Palladium-catalyzed desulfitative heck-type reaction of aryl sulfinic acids with alkenes

Article abstract of DOI:10.1002/chem.201100539

An efficient protocol has been developed for the desulfitative Heck-type reaction of aryl sulfinic acids with a variety of alkenes in the presence of a catalytic amount of Pd(OAc)₂ and inexpensive Cu(OAc)₂ as oxidant. This method does not require a ligand or a base, thereby broadening the scope of Pd-catalyzed coupling reactions. Copyright

Full text of DOI:10.1002/chem.201100539

COMMUNICATION
DOI: 10.1002/chem.201100539
Palladium-Catalyzed Desulfitative Heck-Type Reaction of Aryl Sulfinic
Acids with Alkenes
Guan-Wu Wang* and Tao Miao[a]
The Heck reaction is a powerful tool for the arylation of
alkenes in organic synthesis[1–3] such as natural product total
synthesis.[4] In the Heck reaction, the arylating reagents are
traditionally aryl iodides and aryl bromides (Scheme 1,
[Eq. (1)]).[1] A plethora of variants[2–4] for the aryl halides
ference in the reaction mechanisms for the conventional
Heck reaction and the Heck-type reaction of aromatic or-
ganic acids lies in the different pathways leading to the aryl
palladium(II) species. The former is generated by the oxida-
tive addition of aryl halides or pseudohalide species to palla-
dium(0),[2–4] whereas the latter is produced by the initiation
[5]
À
of palladium(II) and decarboxylative C C bond cleavage /
À
[6]
C P bond cleavage. Herein, we disclose the Pd-catalyzed
Heck-type reaction of another kind of aromatic organic
acid, that is, aryl sulfinic acids, with alkenes initiated by a
palladium(II) species (Scheme 1, [Eq. (4)]).
In our initial study, we investigated the Heck-type reac-
tion of benzenesulfinic acid (1a) with styrene (2a) in the
presence of a palladium catalyst (10 mol%) to optimize the
reaction conditions with various oxidants and solvents.
Silver salts were first chosen as the oxidant with dioxane as
the solvent, and it was found that Ag2CO3 was more effi-
cient than AgOAc, affording (E)-stilbene in 76% and 51%
yield, respectively (entry 2 vs. entry 1, Table 1). In compari-
son, K2S2O8 and O2 were not proper oxidants and dramati-
Scheme 1. Various Heck-type reactions.
Table 1. Heck-type reaction of benzenesulfinic acid with styrene under
various conditions.[a]
have emerged since its discovery in the early 1970s. Aryl tri-
flates, aryl diazonium salts, diaryl iodonium salts, aroyl
chlorides, and aroyl anhydrides as aryl palladium precursors
have subsequently been developed.[2,4] The unreactive aryl
chlorides can also be employed in the Heck reaction by
using bulky, electron-rich phosphanes and carbenes as the li-
gands.[3] In contrast, aromatic organic acids have been
seldom utilized in the Heck reaction, and until now only
aryl carboxylic acids[5] and aryl phosphonic acids[6] have
been described as the source of aryl groups in the Heck re-
action (Scheme 1, [Eq. (2) and (3)]). The most striking dif-
Entry
Oxidant (equiv)
Solvent [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
AgOAc (1)
Ag2CO3 (1)
K2S2O8 (1)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
NMP (100)
DMSO (100)
EtOH (78)[d]
AcOH (100)
CH3CN (81)[d]
DCE (83)[d]
51
76
46
25
85
80
83
55
78
44
39
51
78
37
43
56
[c]
O2
CuACTHNGUETRN(UNG OAc)2·H2O (1)
CuCl2·2H2O (1)
CuBr2 (1)
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
ACHTUNGTRENNUNG
9
ACHTUNGTRENNUNG
10
11
12
13
14
15
16
ACHTUNGTRENNUNG
N
[a] Prof. Dr. G.-W. Wang, T. Miao
AHCTUNGTRENNUNG
Hefei National Laboratory for Physical Sciences at Microscale
CAS Key Laboratory of Soft Matter Chemistry
Joint Laboratory of Green Synthetic Chemistry
and Department of Chemistry
University of Science and Technology of China, Hefei
Anhui 230026 (P. R. China)
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
N
o-xylene (100)
[a] Unless otherwise specified, all reactions were carried out using 10
mol% of Pd(OAc)2, 0.25 mmol of 1a, 0.3 mmol of 2a, and 1.5 mL of sol-
vent under different conditions for 24 h. [b] Yield of isolated product.
[c] Under an oxygen atmosphere. [d] Refluxing temperature of the sol-
vent.
Fax : (+86)551-3607864
E-mail: gwang@ustc.edu.cn
AHCTUNGTRENNUNG
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100539.
Chem. Eur. J. 2011, 17, 5787 – 5790
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5787

Table 2. Heck-type reaction of aryl sulfinic acids with olefins.[a]
cally reduced the yield to 46% and 25%, respectively (en-
tries 3 and 4, Table 1). Pleasingly, when copper sources were
employed, (E)-stilbene was obtained in excellent yield (en-
tries 5–7, Table 1). Copper(II) acetate proved to be more
active than other copper sources, furnishing (E)-stilbene in
85% yield (entry 5, Table 1). Reducing the oxidant loading
decreased the yield significantly, while increasing the load-
ing did not improve the yield (entries 8 and 9, Table 1). Fur-
ther screening of solvents revealed that dioxane was the
best solvent; other polar solvents such as N-methyl-2-pyrro-
lidone (NMP), ethanol, and DMF were harmful to this
transformation (entries 10–12, Table 1). Interestingly, an iso-
lated yield of 78% was achieved when acetic acid was used
as the solvent (entry 13, Table 1). Several low-polar solvents
including acetonitrile, dichloroethane (DCE), and o-xylene
were also examined under similar conditions, but all gave in-
ferior results compared to dioxane (entries 14–16 vs. entry 5,
Table 1). A palladium catalyst is indispensable, as the reac-
tion did not proceed with only silver or copper salts. It is
noteworthy that although aryl sulfonyl chlorides have been
employed for the Pd-catalyzed desulfitative Heck-type reac-
tion,[7] benzenesulfonic acid, instead of benzenesulfinic acid,
proved unreactive towards styrene under our optimal condi-
tions (entry 5, Table 1), and the desired cross-coupling prod-
uct was not obtained. This result demonstrated the unique
properties and privileges of aryl sulfinic acids over aryl sul-
fonic acids in this desulfitative Heck-type reaction.
With the optimized reaction conditions (Pd
ACHTUNGERTN(NUNG OAc)2
(10 mol%), Cu(OAc)2·H2O (1 equiv), dioxane (1.5 mL),
ACHTUNGTRENNUNG
1008C, 24 h) in hand, this Pd-catalyzed desulfitative Heck-
type reaction was then extended to a wide array of aryl sul-
finic acids and styrenes/acrylic derivatives to explore the
scope and limitations of the reaction (Table 2). Benzenesul-
finic acid (1a) reacted efficiently with both electron-rich
and -deficient styrenes (2b and 2c), affording the coupling
products 3ab and 3ac in 75–83% yields. Acrylic esters such
as methyl acrylate (2d), ethyl acrylate (2e), and n-butyl ac-
rylate (2 f) were better substrates than styrenes, and reacted
with 1a to give products 3ad, 3ae, and 3af, respectively, in
higher yields (89–94%). Intriguingly, 1a could also react
with disubstituted olefins such as (E)-ethyl crotonate (2g)
and methyl methacrylate (2h) to generate products 3ag and
3ah with high regioselectivity and stereoselectivity, albeit in
expectedly lower yields (41–57%). Although the reaction
with acrylic amide (2i) under our optimized conditions gave
a disappointingly low yield, the desired product 3ai could be
obtained in 61% yield when the reaction was carried out in
acetic acid at 808C for 24 h under otherwise the same condi-
tions. To further expand the scope of this reaction, we next
examined the coupling reaction of several other aryl sulfinic
acids such as 4-methylbenzenesulfinic acid (1b), 4-chloro-
benzenesulfinic acid (1c), 4-fluorobenzenesulfinic acid (1d),
4-methoxybenzenesulfinic acid (1e), 2,4,6-trimethylbenzene-
sulfinic acid (1 f), and 2-naphthylsulfinic acid (1g) with dif-
ferent olefin substrates. Aryl sulfinic acids bearing methyl,
chloro, and fluoro groups provided the cross-coupling prod-
ucts with either styrene or acrylic esters in high yields (71–
[a] Unless otherwise specified, all reactions were carried out using
0.25 mmol of 1, 0.3 mmol of alkene 2, 0.025 mmol (10 mol%) of Pd-
A
ACHTUGNRTEN(NUGN OAc)2·H2O in dioxane (1.5 mL) at 1008C
AHCTUNGTRENNUNG
92%). Aryl sulfinic acid 1e containing the strong electron-
donating methoxy group decreased the reactivity, but good
5788
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Chem. Eur. J. 2011, 17, 5787 – 5790

Pd-Catalyzed Coupling Reactions
COMMUNICATION
yields (67–85%) could still be achieved with slightly higher
catalyst loading. When the 2,4,6 positions of benzenesulfinic
acid were substituted with methyl groups, that is, 1 f, the
product yield with styrene was reduced dramatically to
52%, probably due to the steric hindrance. However, the re-
action of 1 f proceeded smoothly with acrylic esters, produc-
ing 3 fd and 3 ff in yields of 78% and 73%, respectively.
Moreover, the reaction of 2-naphthylsulfinic acid was also
effective to give the corresponding cross-coupling products
3ga, 3gd, and 3gf in good yields (66–82%).
As seen from Table 2, only one isomer with trans-configu-
ration was identified in each case, reflecting the extremely
high regioselectivity and stereoselectivity of our Heck-type
reaction. In a conventional Heck reaction, a base and a
ligand are usually required for the conversion of the hydri-
dopalladium(II) complex to the active palladium(0) catalyst
and the stabilization of the regenerated palladium(0) spe-
cies, respectively.[1–4] In sharp contrast, our Heck-type reac-
tion did not require any base or ligand.
tion of Pd0 to ArSO2Cl is involved.[7] Elimination of SO2
from complex A generates ArPdX, which inserts into the
olefin to give intermediate B. A b-H elimination from inter-
mediate B furnishes the final coupling product 3 and Pd0
species. Oxidation of Pd0 by Cu
(OAc)2. A palladium(II)-catalyzed pathway with CuACHTUNGTRENNUNG
ACHTUNGTRENNUNG
T
as an oxidant has also been described for the Heck-type re-
action of aryl boronic acids with alkenes.[9]
In the conventional Heck reaction, organic halides usually
cannot contain b-hydrogens because they are easily elimi-
nated to give olefins.[1] Therefore, the use of aliphatic hal-
ides as coupling partners in the Heck reaction is rare and
challenging; aliphatic carboxylic and phosphonic acids as
the alkyl source have not been described.[5,6] We attempted
the Pd-catalyzed reaction of benzylsulfinic acid with 4-
chloroACHTNUTRGNEsNUG tyrene and that with butyl acrylate under our stan-
dard conditions, and obtained the desired coupling products
4ac and 4af only in 6% yield and in trace amounts, respec-
tively. When tricyclohexylphosphine as ligand was added to
Pioneering work by the Myers group on the Pd-catalyzed
decarboxylative Heck reaction is certainly a landmark. Nev-
ertheless, at least one ortho substituent for aryl carboxylic
acids was necessary for the successful decarboxylative palla-
dation to occur.[5] It was found that a high loading of palladi-
and CuACTHNGUTERNU(NG OAc)2 was removed from the reaction systems, the
yields were improved to 22% and 17%, respectively
(Scheme 3).[10] Although the yields were still low, our results
demonstrated the feasibility of the SO2 extrusion from ali-
phatic sulfinic acids to form alkyl palladium and subsequent
coupling with alkenes.
um and silver, excess acid additive, or carbene ligand for the
[5]
À
C C bond fission, and the unusual oxidant Me3NO with
[6]
À
TBAF as the activator for the C P bond cleavage were
crucial in the previous work. Therefore, our protocol, which
employed aryl sulfinic acids with catalytic Pd
ACHTUNGRTENUN(NG OAc)2 and in-
expensive Cu(OAc)2, has its own merits and is complemen-
ACHTUNGTRENNUNG
tary to the existing methodologies.[5,6] Notably, the reaction
of sodium p-toluenesulfinate with alkenes in the presence of
a stoichiometric amount of a palladium(II) salt has been re-
ported,[8] yet our catalytic version is much more efficient.
Although the mechanism of this reaction is not clear right
now, we propose a possible pathway compatible with our
data (Scheme 2). The first step is presumably a ligand ex-
Scheme 3. Palladium-catalyzed reaction of benzylsulfinic acid with al-
kenes.
In conclusion, we have developed an efficient protocol for
the desulfitative Heck-type reaction of aryl sulfinic acids
with a variety of alkenes in the presence of a catalytic
change between PdACHTUNGTRENNUNG(OAc)2 and the aryl sulfinic acid provid-
ing complex A. This step is mechanistically distinct from the
first step in the Pd-catalyzed desulfitative Heck-type reac-
tion of aryl sulfonyl chlorides, in which the oxidative addi-
amount of PdACTHNUGRTENNUG(OAc)2 and cheap CuACHTUNGTRNEN(GUN OAc)2 as oxidant. Our
method doesn’t require a ligand or a base, broadening the
scope of Pd-catalyzed coupling reactions. The investigation
of aryl sulfinic acids as the aryl source in other coupling re-
actions is underway.
Experimental Section
General procedure for the Heck-type reaction of aryl sulfinic acids with
alkenes catalyzed by Pd
a suspension of aryl sulfinic acid (1a–g, 0.25 mmol), Pd
0.025 mmol), and Cu(OAc)2·H2O (50.0 mg, 0.25 mmol) in dioxane
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(1.5 mL) with magnetic stirring. The mixture was stirred at 1008C for
24 h. After completion of the reaction, the solvent was evaporated to dry-
ness in vacuo. The residual was separated on a silica gel column with pe-
troleum ether/ethyl acetate 15/1 as the eluent to get the desired product
3aa–3gf.
Scheme 2. Proposed reaction mechanism.
Chem. Eur. J. 2011, 17, 5787 – 5790
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www.chemeurj.org
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G.-W. Wang and T. Miao
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Acknowledgements
The authors are grateful for the financial support from the National
Basic Research Program of China (2011CB921402) and the National Nat-
ural Science Foundation of China (20972145, 91021004).
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Keywords: alkenes
desulfitation · palladium
·
arylation
·
cross-coupling
·
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[10] The presence of Cu
added.
ACHTUNGRTEN(NUNG OAc)2 was detrimental when a ligand was
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Received: February 18, 2011
Published online: April 13, 2011
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Chem. Eur. J. 2011, 17, 5787 – 5790