Oxidative addition of Pd(0) to Ar-SO2R bonds: Heck-type reactions of sulfones

Article abstract of DOI:10.1021/ol060608y

Phenyl vinyl sulfones and sulfoxides react with Pd(OAc)₂ to form styryl sulfoxides and sulfones according to the first Mizoroki-Heck reaction reported for these thio derivatives. Only sulfones are able to react by using catalytic amounts of Pd

Full text of DOI:10.1021/ol060608y

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2683-2686
Oxidative Addition of Pd(0) to Ar
Bonds: Heck-Type Reactions of
Sulfones
−SO2R
Jose´ Luis Garc´ıa Ruano,* Jose´ Alema´n, and Cristina Garc´ıa Paredes
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
joseluis.garcia.ruano@uam.es
Received March 13, 2006
ABSTRACT
Phenyl vinyl sulfones and sulfoxides react with Pd(OAc)2 to form styryl sulfoxides and sulfones according to the first Mizoroki−Heck reaction
reported for these thio derivatives. Only sulfones are able to react by using catalytic amounts of Pd (up to 1 mol %) in the presence of Ag2CO3.
1,2-Diphenylsulfonyl ethenes, alkynylphenyl sulfones, and other sulfones, less prone to act as acceptors in the Heck-type reactions, can
transfer the aryl group to alkyl acrylates forming cinnamic esters.
Transition-metal-catalyzed C-C bond-forming reactions are
the most powerful methods of organic synthesis.1 The
Mizoroki-Heck reaction, first described in the 1970s,2 is
currently a well-documented and exploited process.3 It
consists of the reaction of aryl halides4 with alkenes giving
rise to styrenes with the formation of a Csp2-Csp2 bond.
Aryl halides are usually iodides or bromides, but reactions
with the less expensive and less reactive chlorides are also
successful using Fu’s catalyst3h,5 or carbene ligands.6 Vogel
and co-workers have recently published the use of arene
sulfonyl chlorides instead of aryl halides to achieve these
reactions.7 This contribution is conceptually interesting
because it is the first general method involving the oxidative
insertion of Pd(0) into the Ph-S bond8 that increases the
scope of the Mizoroki-Heck reaction, so far limited to aryl
halides. However, to our knowledge, the use of other sulfur
compounds such as aryl thioethers, aryl sulfoxides, and aryl
sulfones as substrates of these reactions catalyzed with Pd
in a Heck reaction has never been reported.9 In this paper,
we report our results concerning the behavior of thioethers,
(1) (a) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985. (b) Tsuji, J. Palladium Reagents and Catalysts:
InnoVations in Organic Synthesis; Wiley & Sons: New York, 1995. (c)
Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 4.
(2) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 14, 2320.
(3) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) de Meijere, A.; Meyer,
F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379. (c) Jeffery T. In AdVances
in Metal-Organic Chemistry; Liebeskind, L S., Ed.; JAI: London, 1996;
Vol. 28, p 153. (d) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (e)
Heck, R. F. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon: New York, 1991; Vol. 4, Chapter 4.3. (f). Crip, G. T. Chem.
Soc. ReV. 1998, 27, 427. (g) Beletskaya, I. P.; Cheprakov, A. V. Chem
ReV. 2000, 100, 3009. (h) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 114, 4176. (i) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schu¨lz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359. (j) Alonso, F.; Beletskaya, I.;
Yus, M. Tetrahedron 2005, 61, 11771.
(5) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1290.
(6) Hermman, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b) Zhang,
C.; Huang, J.; Trudell, M. L.; Nolan S. P. J. Org. Chem. 1999, 64, 3804.
(7) (a) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003, 125, 15292.
(b) Dubbaka, S. R.; Vogel, P. Org. Lett. 2004, 6, 95. (c) Dubbaka, S. R.;
Vogel, P. AdV. Synth. Catal. 2004, 346, 1793. (d) Dubbaka, S. R.; Vogel,
P Chem. Eur. J. 2005, 11, 2633. (e) For a review on sulfur compounds as
electrophilic reagents in metal catalyzed reactions, see: Dubbaka, S. R.;
Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674.
(4) (a) Jutand, A.; Mosleh, A. Organometallics 1998, 17, 954. (b)
Shaughnessy, K.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121,
2123. (c) Magnus, C.; Hallberg, A. J. Org. Chem. 1988, 53, 2112. (d) Littke,
A.; Fu G. C. J. Org. Chem, 1999, 64, 10. (e) Crampton, M. R. In Organic
Reaction Mechanisms; Knipe, A. C., Watts, W. E., Eds.; John Wiley &
Sons Ltd.: New York, 1997; p 1995.
(8) Arenesulfonates have been used for cross-coupling reactions. See:
(a) Precer, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060. (b)
Hguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
11818. (c) Miura, M.; Hashimoto, H.; Itoh, K.; Nomura, M. Tetrahedron
Lett. 1989, 30, 975. (d) Miura, M.; Hashimoto, H.; Itoh, K.; Nomura, M. J.
Chem. Soc., Perkin Trans. 1 1990, 8, 2207.
10.1021/ol060608y CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/23/2006

sulfoxides, and sulfones which demonstrate that some of the
arylsulfinyl and arylsulfonyl derivatives are also able to
undergo the oxidative addition of Pd in their Ar-S bond
and therefore may be used in the Mizoroki-Heck reaction
with deactivated olefins (Scheme 1).
Table 1. Reactions of Vinylthio Derivatives with
Stoichiometric Pd(OAc)2 under Different Conditions
Scheme 1
time
conversion
entry
n
T (°C)
(days)
product
(isolated yield) (%)
1
2
3
4
5
6
0
1
1
2
2
2
120
60
120
60
60
120
3
6
5
3
6
3
2
2
5
5
5
65
100 (57)
54
100 (51)
100 (55)11
In the search for new conditions and catalysts to control
the π-facial selectivity of the asymmetric Diels-Alder
reactions of vinyl sulfoxides,10 we found that compound 2
(Scheme 2) was formed as a byproduct in low but significant
only possible for sulfoxides and sulfones, whereas thioethers
are not able to react under the same conditions.
We then tried the crossed reactions of ethyl acrylate and
the aryl thio derivatives 1, 3, or 412 with the aim of obtaining
the cinnamyl esters resulting from the transfer of the phenyl
group from these thio derivatives. The results were identical
to those shown in Table 1, thus indicating that the sulfinyl
and sulfonyl ethylenes are much more efficient as acceptors
than the conjugated esters. The reactions of compounds such
as PhSOnPh and PhSOnMe (n ) 0-2), which do not exhibit
acceptor properties, with ethyl acrylate and Pd(OAc)2 under
different conditions were unfruitful, showing that these thio
derivatives cannot undergo oxidative addition onto the Ph-S
bond.
Before exploring other substrates, it was necessary to look
for conditions that allowed an efficient use of the Pd(OAc)2
in catalytic amounts. Therefore, we investigated the influence
of many additives and bases (Et3N, AcONa, K2CO3, and Na2-
CO3). Finally, we found that only Ag2CO3 was efficient
(AgOAc only provides 10% yield under catalytic conditions).
Thus, compound 5 can be obtained in 59% isolated yield by
heating 4 in DMF at 110 °C with Ag2CO3 (10 mol %) and
5 mol % of the Pd(OAc)2. The complete conversion of 4
can also be achieved with 1 mol % of catalyst, but the
reaction is not so clean, the isolated yield is lower (55%),
and it required longer reaction time to be complete (4 days).
Under catalytic conditions, sulfoxide 1 evolved into com-
pound 2 but with very low conversion, which suggests that
the process is not catalytic starting from sulfoxides.
A reasonable mechanism compatible with our data is
indicated in Scheme 3. The first step would involve the
coordination of the palladium to the double bond of the
sulfone (thus explaining the absence of reactivity of diaryl
and aryl alkyl sulfones), making easier (entropic reasons)
the oxidative addition to the Ar-S bond (second step).
Finally, coordination of palladium to the double bond of the
acceptor molecule (easier for 1 and 4 than for acrylic esters),
insertion, and â-elimination complete the catalytic cycle
(Scheme 3).
Scheme 2
yield when vinyl phenyl sulfoxide was heated with dienes
for long periods of time in the presence of Pd(OAc)2.
To rationalize this result, we assumed the oxidative
addition of Pd into the C-S bond as the initial step in a
Mizoroki-Heck- type process with the vinyl sulfoxide acting
as an acceptor (Scheme 2). However, when we searched the
literature for results which could support this explanation,
we realized that such processes had never been reported for
sulfoxides. This prompted us to investigate this reaction.
We first studied the reactions of vinyl phenyl thioether
(3), vinyl phenyl sulfoxide (1), and vinyl phenyl sulfone (4)
with 1 equiv of Pd(OAc)2 under different conditions,
obtaining the results indicated in Table 1.
Thioether 3 did not react under any of the conditions used.
After 3 days at 120 °C in DMF it remains unaltered (entry
1, Table 1). By contrast, sulfoxide 1 slowly reacted into the
desired derivative 2 (entries 2 and 3, Table 1). The starting
material completely disappeared after 5 days at 110 °C.
Sulfone 4 could also be transformed into 5 under similar
conditions (entries 4-6, Table 1). The reactivity of the
sulfone is higher than that of the sulfoxide (compare entries
2 and 3 with 5 and 6, respectively, Table 1). These results
suggest that intramolecular Mizoroki-Heck reactions are
(9) A desulfonylative Kumada reaction catalyzed by Ni(acac)2 was
described in: (a) Clayden, J.; Cooney, J. J. A.; Julia, M. J. Chem. Soc.,
Perkin Trans. 1 1995, 7. Suzuki and Negishi reactions have been carried
out with vinyl sulfoxides: See: (b) Ma, S.; Ren, H.; Wei, Q. J. Am. Chem.
Soc. 2003, 125, 4817.
(10) Garc´ıa Ruano, J. L.; Alemparte, C.; Clemente, F. R.; Gonza´lez
Gutierrez, L.; Gordillo, R.; Mart´ın Castro, A. M.; Rodr´ıguez Ramos, J. H.
J. Org. Chem. 2002, 67, 2919 and references therein.
(11) Despite the fact that the yield (55%) is lower than the conversion
(100%), no other byproduct was detected in the reaction mixture after the
workup.
(12) All the reactions were carried out by using 2.20 mmol of the ester,
0.55 mmol of substrate and catalyst, and 2 mL of dried DMF.
2684
Org. Lett., Vol. 8, No. 13, 2006

Scheme 3
Table 2. Reactions of the Sulfones 6-11 with Alkyl Acrylates
and Pd(OAc)2 (5 mol %) under Different Conditions
entry
phosphine
sulfone
R
time
yield (%)
1
2
3
4
5
6
7
8
9
6
6
6
7
Et
3 d
3 d
24 h
3 d
30 h
3 d
3 d
4 d
2 d
4 d
42
53
68
53
56
41
53
45
25
65
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
P(Cy)3 (10%)
P(Cy)3 (10%)
7
8a
8a
9a
10
11
P(Cy)3 (10%)
P(Cy)3 (10%)
This mechanistic proposal suggests that the coordination
of palladium to the double bond is required as a preliminary
step to its oxidative addition into the Ar-S bond. Moreover,
to achieve the cross-coupling reaction it would be necessary
to decrease the acceptor character of the sulfones without
altering their capability to undergo oxidative addition.
In this sense, we have studied the behavior of the sulfones
depicted in Figure 1. The second sulfonyl group present in
10
The use of the (E)-sulfone 7 gave similar results (entries
4 and 5, Table 2) but lower yields when the reactions were
conducted under PCy3 (compare entries 3 and 5, Table 2).
The reactions with the alkynyl sulfones 8a and 9a were also
efficient, with slightly better results when using the silylated
compounds (entries 5-8, Table 2). At this point, it is
remarkable that Liebeskind and co-workers 14 had found that
the oxidative addition occurrs at the C(sp)-S bond for
alkynyl arylthioethers, [CuTC, Pd(PPh3)4, THF at 45-50 °C],
whereas in the case of the sulfones 8 and 9 it takes place at
the Ar-S bond, which reveals the influence of the oxidation
state at sulfur on the course of the reaction (Scheme 4).
Figure 1. Other sulfones used in this study.
Scheme 4
sulfones 6 and 7 should impose steric restrictions to the
coupling process and thus decrease their reactivity and allow
the reaction with other acceptors. Sulfones 10 and 11 cannot
act as acceptors but support a functional group able to
associate with Pd in the first step. Finally, the alkynyl
sulfones 8a and 9a were chosen because the triple bonds
are not common acceptors in Heck-type reactions. All of
them were found to give cross-coupling with acrylic esters.
A summary of the most significant results is given in Table
2. Starting from the (Z)-sulfone 6, we found that the use of
butyl esters provides better yields than ethyl esters (compare
entries 1 and 2, Table 2). The addition of phosphines
improved the yields in some cases. We have studied the
influence of several phosphines on the reactivity. Many of
them have a negative influence (PPh3, dppf, dppp, and Pt-
Bu3),13 but the addition of tricyclohexyl phosphine, PCy3
(10%), improves the isolated yield of compound 12a (68%)
and reduces the required time for completion of the reaction
(1 day, entry 3, Table 2).
Reactions of sulfone 10 with butyl acrylate also yielded
compound 13a (entry 9). Despite the low yield obtained in
this reaction, this result is highly significant because it
supports the suggested need of the existence of a group able
to fix the palladium as a preliminary step to the oxidative
coupling. Finally, reaction of ethyl acrylate and the allyl
sulfone 11 under Pd(OAc)2 catalysis (entry 10, Table 2),
yielding compound 13a, pointed out that the coordination
to the palladium catalyst is once more an essential step in
this Heck reaction.
The last part in this research has been to study the
influence of the electronic effects of the substituents at the
aryl ring on the relative ease of the oxidative addition. We
have chosen alkynyl aryl sulfones 8 and 9 as they were
(13) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
Org. Lett., Vol. 8, No. 13, 2006
(14) Savarin, C.; Srogl, J.; Liebeskind L. S. Org. Lett. 2001, 3, 91.
2685

obtained readily from alkynes.13 Their reaction with butyl
acrylate afforded cinnamic esters 12 and 13 (Table 3)
groups improves the yields (compare entries 5 and 8 with 3
and 4, respectively). The presence of chlorine in the aryl
group had a negative effect on the yield (compare entries 6
and 7 in Table 3 with 4 and 2, respectively). Finally, as
occurred for phenyl derivatives 8a and 9a (entries 2 and 4),
lower yields were obtained starting from the TMS-protected
acetylene 9d than from the unprotected acetylene 8d
(compare entries 6 and 7). Therefore, the use of n-butyl esters
instead of ethyl esters (entries 3 and 4) also improves the
yields. It is remarkable that under these conditions only
compounds 12d and 13d, resulting in the C-S oxidative
addition, were identified in the reactions of chloro derivatives
8d and 9d. We could not detect the presence of the products
corresponding to the C-Cl oxidative addition in the crude
reaction.
Table 3. Different Reactions to Aryl Ethynyl Sulfones
entry
Ar
R′
R
time product yield (%)
1
2
3
4
5
6
7
8
9
p-MeO-C6H4 (9b) TMS Bu
3 d
3 d
3 d
3 d
3 d
3 d
3 d
13b
13a
12a
13a
13c
13d
13d
13e
13f
30
53
40
45
55
25
35
47
41
Ph (8a)
Ph (9a)
Ph (9a)
H
Bu
In conclusion, the desulfonative Mizoroki-Heck-type
arylation of alkenes can be carried out using a sulfone bearing
an additional coordinating group, such as a conjugated or
allylic double bonds, triple bond, and methylphosphine
attached to the sulfur function. Maximum oxidation of the
sulfur atom (SO2) was necessary to obtain the best yields.
TMS Et
TMS Bu
p-NO2-C6H4 (9c) TMS Bu
p-Cl-C6H4 (9d)
p-Cl-C6H4 (8d)
p-CF3-C6H4 (8e)
p-Me-C6H4 (8f)
TMS Bu
H
H
H
Bu
Bu 30 h
Bu 3 d
Acknowledgment. We thank the Spanish Government
for financial support (Grant No. BQU2003-04012). J.A.
thanks the Ministerio de Ciencia y Tecnolog´ıa for a predoc-
toral fellowship. We thank Professor L. S. Liebeskind for
his helpful suggestions and Susana I. Dinis Pereira for her
help with the English version of this manuscript.
exclusively. This confirms that triple bonds exhibit poorer
acceptor character than the double bond of the butyl acrylate
(Table 3) in this oxidative addition.
The only moderate yield (40%) obtained in the transfer
of the phenyl group (entry 4, Table 3) is worse (30%) when
electron-donating groups, such as methoxy group, are present
on the ring (entry 1, Table 3). Analogously, the transfer of
the p-Tol group is slightly less efficient than that of the Ph
group (compare entries 9 and 2, Table 3). On the contrary,
the electron-withdrawing effect of the p-NO2 and p-CF3
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060608Y
2686
Org. Lett., Vol. 8, No. 13, 2006