Unprecedented palladium-catalyzed cross-coupling reaction of α-bromo sulfoxides with boronic acids

Article abstract of DOI:10.1021/ol034358m

(Matrix presented) A new Suzuki-type palladium-catalyzed reaction of boronic acids with α-bromo sulfoxides has been developed using a protocol similar to the well-documented reaction of boronic acids with aryl halides. Both cross-coupling and homocoupling processes were observed. The best yields in cross-coupling products were obtained when the presence of oxygen was carefully excluded using degassed solvents. The oxidative addition palladium complex intermediate could be isolated and characterized by X-ray single-crystal diffraction.

Full text of DOI:10.1021/ol034358m

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1705-1708
Unprecedented Palladium-Catalyzed
Cross-Coupling Reaction of r-Bromo
Sulfoxides with Boronic Acids
Nuria Rodr´ıguez, Ana Cuenca, Carmen Ram´ırez de Arellano,
Mercedes Medio-Simo´n,* and Gregorio Asensio*
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia,
AVda Vicent Andres Estelles s/n 46100 Burjassot-Spain
mercedes.medio@uV.es
Received February 28, 2003
ABSTRACT
A new Suzuki-type palladium-catalyzed reaction of boronic acids with r-bromo sulfoxides has been developed using a protocol similar to the
well-documented reaction of boronic acids with aryl halides. Both cross-coupling and homocoupling processes were observed. The best
yields in cross-coupling products were obtained when the presence of oxygen was carefully excluded using degassed solvents. The oxidative
addition palladium complex intermediate could be isolated and characterized by X-ray single-crystal diffraction.
Palladium-catalyzed cross coupling reactions have been used
widely to connect two sp2 carbon centers.1 The formation
of sp2-sp3 C-C bonds is comparatively less common and
in general comes from the reaction of aryl halides with
enolates.2 The direct arylation of carbonyl CH-acids (in situ
generated enolates) has received attention in recent years,3
but in contrast, the reaction with sulfonyl or sulfinyl CH-
acids has been scarcely explored. Recently, a procedure for
direct palladium-catalyzed monoarylation of several func-
tionalized sulfones has been described, but it occurs only in
the presence of an additional electron-withdrawing R-sub-
stituent, and for this reason, the scope of the method is
limited to the arylation of strongly CH-acidic sulfones.4 On
the other hand, the lack of reactivity of lithium anions derived
from sulfones and sulfoxides in cross-coupling palladium-
catalyzed reactions was reported by Negishi years ago.5 Thus,
the palladium-catalyzed arylation of simple sulfones or
sulfoxides remains a challenge. Sulfones are important
synthons widely used in the synthesis of useful organic
compounds.6 Sulfoxides possess similar features with the
added value of their chirality, which makes of these
compounds valuable auxiliaries in asymmetric synthesis.7
Owing to the versatility and popularity of sulfoxide chemistry
in synthesis, we decided to explore the palladium-catalyzed
reactions of methyl sulfoxides as a suitable route to the
arylation of these compounds.
In a preliminary series of experiments, we attempted
unsuccessfully the direct arylation of sulfoxides with halo-
arenes under similar conditions as described for the arylation
(1) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4177. (b)
Driederich, F.; Stang, P. J. Metal Catalyzed Cross-Coupling Reactions;
Wiley-VCH: New York, 1998. (c) Tsuji, J. Palladium Reagents and
Catalysts, InnoVations in Organic Synthesis; Wiley: New York, 1995.
(2) Miyaura, N. Cross-Coupling Reactions; Springer-Verlag: Berlin
Heidelberg, 2002.
(3) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360. (b) Jorgensen, M.; Lee, S.; Liu, X.; Wolkowski, J.
P.; Hartwig J. F. J. Am. Chem. Soc. 2002, 124, 12557 and references therein.
(4) Kashin, A. N.; Mitin, A. V.; Belestkaya, I. R.; Wife R. Tetrahedron
Lett. 2002, 43, 2539.
(5) Negishi, F.; Luo, F. T. J. Org. Chem. 1983, 48, 1562.
(6) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press:
Oxford, 1993.
(7) Garc´ıa-Ruano, J. L. Top. Curr. Chem. 1999, 204, 1. Carren˜o, M. C.
Chem ReV. 1995, 95, 1717.
10.1021/ol034358m CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/12/2003

of ketones.8 For instance, a mixture of 3-bromoanisole and
methyl phenyl sulfoxide was heated at reflux in the presence
of NaO-t-Bu and 2% Pd2(dba)3/BINAP, but the reactants
were recovered unchanged. The failure of the method could
be attributed, at first, to an inefficient generation of the
sodium R-sulfinyl anion due to the weaker CR-H acidity of
sulfoxides if was compared with the acidity of carbonyl
compounds. Since the base-mediated direct arylation seemed
unattainable, we then evaluated the possibility of arylation
of the sulfinyl anion. However, attempts at arylating lithium
R-sulfinyl anions were reported to be unsuccessful by
Negishi.5 In addition, methylsulfinyl anions react with
haloarenes without a catalyst to give mixtures of several
compounds as reported by Corey and co-workers in their
pioneering work on the reactivity of methylsulfinyl carb-
anions.9
These disappointing results in the palladium-catalyzed
reaction of aryl halides with sulfoxides prompted us to
change our strategy and to attempt the palladium-catalyzed
arylation of sulfoxide derivatives using arylboronic acids.
Recently, the R-arylation of carbonyl compounds by a Suzuki
type reaction of the corresponding R-halo carbonyl deriva-
tives with arylboronic acids has been achieved.10 Competitive
cross-coupling and homocoupling processes occur, and the
control of the selectivity depends on the nature of the
phosphine ligand on palladium.10a However, despite this
precedent, we have found that Pd(PPh3)4 catalyzes the cross
coupling reaction of R-bromo sulfoxides 111 with boronic
acids 2 under mild conditions in the presence of aqueous
Na2CO3 to give the corresponding R-monoarylated sulfoxides
3 with high to moderate yields (Scheme 1, Table 1).12 This
Table 1. Reaction of R-Bromo Sulfoxides 1 with Boronic
Acids 2
convnb
ratio
run
1
2
methoda
(%)
3 (%)
5 (%)
3/4
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
a
a
a
a
a
a
a
a
a
a
a
a
b
b
b
a
a
a
a
a
b
c
d
d
e
f
A
A
A
A
B
A
Ac
Ad
B
Ac,d
A
B
A
A
B
100
100
90
74
89
100
26
62
13
22
38
22
85
72
60
90
100
76
25
a (80)
b (87)
c (76)
d (53)
d (56)
e (60)
f (7)
f (25)
f (0)
g (0)
h (11)
h (0)
i (43)
j (43)
j (0)
d (81)
h (70)
f (39)
g (0)
a (20)
a (13)
a (13)
a (21)
a (34)
a (40)
a (19)
a (37)
a (13)
a (22)
a (27)
a (22)
be (23)
b (29)
bf (19)
a (9)
2:1
2.5:1
1.7:1
1:1
1.1
2.3:1
1:2.4
1:2.2
0
0
1:3
f
f
g
h
h
a
e
e
d
h
f
0
2.6:1
3.0:1
0
2.8:1
2:1
C
C
C
Cc
a (30)
a (37)
a (25)
1:1.5
0
g
a Method A: MeOH, Na2CO3 2 M, 10% catalyst, 16 h. Method B: DME,
Na2CO3 2 M, 10% catalyst, 16 h. Method C: Conditions A using degassed
solvents. b Conversion of 1 determined by NMR. c Reaction time 32 h.
d 20% catalyst. e Compound 5c (19%) was also obtained. f Compound 5c
(41%) was also obtained.
Concerning the mechanism of the arylation reaction, we
were able to prove that the arylation occurs through the
conventional catalytic cycle (oxidative addition, trans-
metalation and reductive elimination). The R-sulfinylpalla-
dium(II) complex Ia (R1 ) H; Hal ) Br) (Figure 1) derived
Scheme 1
Figure 1. Oxidative addition (I) and transmetalation (II) of
palladium intermediates in the arylation of R-bromo sulfoxides 1.
aThermal ellipsoid plot (50%) probability of compound Ia (R1 )
H; Hal ) Br).
reaction is unprecedented and represents to the best of our
knowledge the first example of participation of a methyl
sulfoxide derivative in a palladium catalyzed C(sp3)-C(sp2)
bond formation reaction.
from the oxidative addition of 1a to Pd(PPh3)4 was stable
enough to be isolated and characterized by X-ray single-
(10) Goossen, L. J. Chem. Commun. 2001, 669. (b) Lei, A.; Zhang, X.
Tetrahedron Lett. 2002, 43, 2525. (c) Lu, T.-Y.; Xue, C.; Luo, F.-T.
Tetrahedron Lett. 2003, 44, 1587
(8) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(9) Corey E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1345
(11) Cinquini, M.; Colonna, S. J. Chem. Soc., Perkin Trans. 1 1972,
1883.
1706
Org. Lett., Vol. 5, No. 10, 2003

crystal diffraction.13 The crystal structure shows a slightly
distorted square planar palladium complex with the sulfinyl
ligand trans to bromine (Figure 1). A similar complex I (R1
) H; Hal ) Cl) was characterized by Floriani14 by reaction
of cis-[PdCl2(PPh3)2] with potassium R-sulfinyl anion. To
ensure that Ia is an intermediate in the arylation of 1a, it
was allowed to react with 2a leading, as expected, to the
formation of the cross-coupling product 3a.
sulfoxide 1a under our standard conditions with predomi-
nance of the homocoupling reaction.
The palladium-catalyzed arylation was also tested with the
R-bromoethyl sulfoxide 1b. Reaction with boronic acids 2a
and 2e gave mainly the corresponding R arylated derivatives
3i and 3j although vinyl sulfoxide 5c was also formed by
â-elimination from the intermediate complexes I (R1 ) CH3;
Hal ) Br) and II (R1 ) CH3; Ar ) C6H5, p-BrC6H4).
Although â-elimination is a highly favored process in
palladium chemistry, cross-coupling products predominate
under mild conditions (method A). The use of higher reaction
temperatures (method B) favors the formation of the elimina-
tion product 5c.
The poor results obtained in the cross-coupling reaction
with some of the boronic acids tried prompted us to run the
reaction of 1 with 2 with the complete absence of oxygen
using degasified solvents (runs 16-19, Table 1), and in some
cases, with longer reaction times (run 16, Table 1). The yield
in 3 increased significantly under these conditions. For
instance, in the case of the o-methoxy-substituted acid 2d
the yield increased from 56% to 81% (runs 5 and 16, Table
1), and, more strikingly, the p-nitroboronic acid 2h gave the
cross-coupled sulfoxide 3h in 70% yield (runs 11 and 17,
Table 1). By contrast, the results obtained with thiophene-
boronic acids 2f and 2g were roughly the same in the
presence or absence of oxygen.
Self-coupling of aryl boronic acids in regular Suzuki
reactions15 occurs when the cross-coupling is very slow.
Moreno-Man˜as and co-workers16 showed that self-coupling
reactions are accelerated in atmosphere of oxygen and also
by the presence of an electron donor substituent at the
boronic acid moiety. In the same way, under standard Suzuki
conditions large amounts of biaryls are formed in the reaction
of arylboronic acids and R-bromo esters,10b a reaction
inhibited by the use of bulky, not too electron rich
phosphines.10a In the case of the reaction of R-bromo
sulfoxides with boronic acids reported herein, several
alternative and simultaneous reaction paths are envisaged to
account for the formation of homocoupling products. At first,
Pd(PPh3)2 species present in the medium would promote by
oxidative addition (transmetalation) the direct self-coupling
of boronic acids.16,17 A second mechanism would involve
an oxidative homocoupling through the formation of a pal-
ladium(II) peroxide by reaction of oxygen with a Pd(PPh3)2
complex.18 These two mechanisms do not involve at all the
participation of bromo sulfoxides 1 in the process leading
to the formation of homocoupling products 4. Alternatively,
the homocoupling reaction might take place by a double
transmetalation through the oxidative addition complex I in
a similar way as proposed by Zhang for the homocoupling
reaction observed in the reaction of R-halo carbonyl com-
In the palladium-catalyzed reaction of 1a with 2a the cross-
coupling derivative 3a was the main product, but formation
of the homocoupling compound 4a was also detected. The
3a/4a ratio was 2:1, thus showing a remarkable chemo-
selectivity for the cross-coupling process. The homocoupling
derivative 4a was formed along with debrominated sulfoxide
5a generated by reduction of starting bromo sulfoxide 1a.
A similar reductive side reaction also happens when R-bromo
carbonyl compounds are reacted with boronic acids.10b
The generality of the C(sp3)-C(sp2) cross-coupling reac-
tion was investigated using a number of arylboronic acids
2a-h and the secondary bromo sulfoxide 1b (Scheme 1,
Table 1). The reaction of 1a with electron-rich substituted
boronic acids 2b and 2c using the same conditions as in the
case of the parent compound 2a gave 3b and 3c, respectively,
with similar chemoselectivity and conversion. The presence
of the o-methoxy group in acid 2d resulted in a lower
chemoselectivity with only partial conversion of the starting
bromo sulfoxide 1a. Although the chemoselectivity was only
moderate in this case, the cross-coupling reaction was also
the main process. The use of dimethoxyethane as solvent
(conditions B) allowed an increased reaction temperature and
complete solubilization of the catalyst Pd(PPh3)4, but these
modifications did not lead to significant changes in the
chemoselectivity or the degree of conversion of the starting
bromosulfoxide 1a. The effect of the presence of electron-
withdrawing groups in the boronic acid moiety was also
studied. Bromo-substituted boronic acid 2e reacted with 1a
to completion. The cross-coupling was the main process with
a chemoselectivity similar to the case of the o-methoxy
substituted acid 2d. With the nitro-substituted acid 2h, the
homocoupling was the main reaction observed giving rise
to the formation of biaryl 4h and only 11% yield in the cross-
coupling product 3h (see Table 1). Thiophene boronic acids
2f and 2g led only to partial conversion of the starting bromo
(12) Representative Procedure. A mixture of R-bromo sulfoxide 1a
(0.4 mmol), boronic acid 2 (0.8 mmmol), and Pd(PPh3)4 (0.04 mmol) in
aqueous 2 M Na2CO3 (0.8 mL, 1.6 mmol) and methanol (8 mL) was heated
at reflux for 16 h. The reaction mixture was then cooled to room temperature,
quenched with water (10 mL), and extracted with diethyl ether (2 × 15
mL) and dichloromethane (2 × 15 mL). The combined organic extracts
were dried with Na2SO4 and evaporated under reduced pressure.
(13) X-ray crystal structure of Ia: pale yellow prism of 0.40 × 0.20 ×
0.20 mm size, triclinic, P-1, a ) 12.171(2) Å, b ) 12.483(3) Å, c )
15.933(3) Å, R ) 93.98(3)°, â ) 101.23(3)°, γ ) 118.61(3)°, V ) 2046.9(7)
Å3, Z ) 2, Dc ) 1.520 g cm-3, 2θmax ) 53°, diffractometer Kappa CCD,
Mo KR (λ ) 0.710 73 Å), ω-scan, T ) 173(2) K, 16 376 reflections
collected of which 8357 were independent (Rint ) 0.066), direct primary
solution and refinement on F2 (SHELXL-97, G. M. Sheldrick, University
of Go¨ttingen, 1997), 508 refined parameters, riding hydrogen atoms, The
PhSO group is disordered over two sites, R1[I > 2σ(I)] ) 0.0490, wR2
(all data) ) 0.1033.
(15) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.; Naeslund, C. G.
M. J. Chem. Soc., Chem. Commun 1994, 2393. (b) Gillmann, T.; Weeber,
T. Synlett 1994, 649. (c) Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994,
59, 33.
(16) Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. J. Org. Chem. 1996,
61, 2346.
(17) Wong, M. S.; Zhang, X. L. Tetrahedron Lett. 2001, 42, 4087.
(18) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
2003, 44, 1541.
(14) Veya, P.; Floriani, C.; Chiesi-Villa, A.; Rizzoli, C. Organometallics
1994, 13, 441.
Org. Lett., Vol. 5, No. 10, 2003
1707

pounds with boronic acids10b or in the Pd(OAc)2-promoted
homocoupling of aryl boronic acids.16 Indeed, biaryl 4h was
obtained by treatment of complex I (R1 ) H; Hal ) Br)
with boronic acid 2h in the presence of oxygen, but we can
argue that I decomposes prior to that to give a Pd(PPh3)n
species which reacts with 2h according to the reaction paths
described above. In fact, we did not find a correlation
between the amount of biaryls 4 and sulfoxides 5 obtained
in the coupling processes collected in Table 1 as would be
expected if biaryls 4 would arise exclusively through the
double transmetalation mechanism. In general, the formation
of dehalogenation products is uncommon in typical Suzuki
coupling reactions.19
Although details of the reaction pathway remain unclear
at present, the results of the palladium-catalyzed reaction of
compounds 1 and 2 show that the relative extent of the cross-
coupling and homocoupling processes depends on the
electron-donating or -withdrawing character of the substit-
uents in 2 and the presence or absence of oxygen in the
reaction medium. This behavior could be related to the ability
of 2 to undergo the transmetalation reaction with the
intermediate complex I produced in the oxidative addition
step and also to the stability of the complex II (Figure 1). If
the transmetalation step is slow (electron-poor substituted
Ar groups in 216), the formation of complex I would be
unproductive leading by disproportion and/or hydrolysis to
dehalogenation products 5. In addition, partial phosphine
oxidation occurs when reactions are carried out without
careful exclusion of oxygen. Then, direct Pd0- and PdII-
catalyzed homocoupling of 2 accounts for the formation of
biaryls 4. Alternatively, boronic acids 2 carrying groups with
ability to coordinate palladium (2f and 2g) or with strong
electron-withdrawing character (2h) could afford adducts
II15,20 stable enough to undergo a second transmetalation
leading to the homocoupling products.
Our data show that R-bromo sulfoxides are better sub-
strates than R-bromo carbonyl compounds in Suzuki-type
cross-coupling reactions since the parent triphenylphosphine
is a suitable ligand in the case of sulfoxides while bulky
phosphines are required for carbonyl derivatives. The high
reactivity of the R-sulfinylpalladium(II) complexes shown
in the cross-coupling is noteworthy if compared to the rather
low reactivity exhibited by these complexes in insertion
reactions.14
In conclusion, this new reaction allows the CR-arylation
of alkyl sulfoxides with high yields under mild conditions.
The palladium catalyzed process allows the substitution of
bromine in R-bromo sulfoxides for nucleophiles opening new
perspectives in sulfoxide chemistry. Work is in progress to
amplify the synthetic value of this method with the conver-
sion of the sulfoxide group in other functions and to clarify
the detailed mechanism of the undesired competitive homo-
coupling reaction.
Acknowledgment. Financial support by the Spanish
Direccio´n General de Investigacio´n Cient´ıfica y Te´cnica
(BQU2000-1426) and the Generalitat Valenciana (GV
CTIDIB 2002/239) is gratefully acknowledged. N.R and C.R.
de A. thank the Spanish Ministerio de Educacio´n y Ciencia
and A.C. the Generalitat Valenciana for fellowships. We
gratefully acknowledge the SCSIE (Universidad de Valencia)
for the access to the instrumental facilities.
Supporting Information Available: Experimental details
for the synthesis and characterization of compounds 3 and
4 and X-ray crystallographic data in CIF format for
compound Ia. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL034358M
(19) Handy, S. T.; Bregman, H.; Lewis, J.; Zhang, X.; Zhang, Y.
Tetrahedron Lett. 2003, 44, 427.
(20) Drago, D.; Pregosin, P. S.; Tschoerner, M.; Albinati, A. J. Chem.
Soc., Dalton Trans. 1999, 2270.
1708
Org. Lett., Vol. 5, No. 10, 2003