Palladium-catalyzed desulfinylative Negishi C-C bond forming cross-couplings of sulfonyl and organozinc chlorides

Article abstract of DOI:10.1016/j.tetlet.2006.03.101

Arene-, phenylmethane- and alkenesulfonyl chlorides are suitable electrophilic reagents in desulfinylative carbon-carbon bond formation cross-coupling reactions with organozinc reagents.

Full text of DOI:10.1016/j.tetlet.2006.03.101

Tetrahedron Letters 47 (2006) 3345–3348
Palladium-catalyzed desulfinylative Negishi C–C bond
forming cross-couplings of sulfonyl and organozinc chlorides
Srinivas Reddy Dubbaka and Pierre Vogel*
`
´
Laboratoire de Glycochimie et de Synthese Asymetrique, Ecole Polytechnique Federale de Lausanne (EPFL),
´ ´
BCH CH-1015 Lausanne, Switzerland
Received 6 February 2006; revised 13 March 2006; accepted 15 March 2006
Abstract—Arene-, phenylmethane- and alkenesulfonyl chlorides are suitable electrophilic reagents in desulfinylative carbon–carbon
bond formation cross-coupling reactions with organozinc reagents.
Ó 2006 Elsevier Ltd. All rights reserved.
The search of efficient methods for the construction of
carbon–carbon bonds represents an ongoing, central
theme of research of organic synthesis.1 Transition
metal catalyzed cross-coupling of organometallic reagents
with halides or triflates constitute today one of the most
powerful methods to generate carbon–carbon bonds.2
Arene- and alkanesulfonyl chlorides are inexpensive
and readily available compounds. They have been used
for more than a century in material sciences and medic-
inal chemistry.3a–f Recently, we have shown that Stille,
carbonylative Stille,4 Suzuki–Miyaura,5 Sonogashira–
Hagihara6 type cross-couplings and Mizoroki–Heck7
type arylations can be carried out using sulfonyl chlo-
rides as electrophilic partners under desulfinylation
conditions.8 Although, the palladium-catalyzed Stille
condensation has proved to be a highly versatile method
for the C–C bond formation it suffers from the fact that
it requires toxic organostannanes as nucleophilic carbon
reagents. The alternative Suzuki–Miyaura cross-cou-
pling reaction does not suffer from this inconvenience
as it uses nontoxic organoboron reagents, but it requires
costly copper salts as activators. Among the earliest and
most useful organometallic nucleophilic reagents are the
Grignard reagents which can be coupled with all kinds
of electrophilic partners, as for the transition-metal cata-
lyzed Kumada reactions.9 The latter have never been
applied to sulfonyl chlorides. Since 1929 it is known that
Grignard reagents displace sulfonyl chlorides to gener-
ate the corresponding sulfones (Scheme 1A).10a We have
now found reaction conditions under which desulfinyl-
ation occurs and generate products of C–C cross-cou-
plings (Table 1).
As we have reported that most transition-metal desulf-
inylative C–C bond forming reactions4–8 occur above
60 °C, we envisioned that heating sulfonyl chlorides with
Grignard reagents under similar conditions might also
lead to products of C–C cross-coupling. In fact, when
we heated a 1:1 mixture of 2-methylbenzenemagnesium
chloride and 4-methylbenzenesulfonyl chloride in boil-
ing THF in the presence of 1–20 mol % Pd[P-
(t-Bu)3]2,11a only products of Grignard reagent homo-
coupling (Ar–Ar:(2-MeC6H4)2) were formed (Scheme
1B) together with small amounts of the expected sulfone
4-MeC6H4SO2–C6H4–2-Me.12 The same result was
obtained using other palladium catalysts such as
Pd2(dba)3 with carbenes or bulky ligands.11b
As the desulfinylative Kumada cross-coupling reaction
is not a reality yet with the case studied above, we
explored metal/metal exchange with the arylmagnesium
THF
RSO2Ar + MgXCl
Ar-Ar
RSO2Cl + ArMgX
A)
B)
ice
23 oC
Pd[P(t-Bu)3]2 cat.
Keywords: Couplings; Negishi reaction; Organomagnesium reagents;
Organozinc reagents; Palladium; Sulfones; Sulfonyl chlorides.
70 oC, THF
*
Corresponding author. Tel.: +41 216939371; fax: +41 216939375;
e-mail addresses: srinivasreddy.dubbaka@epfl.ch; pierre.vogel@
epfl.ch
Scheme 1. Sulfones synthesis13,14 and Grignard reagents C–C homo-
coupling.15
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.101

3346
S. R. Dubbaka, P. Vogel / Tetrahedron Letters 47 (2006) 3345–3348
Table 1. Palladium-catalyzed desulfinylative Negishi cross-couplings
of sulfonyl chlorides and organozinc halides
(control of the completion of the Mg/Zn exchange) were
degassed by freeze–thaw cycles under vacuum (three
times) followed by addition of degassed (He bubbling)
of THF solutions of the sulfonyl chloride (RSO2Cl)
and the palladium catalyst. The latter solutions are
better prepared in a glove box.21
R'-MgCl
ZnCl2
3-5 mol% Pd[P(t -Bu)3]2
R-SO2Cl + R'-ZnCl
R-R' + R'-R'
major minor
THF, reflux, 15-24 h
As seen (Table 1), the yield of the C–C cross-coupled
products depends on the nature of reagents. They are
better for arenesulfonyl chlorides than for other sulfonyl
chlorides (entries 13–16). With benzylzinc chloride
(entry 14) the yield is poor, suggesting that arylzinc
reagents are better behaved than alkylzinc reagents. In
the case of 1-hexanesulfonyl chloride (entry 17), no
product of C–C coupling was observed. This is probably
due to the b-elimination of the 1-hexylpalladium inter-
mediate that is expected to be fast in boiling THF. All
reactions were accompanied with the concurrent forma-
tion of homocoupling product R0-R0 of organozinc
chloride.22 With the hope to reduce this undesired reac-
tion we examined whether Mg/Cu exchange would be a
better option than Mg/Zn metal/metal exchange. Thus
2-methylbenzenemagnesium chloride (entry 3) was trea-
ted with CuCNÆ2LiCl23 in THF within 3 h at ꢀ78 to
0 °C before mixing with a THF solution of 1-naphtha-
lenesulfonyl chloride and 4 mol % Pd[P(t-Bu)3]2. After
heating under reflux overnight (until disappearance of
1-naphthalenesulfonyl chloride) analysis of the crude
reaction mixture (1H NMR) showed less product of
C–C cross-coupling than for the reaction using the
organozinc analogue.
Entry
R
R0
Yielda,b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Methylphenyl
4-Biphenyl
Phenyl
Phenyl
2-Methylphenyl
58
32c
20d
64
2-Methylphenyl
3-Methylphenyl
4-Methylphenyl
Phenyl
2-Methylphenyl
3-Methylphenyl
1-Naphthyl
Phenyl
4-Methylphenyl
Phenyl
Benzyl
Phenyl
2-Methylphenyl
2-Methylphenyl
61
60
58
62
64
70
38
68
32e,f
21e,f
20e,f
20e,f
0
4-Biphenyl
(E)-PhCH@CH
1-Naphthyl
Benzyl
Methallyl
1-Hexyl
a Yields of cross-coupling products, determined after flash chromato-
graphy.
b The products are known, the characterizations are described in our
previous letters.4a,5
c PhZnCl solution was not degassed.
d In situ prepared organocopper was engaged as the coupling
partner.23
The postulated mechanism of the reaction is shown in
Scheme 2. The reactive unsaturated Pd(0)24 catalyst
undergoes oxidative addition of the SO2–Cl bond of
the sulfonyl chloride to give first a chloro palladium(II)
sulfinate of type II. At temperature >66 °C desulfinyla-
tion occurs rapidly and an R–Pd–Cl complex of type
III forms, which then undergoes the cross-coupling
reaction with the organozinc halides IV, in a way similar
to that of aryl halides or triflates in Negishi
condensations.19
e 1H NMR analysis of the crude.
f Lower yield due to the self-coupling of the organozinc reagent.
chlorides16 and first we generated the corresponding
organozinc reagents with the hope that they will under-
go the desulfinylative Negishi C–C cross-coupling reac-
tions with sulfonyl chlorides. There are numerous
palladium11,17 and nickel-catalyzed18 cross-coupling
reactions between aryl and heteroaryl halides or sulfo-
nates, and arylzinc reagents to form carbon–carbon
bonds.19
R-SO2-Cl
R-R'
Allylzinc compounds have been reported to displace
arenesulfonyl chlorides to give the corresponding sulf-
ones20 (reaction analogous to that of Scheme 1A). With
organozinc chlorides (R0ZnCl) and the sulfonyl chlo-
rides (RSO2Cl) of Table 1, no reaction was observed
at 20 °C in THF and in the absence of catalyst. Upon
heating in THF under reflux, slow decomposition was
observed. However, in the presence of 1–5 mol % of
Pd(0) catalyst such as Pd[P(t-Bu)3]2, smooth reactions
occurred with elimination of SO2 and formation of
products (R–R0) of C–C cross-coupling (Table 1). The
reaction was optimized for 1-naphthalenesulfonyl chlo-
rides and 2-methylbenzenezinc chloride (generated
I
Pd0
VI
R-PdII-R'
R-SO2-PdII-Cl
V
II
> 66oC
-SO2
ZnClX
R-PdII-Cl
in situ from the corresponding Grignard reagent) using
III
11a
R'ZnX
3–5 mol % Pd[P(t-Bu)3]2
as catalyst in boiling THF.
IV
These conditions were then applied to the other reaction
mixtures shown in Table 1. The best yields were
obtained when the organozinc chloride solutions
Scheme 2. Probable catalytic cycle for desulfinylative cross-coupling of
sulfonyl and organozinc chlorides.

S. R. Dubbaka, P. Vogel / Tetrahedron Letters 47 (2006) 3345–3348
3347
J. Chem. Soc., Chem. Commun. 1972, 144–145; (c)
Yamamura, M.; Moritani, I.; Marahashi, S. I. J. Organo-
met. Chem. 1975, 91, C39–C42; (d) Minato, A.; Suzuki,
K.; Tamao, K.; Kumada, M. J. Chem. Soc. Chem. Chem.
This work discloses the first examples of desulfinylative
Negishi cross-coupling reactions that combine arene-,
phenylmethane- and alkenesulfonyl chlorides with
organozinc chlorides obtained in situ from the corre-
sponding Grignard reagents.25
´
1984, 511–513; (e) Bonnet, V.; Morgin, F.; Trecouret, F.;
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Queguiner, G.; Knochel, P. Tetrahedron Lett. 2001, 42,
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Acknowledgements
10. (a) Gilman, H.; Fothergill, R. E. J. Am. Chem. Soc. 1929,
51, 3501–3508; see also the reaction of sulfonyl chlorides
with diphenyl cadmium: (b) Khodair, A. I.; Osman, A.;
Abdel-Wahab, A.-M. A. Int. J. Sulfur Chem. 1976, 8, 613–
614; see also the reaction of sulfonyl chlorides with
organostannanes: (c) Neumann, W. P.; Wicenec, C. Chem.
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We thank the Swiss National Science Foundation
(Grant No. 2000-20100002/1) and the ‘Secretariat d’Etat
´
`
´
`
a l’education et a la recherche (SER)’ (Grant No.
03.0738, TRIoH, FP6).
11. (a) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2714–
2719; Recent a review on electron-rich, and sterically
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References and notes
12. Typical sulfone synthesis (Scheme 1A): In a two-necked
round bottom flask, dried under vacuum were placed the
corresponding sulfonyl chloride (2.00 mmol), then THF
(5 mL) at 0 °C and the organomagnesium chloride
(2.6 mmol) under an argon atmosphere. The mixture was
allowed to reach room temperature. The reaction was
monitored by TLC. After completion of the reaction, the
mixture was diluted with ether and washed with water.
The aqueous layer was extracted again with ether (three
times). The combined organic phases were dried (Na2SO4),
filtered and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel.
Phenyl p-tolyl sulfone 60%,13b o-methylphenyl p-tolyl
sulfone 58%,13b m-methylphenyl p-tolyl sulfone 62%,13b
p-fluorophenyl phenyl sulfone 50%,13b 1-naphthyl phenyl
sulfone 42%13b and p-phenylphenyl phenyl sulfone
60%.13b
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S. R. Dubbaka, P. Vogel / Tetrahedron Letters 47 (2006) 3345–3348
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0.5 M in THF) was added. The mixture was allowed to
reach room temperature. After stirring for the time
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by freeze–thaw cycles three times, Pd[P(t-Bu)3]2 (0.03–
0.05 mmol) and the corresponding sulfonyl chloride
(1.00 mmol) were added (both were weighed in a glove
box), followed by THF (5 mL). The mixture was heated
under reflux for 15–24 h. After completion of the reaction,
the mixture was cooled to room temperature, diluted with
ether and washed with water. The aqueous layer was
extracted again with ether (three times). The combined
organic phases were dried (Na2SO4), filtered and concen-
trated under reduced pressure under reflux on cooling to
ꢀ20 °C. The residue was purified by flash chromatography
on silica gel.
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