Palladium-catalyzed aromatic sulfonylation: A new catalytic domino process exploiting in situ generated sulfinate anions

Article abstract of DOI:10.1055/s-0031-1289880

Allylic sulfones are excellent precursors of aryl sulfones via a new Pd-catalyzed domino sequence involving in situ generation of sulfinate anions and subsequent cross-coupling with aryl -iodides or bromides. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289880

LETTER
2943
Palladium-Catalyzed Aromatic Sulfonylation: A New Catalytic Domino
Process Exploiting in situ Generated Sulfinate Anions
P
alladium-Catalyz
a
e
d
A
romati
ë
c
S
ulfonyla
t
tion an Le Duc,a Elise Bernoud,a Guillaume Prestat,a Sandro Cacchi,b Giancarlo Fabrizi,b Antonia Iazzetti,b
David Madec,*c Giovanni Poli*a
a
UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire (UMR CNRS 7201), FR 2769, case 183, 4 Place Jussieu, 75005 Paris,
France
Fax +33(01)44277360; E-mail: giovanni.poli@upmc.fr
Dipartimento di Chimica e Tecnologie del Farmaco, La Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Université de Toulouse, UPS, CNRS, LHFA UMR 5069, bât. 2R1, 118 route de Narbonne, 31062 Toulouse, France
Fax +33(0)561558204; E-mail: madec@chimie.ups-tlse.fr
b
c
Received 3 September 2011
Dedicated to Dr. Christian Bruneau on the occasion of his 60th birthday
ready described as an efficient catalytic system for sulfur-
based nucleophiles10 and specifically for sulfinate an-
ions,6 was selected as the catalytic system. As to the inter-
cepting nucleophile, we selected potassium tert-butoxide,
as it showed to be a competent nucleophile in our previous
study7 (Table 1).
Abstract: Allylic sulfones are excellent precursors of aryl sulfones
via a new Pd-catalyzed domino sequence involving in situ genera-
tion of sulfinate anions and subsequent cross-coupling with aryl
iodides or bromides.
Key words: sulfones, sulfinate anions, catalysis, palladium, domi-
no reaction
Nu
Aromatic sulfones1 are compounds of considerable inter-
est embedding a number of positive features such as sta-
O
O
[Pd(0)]
Nu
?
S
ArSO2
Pd
Ar
ArSO2
bility, crystallinity, chromophoric activity,2 as well as
antibacterial, antifungal, and antitumor activities.3 Classi-
cal strategies to access these compounds rely on the oxi-
dation of aryl thioethers, electrophilic aromatic
substitution on sulfonyl halides, reaction of organometal-
lic reagents with sulfonate esters, and arylation of sulfi-
nate anions.4 With regard to the last method, transition-
metal-catalyzed allylic5 and aromatic6 sulfonylations re-
cently appeared as an interesting method to generate the
corresponding allyl and aryl sulfones.
[Pd(0)]
Scheme 1 Hypothesis of Pd(0)-catalyzed sulfinate anion generation
from allyl sulfones
Table 1 Optimization of the Pd-Catalyzed Aromatic Sulfonylationa
Pd2dba3
Xantphos
O
O
O
O
I
S
S
+
Tol
Tol
KOt-Bu
additive
toluene
OMe
OMe
1a
We recently reported that, under palladium catalysis, allyl
sulfoxides can generate sulfenate anions, which can in
turn be easily cross-coupled to afford aryl sulfoxides.7,8 In
this communication we report a successful extension,
from sulfoxides to sulfones, of our Pd-catalyzed allyl-to-
aryl conversion domino process.
Entry
Additive
–
Temp (°C)
Yield (%)b
1
2
3
4
5
80
–
n-Bu4NCl
n-Bu4NBr
n-Bu4NHSO4
n-Bu4NBr
80
–
80
65
15
88
Accordingly, we envisaged to generate the required sulfi-
nate anion via oxidative addition of an allylic sulfone onto
a Pd(0) complex.9 Subsequent nucleophilic interception
of the thus formed h3-allyl palladium complex is then ex-
pected to trigger the sulfinate anion release, which may in
turn be further reacted in a palladium-catalyzed arylation
reaction (Scheme 1).
80
reflux
a Reagents and conditions: 4-iodoanisole (1.2 equiv), allyl p-tolyl sul-
fone (1.0 equiv), Pd2dba3 (2 mol%), Xantphos (5 mol%), additive (if
used, 2.0 equiv), KOt-Bu (2.0 equiv).
b Yields are given for isolated products.
The palladium-catalyzed sulfonylation reaction between
allyl p-tolyl sulfone and 4-iodoanisole was chosen as the
model reaction. The Pd2dba3/Xantphos combination, al-
Preliminary experiments performed in toluene at 80 °C
according to our preceding studies of arylic sulfinylation,
in the absence (Table 1, entry 1) or in the presence
(Table 1, entry 2) of an overstoichiometric amount of
SYNLETT 2011, No. 20, pp 2943–2946
x
x
.x
x
.2
0
1
1
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289880; Art ID: B17111ST
© Georg Thieme Verlag Stuttgart · New York

2944
G. Le Duc et al.
LETTER
n-Bu4NCl, led to total degradation of the substrates. The The reaction was next studied using differently substi-
latter result is surprising if we consider the efficiency of tuted allyl sulfones as the sulfinate anion source and vari-
n-Bu4NCl as additive in couplings previously described ous aryl iodides (Table 3). Starting from allyl p-tolyl
by some of us,6 and could be due to the generation of an sulfone, the reaction with m-iodoanisole afforded sulfone
unreactive dimeric [Pd(h3-allyl)Cl]2 complex. Satisfying- 2b in 55% yield (Table 3, entry 2), to compare with 88%
ly, replacement of n-Bu4NCl with n-Bu4NBr allowed the yield previously obtained with p-iodoanisole (Table 3, en-
desired aromatic sulfonylation to take place, affording the try 1). Under the same reaction conditions o-iodoanisole
expected anisyl-tolyl sulfone in 65% yield (Table 1, entry did not allow the generation of the expected sulfone
3). Switch to n-Bu4NHSO4 as additive gave a much poorer (Table 3, entry 3). This suggests that the present coupling
result (15% yield, Table 1, entry 4), whereas heating the is very sensitive to steric hindrance in the vicinity of the
reaction mixture at reflux of toluene for eight hours raised aryl halide reacting center. Starting from allyl p-anisyl
the yield of sulfone to 88% (Table 1, entry 5). It is worthy sulfone as sulfonylating agent reaction with 4-iodo tolu-
to note that after one hour reaction the allylic sulfone is to- ene afforded the corresponding arylation product 1a in
tally consumed, whereas the formation of the aromatic 40% yield (Table 3, entry 4).
sulfone is still rising. This observation suggests that, as
mechanistically required (see later), the rate of sulfinate
Table 3 Scope of the Reactiona
generation is higher than that of sulfinate arylation, and
that such anions may accumulate at the entrance of the
arylation catalytic cycle.
O
O
I
S
R1
Pd(0)
O
O
R2
R2
+
S
KOt-Bu
R1
With the optimized reaction conditions in hand, the scope
and limitations of this transformation were studied, react-
ing allyl p-tolylsulfone with a variety of substituted aryl
halides (Table 2). In the event, 4-iodotoluene afforded the
corresponding sulfone 1b in 66% yield (Table 2, entry 2),
whereas the electron-poor 4-trifluoromethyl iodobenzene
gave the aryl sulfone 1c in a meager 16% yield, and 4-ni-
tro iodobenzene gave only degradation products (Table 2,
entry 4).
Entry
R1
R2
Yield (%)b
1
2
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
2-naphthyl
2-naphthyl
Bn
4-MeO
3-MeO
2-MeO
4-Me
1a
2b
–
88
55
–
3
4
1a
2d
2e
–
40
37
21
–
5
4-MeO
4-Me
Aryl bromides could be successfully used as partners. In-
deed, 4-bromoanisole and 4-bromotoluene gave the corre-
sponding sulfones 1a and 1b in 48% and 52% yield,
respectively (Table 2, entries 5 and 6). On the other hand,
4-chloroanisole did not allow the desired coupling to take
place (Table 2, entry 7).
6
7
4-MeO
4-Me
8
3a
3b
–
60
61
9
4-MeO
4-MeO
Table 2 Scope of the Pd-Catalyzed Aromatic Sulfonylationa
c
10
–
O
O
a Reaction conditions: aryl halide (1.2 equiv), allyl sulfoxide (1.0
equiv), Pd2dba3 (2 mol%), Xantphos (5 mol%), KOt-Bu (2.0 equiv),
16 h, toluene, reflux.
Pd2dba3
O
O
S
X
Xantphos
Tol
S
+
Tol
KOt-Bu
n-Bu4NBr
toluene, reflux
b Yields are given for isolated products.
R
R
c Complete degradation of the reaction mixture.
Entry
X
I
R
Product
Yield (%)b
Similarly, symmetrical sulfone 2d was isolated in 37%
yield when starting from 4-iodoanisole (Table 3, entry 5),
whereas starting from allyl 4-nitrophenyl sulfone and 4-
iodotoluene, sulfone 2e was obtained in a poor 21% yield
(Table 3, entry 6). Under the same reaction conditions, 4-
iodoanisole did not afford the expected sulfone (Table 3,
entry 7). Starting from the 2-naphthyl sulfinate precursor,
reaction with 4-iodotoluene and 4-iodoanisole afforded
the corresponding arylation products 3a and 3b in 60%
and 61% yield, respectively (Table 3, entries 8 and 9).
Rather disappointingly, reaction between the benzyl sulfi-
nate precursor and 4-iodoanisole brought about only total
degradation of the reaction mixture (Table 3, entry 10).11
1
2
3
4
5
6
7
OMe
Me
1a
1b
1c
–
88
66
16
I
I
CF3
NO2
OMe
Me
c
I
–
Br
Br
Cl
1a
1b
–
48
52
c
OMe
–
a Reaction conditions: aryl halide (1.2 equiv), allyl p-tolyl sulfone (1.0
equiv), Pd2dba3 (2 mol%), Xantphos (5 mol%), KOt-Bu (2.0 equiv),
16 h, toluene, reflux.
A mechanistic proposal for the palladium-catalyzed sulfi-
nate generation–arylation pseudo-domino12 catalytic se-
b Yields are given for isolated products.
c No reaction.
Synlett 2011, No. 20, 2943–2946 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Aromatic Sulfonylation
2945
Ar1SO2
K
Ot-Bu
Ar2X
Ar2[Pd]X
t-BuO
K
KX
sulfinate
generation
sulfinate
arylation
[Pd(0)]
Ar2[Pd]SO2Ar1
Ar1SO2
Pd
O
O
O
O
S
Ar1
S
Ar1
Ar2
Scheme 2 Proposed mechanism
quence is depicted in Scheme 2. First, oxidative addition tion mechanism of this aromatic sulfonylation are
of the allylic sulfone to Pd(0) is expected to afford the cor- presently under investigation and will be reported in due
responding h3-allylpalladium(II) complex.
course.
Interception of the allyl moiety of the palladium complex
by potassium tert-butoxide liberates the sulfinate anion as
well as Pd(0), which are both set to enter the second cata-
lytic cycle.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Halide-to-sulfinate ligand exchange on the s-arylpalladi-
um(II) complex in turn generated from oxidative addition
of the aryl iodide to Pd(0) gives, after reductive elimina-
tion, the corresponding aromatic sulfone. It should be not-
ed that the task of potassium tert-butoxide is essential in
that it irreversibly intercepts the allyl ligand in the first
catalytic cycle thereby generating the required sulfinate
anion and Pd(0), yet, not perturbing the second catalytic
cycle.13
Acknowledgment
This work is the fruit of a collaborative project from COST, Action
D40 ‘Innovative Catalysis: New Processes and Selectivities’.
References and Notes
(1) Grossert, J. S. In The chemistry of Sulfones and Sulfoxides;
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(2) For a review, see: Alba, A.-R.; Companyó, X.; Rios, R.
Inspection of this mechanism reveals that such a pseudo-
domino process can only be successful if the oxidative ad-
dition of the allyl sulfone to the Pd(0) complex is faster
than that associated to the aryl halide. Indeed, otherwise,
the second catalytic cycle (sulfinate arylation) would
probably stall at the irreversibly generated s-arylpalladi-
um(II) complex stage and no spare Pd(0) complex would
be available to feed the first catalytic cycle (sulfinate gen-
eration). Such analysis is in full accord with the experi-
mental finding that in the case of 1a (Table 1) the rate of
sulfinate generation was found to be higher than that of
sulfinate arylation, and with the fact that electron-poor
aryl halides, which are associated to a fast oxidative addi-
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and 4).
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sequence involving the palladium-catalyzed generation of
sulfinate anions followed by their arylation to afford aro-
matic sulfones. Studies to elucidate the details of the reac-
Synlett 2011, No. 20, 2943–2946 © Thieme Stuttgart · New York

2946
G. Le Duc et al.
LETTER
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(13) Representative Experimental Procedure for the Domino
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To a solution of tris(dibenzylideneacetone)dipalladium (2
mol%) in toluene (500 mL) was added Xantphos ligand (5
mol%). The solution was stirred at r.t. for 5 min. Then, a
solution of allyl sulfone (0.30 mmol in 1.0 mL of toluene,
1 equiv), a solution of aryl halide (0.36 mmol in 500 L of
toluene, 1.2 equiv.), TBAB (0.60 mmol, 2 equiv), and KOt-
Bu (0.60 mmol, 2 equiv) were successively added. The
resulting system was stirred at reflux for 16 h. Then, after
cooling to r.t., a sat. aq NH4Cl solution (3 mL) were added,
and the aqueous phase was extracted three times with CH2Cl2.
The collected organic layers were dried over anhyd MgSO4,
and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography.
Synlett 2011, No. 20, 2943–2946 © Thieme Stuttgart · New York

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