabara, T.; Tanaka, M. Tetrahedron Lett. 2005, 46,
7125.
(35) Wang, G.-W.; Miao, T. Chem. Eur. J. 2011, 17, 5787.
(36) Hu, S.; Ping, X.; Cheng, K.; Qi, C. Appl. Organomet. Chem.
2013, 27, 188.
(37) (a) Liu, B.; Guo, Q.; Cheng, Y.; Lan, J.; You, Y. Chem. Eur.
J. 2011, 17, 13415. (b) Wang, M.; Li, D.; Zhou, W.; Wang,
L. Tetrahedron 2012, 68, 1926.
(21) Zeng, X.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011,
133, 17638.
(38) Sato, K.; Okoshi, T. US 5159082, 1992; Chem. Abstr. 1991,
114, 121787
(22) Zhang, M.; Zhang, S.; Liu, M.; Cheng, J. Chem. Commun.
2011, 47, 11522.
(39) Zhou, C.; Liu, Q.; Li, Y.; Zhang, R.; Fu, X.; Duan, C. J. Org.
Chem. 2012, 77, 10468.
(23) (a) Liu, B.; Li, J.; Song, F.; You, J. Chem. Eur. J. 2012, 18,
10830. (b) Yu, X.; Li, X.; Wan, B. Org. Biomol. Chem.
2012, 10, 7479.
(24) Yang, F.-L.; Ma, X.-T.; Tian, S.-K. Chem. Eur. J. 2012, 18,
1582.
(25) Garves, K. J. Org. Chem. 1970, 35, 3273.
(26) Selke, R.; Thiele, W. J. Prakt. Chem. 1971, 313, 875.
(27) (a) Schank, K.; Kessler, U.; Bell, K. Phosphorus, Sulfur
Silicon Relat. Elem. 1999, 153, 377. (b) Kice, J.; Bowers, K.
J. Am. Chem. Soc. 1962, 605. (c) Horner, L.; Basedow, O. H.
Liebigs Ann. Chem. 1958, 612, 108.
(40) Chen, W.; Li, P.; Miao, T.; Meng, L.-G.; Wang, L. Org.
Biomol. Chem. 2013, 11, 420.
(41) Zhao, F.; Tan, Q.; Xiao, F.; Zhang, S.; Deng, G.-J. Org. Lett.
2013, 15, 1520.
(42) Colomb, J.; Billard, T. Tetrahedron Lett. 2013, 54, 1471.
(43) (a) Sévigny, S.; Forgione, P. Chem. Eur. J. 2013, 19, 2256.
(b) Sévigny, S.; Forgione, P. New J. Chem. 2013, 37, 589.
(44) Ortgies, D. H.; Barthelme, A.; Aly, S.; Desharnais, B.;
Rioux, S.; Forgione, P. Synthesis 2013, 45, 694.
(45) Anthony, E. J.; Granatstein, D. L. Prog. Energy Combust.
Sci. 2001, 27, 215.
(28) Rao, B.; Zhang, W.; Hu, L.; Luo, M. Green Chem. 2012, 14,
3436.
(46) Ober, J. A. U.S. Geol. Surv., Mineral Commodity Summaries
1998, 166; for archives at USGS, see:
(29) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem. Soc.,
Chem. Commun. 1979, 637.
(30) Rao, H.; Yang, L.; Shuai, Q.; Li, C.-J. Adv. Synth. Catal.
2011, 353, 1701.
(31) (a) Behrends, M.; Sävmarker, J.; Sjöberg, P. J. R.; Larhed,
M. ACS Catal. 2011, 1, 1455. (b) Chen, J.; Sun, Y.; Liu, B.;
Liu, D.; Cheng, J. Chem. Commun. 2012, 48, 449. (c) Miao,
T.; Wang, G.-W. Chem. Commun. 2011, 47, 9501. (d) Liu,
J.; Zhou, X.; Rao, H.; Xiao, F.; Li, C.-J.; Deng, G.-J. Chem.
Eur. J. 2011, 17, 7996.
http://minerals.usgs.gov/minerals/pubs/commodity/sulfur/.
(47) For examples on ligand-free Pd-mediated reactions see:
(a) Khedkar, M. V.; Tambade, P. J.; Qureshi, Z. S.; Bhanage,
B. M. Eur. J. Org. Chem. 2010, 6981. (b) MacQuarrie, S.;
Barnes, J.; McEleney, K.; Horton, J. H.; Loock, H. P.;
Crudden, C. M. Angew. Chem. Int. Ed. 2008, 47, 3279.
(c) Tambade, P. J.; Patil, Y. P.; Bhanushali, M. J.; Bhanage,
B. M. Synthesis 2008, 2347.
(48) Negishi, E. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Vol. 1; Negishi, E., Ed.; Wiley: New
York, 2002, 31.
(49) (a) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc. 1979, 101,
6319. (b) Fauvarque, J.-F.; Pflüger, F. J. Organomet. Chem.
1981, 208, 419.
(32) Zhou, X.; Luo, J.; Liu, J.; Peng, S.; Deng, G.-J. Org. Lett.
2011, 13, 1432.
(33) Chen, W.; Zhou, X.; Xiao, F.; Luo, J.; Deng, G.-J.
Tetrahedron Lett. 2012, 53, 4347.
(34) (a) Wu, M.; Luo, J.; Xiao, F.; Zhang, S.; Deng, G.-J.; Luo,
H.-A. Adv. Synth. Catal. 2012, 354, 335. (b) Chen, R.; Liu,
S.; Liu, X.; Yang, L.; Deng, G.-J. J. Org. Biomol. Chem.
2011, 9, 7675.
(50) For reviews on nitriles as ligands, see: (a) Michelin, R. A.;
Mozzon, M.; Bertani, R. Coord. Chem. Rev. 1996, 147, 299.
(b) Walton, R. A. Q. Rev. Chem. Soc. 1965, 19, 126.
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