Palladium-catalyzed allylic alkylation of α-sulfinyl carbanions under biphasic conditions

Article abstract of DOI:10.1055/s-2006-939702

Palladium-catalyzed allylic alkylation of α-sulfinyl carbanions can take place under biphasic conditions. These new conditions provide a simple, mild and efficient route to allylated sulfoxides in good yields. The reaction tolerates a wide variety of EWG

Full text of DOI:10.1055/s-2006-939702

LETTER
1055
Palladium-Catalyzed Allylic Alkylation of a-Sulfinyl Carbanions under
Biphasic Conditions
A
llylic Alkylation
u
of
a
-Sulfiny
i
l
Carba
l
nions laume Maitro, Guillaume Prestat, David Madec,* Giovanni Poli*
Université Pierre et Marie Curie – Paris 6, Laboratoire de Chimie Organique (UMR CNRS 7611), Institut de Chimie Moléculaire (FR 2769),
case 183, 4 place Jussieu, 75252 Paris cedex 05, France
Fax +33(1)44277567; E-mail: giovanni.poli@upmc.fr; E-mail: madec@ccr.jussieu.fr
Received 23 January 2006
Dedicated to the memory of Professor Marcial Moreno Mañas.
Table 1 Palladium-Catalyzed Intramolecular Allylic Alkylation of
Abstract: Palladium-catalyzed allylic alkylation of a-sulfinyl car-
banions can take place under biphasic conditions. These new condi-
tions provide a simple, mild and efficient route to allylated
sulfoxides in good yields. The reaction tolerates a wide variety of
EWG groups as additional carbanion stabilizing groups such as
ester, acetyl, cyano, amide, sulfonyl and sulfinyl functions.
Sulfur Stabilized Amidesa
O
O n
n
OAc
Pd2(dba)3
PPh3
S
Ph
S
Ph
base
O
THF, reflux
O
N
N
Key words: palladium, sulfoxides, carbanions, catalysis, allylic
alkylation
Bn
Bn
Entry
n
2
0
1
Base
Yield (%)b
1
2
3
BSA/AcOK
NaH
78
58
0
Transition-metal-catalyzed allylic substitutions have
proven to be a fundamental tool for carbon–carbon bond
formation.1 In this context, whereas the palladium-cata-
lyzed allylic alkylation of stabilized a-sulfenyl- and a-sul-
fonyl carbanions has been amply described,2 the
corresponding reaction involving a-sulfinyl carbanions,
despite the stereogenic character of the sulfur atom, has
been so far virtually neglected.3 Such a fact is probably
due to the high coordination power of the sulfoxide func-
tion toward palladium,4 which prevents the direct transpo-
sition of classical reaction conditions from a-sulfenyl- or
a-sulfonyl-activated carbanions to the corresponding a-
sulfinyl analogues. For example, in the course of our pre-
vious studies on the palladium-catalyzed intramolecular
allylic alkylation of unsaturated amides,5 the expected
vinylpyrrolidones could be satisfactorily obtained when a
sulfenyl- or a sulfonyl-based additional carbanion stabi-
lizing group (ACSG) was present, whereas under the
same conditions the corresponding sulfinyl-based deriva-
tive refused to cyclize (Table 1).6
NaH
a Reagents and conditions: substrate, Pd2(dba)3 (5 mol%), PPh3 (50
mol%), base (BSA, 1.2 equiv and AcOK, 10 mol% or NaH, 1.1
equiv) in THF, reflux, 12 h.
b Yields are given for isolated products.
a model reaction. The reaction was very sluggish using the
classical system [Pd(C3H5)Cl]2 (5 mol%), dppe (12.5
mol%), NaH (1.1 equiv), in THF at room temperature. Af-
ter five days, the desired allylated product was isolated in
a poor (£15%) yield (Table 2, entry 1). Thermal treatment
led to the degradation of the starting material after two
hours at reflux (entry 2). To our satisfaction, switch to the
above-mentioned biphasic conditions resulted in sub-
stantial improvement.9
Indeed, the use of n-Bu4NBr (10 mol%) as the phase trans-
fer agent, [Pd(C3H5)Cl]2 (2 mol%) as the palladium
source, dppe (5 mol%) as the ligand, and KOH (2.0 equiv)
as the base, in a biphasic CH2Cl2–H2O (1:1; v/v) system
led after 30 minutes to the desired allylation product 2 (1:1
diastereomeric ratio) in 44% yield at room temperature
We recently reported that the palladium-catalyzed in-
tramolecular allylic alkylation of unsaturated amides
could be efficiently run under phase-transfer conditions
(Equation 1).7 These conditions were milder and higher
yielding than those previously reported in a homogenous
medium.
OAc
[Pd(C3H5)Cl]2
dppe
n-Bu4NBr
Given the remarkable efficiency of these reaction condi-
tions, we decided to test this new system in the so far elu-
sive palladium-catalyzed allylation of sulfinyl-based
carbanions. The allylic alkylation of tert-butyl benzene-
sulfinyl acetate (1)8 with allyl acetate was first studied as
EWG
O
EWG
O
KOH aq
CH2Cl2–H2O, r.t.
N
N
Bn
Bn
72–96%
EWG = CO2Me, COMe, CN, SPh, SO2Ph
Equation 1 Palladium-catalyzed intramolecular allylic alkylation
under phase-transfer conditions
SYNLETT 2006, No. 7, pp 1055–1058
Advanced online publication: 24.04.2006
0
3.
0
5.
2
0
0
6
DOI: 10.1055/s-2006-939702; Art ID: G01606ST
© Georg Thieme Verlag Stuttgart · New York

1056
G. Maitro et al.
LETTER
Table 3 Influence of the Nature of the ACSGa
Table 2 Palladium-Catalyzed Allylation of tert-Butyl Benzene-
sulfinyl Acetate: Optimization of the Reaction Conditionsa
O
S
O
O
EWG
O
S
EWG
OAc
Ar
[Pd(C3H5)Cl)]2
dppe
Ar
+
S
CO2t-Bu
S
CO2t-Bu
OAc
1a–g
2a–f
+
conditions
Entry
Ar
EWG
Product
2a
Time
–
Yield (%)b
2
1
1
2
3
4
5
6
7
8
Ph
CO2Me
CO2t-Bu
COMe
CN
0
62
86
96
52c
46e
24f
nr
Entry Conditions
Time
120 h
2 h
Yield (%)b
Ph
2b
5 min
15 min
1 min
1 h
1
2
3
4
NaH, THF, r.t.
NaH, THF, reflux
£15
Ph
2c
0
Ph
2d
KOH, H2O–CH2Cl2, n-Bu4NBr, r.t. 30 min 44
KOH, H2O–CH2Cl2, r.t. 5 min 62
Ph
CONPh2
SOTold
SO2Tol
STol
2e
Tol
Tol
Tol
2f
21 h
3 h
a Reagents and conditions: allyl acetate (1 equiv), substrate (1.1
equiv), [Pd(C3H5)Cl]2 (2 mol%), dppe (5 mol%) and base.
b Yields are given for isolated product. The allylated product was iso-
lated as a 1:1 mixture of diastereomers.
2g
2h
24 h
a Reagents and reaction conditions: allyl acetate (1 equiv), a-sulfinyl
activated substrate (1.1 equiv), [Pd(C3H5)Cl]2 (2 mol%), dppe (5
mol%), KOH (50% aq solution, 2.0 equiv), CH2Cl2–H2O (1:1), r.t.
b Yields are given for isolated products. Unless otherwise stated, the
allylated products were isolated as a 1:1 mixture of diastereomers.
(entry 3). Interesting to note, the yield could be sizeably
improved (62%) by simply omitting n-Bu4NBr (entry 4).
It thus appears that the phase-transfer agent is not only c A 70:30 diastereomeric ratio was obtained.
d A 1:1 mixture of diastereomers was used as starting material.
unnecessary to the allylation reaction, but also somehow
detrimental.10 In a second set of experiments, the in-
fluence of the nature of the ACSG was studied. Table 3 il-
lustrates our results.11 Methyl benzenesulfinyl acetate did
not afford the corresponding allylation product owing to
competitive saponification of the starting material (entry
1). Although this result was not completely unexpected, it
is worth noting that such a problem was not met in the
previously reported methyl ester stabilized intramolecular
allylation under identical conditions (Equation 1).
Acetyl-,12 cyano-,13 amide-,14 and sulfinyl-15 ACSGs
allowed also formation of the corresponding allylated
products 2b–f in good to excellent yields (Table 3, entries
3–6), the sulfonyl group16 being the only ACSG affording
a poor yield of the corresponding product 2g (entry 7).
e The allylated product was isolated as a mixture of three diastere-
omers.
f The allylated product was isolated as a single diastereomer.
Gratifyingly, the optimized conditions converted these
substrates into the corresponding allylated products 5b–e
in good to excellent yields (Table 4).
Since 2b–e and 5b–e were obtained as mixtures of two
and four isomers, respectively, oxidation of the allylated
sulfoxides into the corresponding sulfones was con-
Table 4 Scope of the Reaction Using 3-Acetoxy Cyclopentenea
O
O
S
EWG
In experiments of entries 6 and 7, the a,b–g,d-unsaturated
sulfoxide 317 and sulfone 4,18 resulting from sulfenic acid
elimination,19 were isolated in 32% and 11% yield, re-
spectively (Equation 2). Noteworthy, 1f required 21 hours
to afford the desired product, whereas the sulfenyl-substi-
tuted precursor 1h was completely inert under the reaction
conditions (entry 8). These results might be related to the
comparatively low acidity of 1f and 1h.20 To further ex-
plore the scope of this new process, we investigated next
the palladium-catalyzed allylic alkylation of acetyl-, tert-
butoxycarbonyl-, cyano- and diphenylaminocarbonyl-
stabilized precursors 1b–e with 3-acetoxy-cyclopentene.
S
EWG
OAc
+
1b–e
5b–e
Entry
EWG
Product
Time
5 min
5 min
5 min
3 h
Yield (%)b
1
2
3
4
COMe
5b
5c
5d
5e
86
93
95
52
CO2t-Bu
CN
CONPh2
a Reagents and reaction conditions: 3-acetoxy-cyclopentene
(1 equiv), a-sulfinyl-activated substrate (1.1 equiv), [Pd(C3H5)Cl]2
(2 mol%), dppe (5 mol%), KOH (50% aq solution, 2.0 equiv),
CH2Cl2–H2O (1:1), r.t.
O
H
Tol
S
– TolSOH
3, EWG = TolSO, 11%
4, EWG = TolSO2, 32%
EWG
EWG
b Yields are given for isolated products. The allylated products were
isolated as a mixture of four isomers.
Equation 2 Formation of dienic compounds via elimination.
Synlett 2006, No. 7, 1055–1058 © Thieme Stuttgart · New York

LETTER
Allylic Alkylation of a-Sulfinyl Carbanions
1057
sidered, so as to reduce the number of diastereomers in the
adducts. Such an oxidation turned out to be rather delicate
since the starting sulfoxides tend to suffer easy sulfenic
acid elimination to the corresponding 1,3-dienes. After
some experimentation we eventually found that the CrO3-
catalyzed oxidation, according to Trudell et al.,21 allowed
isolation of the desired sulfones 6e–h in satisfactory
yields (Table 5).
References and Notes
(1) For reviews, see: (a) Tsuji, J. In Handbook of
Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., Ed.; John Wiley and Sons: New York, 2002,
1669. (b) Trost, B. M.; Vranken, D. L. V. Chem. Rev. 1996,
96, 395. (c) Hegedus, L. S. Transition Metals in the
Synthesis of Complex Organic Molecules; University
Science Book: Mill Valley, 1994.
(2) For palladium-catalyzed allylic alkylation of a-sulfonyl
activated carbanions, see: (a) Giambastiani, G.; Poli, G. J.
Org. Chem. 1998, 63, 9608. (b) Cuvigny, T.; Julia, M.;
Rolando, C. J. Organomet. Chem. 1985, 285, 395.
(c) Colobert, F.; Genêt, J.-P. Tetrahedron Lett. 1985, 26,
2779. For palladium-catalyzed allylic alkylation of a-
sulfenyl activated carbanions, see: (d) Hiroi, K.; Hidaka, A.;
Sezaki, R.; Imamura, Y. Chem. Pharm. Bull. 1997, 45, 769.
(e) Hiroi, K.; Koyama, T.; Anzai, K. Chem. Lett. 1990, 235.
(3) To our knowledge, only two examples in the literature report
the use of a-sulfinyl carbanions as nucleophilic partners in
Pd-mediated allylic alkylation. For a stoichiometric example
see: (a) Trost, B. M.; Weber, L.; Strege, P.; Fullerton, T. J.;
Dietsche, T. J. J. Am. Chem. Soc. 1978, 100, 3426. (b)Fora
catalytic example see: Hiroi, K.; Suzuki, Y.; Kato, F.; Kyo,
Y. Tetrahedron: Asymmetry 2001, 12, 37.
Table 5 Oxidation of the Allylated Sulfoxides to the Corresponding
Sulfonesa
O
O
O
H5IO6
CrO3 cat.
S
EWG
S
EWG
R
R
EtOAc–MeCN
–35 °C
6b–e
2b–e, 5b–e
Entry
1
Substrate EWG
R
Product Yield (%)b
2b
CO2t-Bu
6b
96
2
3
4
5
2c
2d
2e
5b
COMe
CN
6c
75
99
91
57c
6d
6e
(4) For reviews concerning the use of sulfoxide ligands in
palladiumcatalysis, see: (a) Fernandez, I.; Khiar, N. Chem.
Rev. 2003, 103, 3651. (b) Hanquet, G.; Colobert, F.;
Lanners, S.; Solladié, G. ARKIVOC 2003, (vii), 328.
(5) Poli, G.; Giambastiani, G.; Pacini, B.; Porcelloni, M. J. Org.
Chem. 1998, 63, 804.
CONPh2
CO2t-Bu
6¢b
43c
40c
50c
(6) Giambastiani, G. PhD Thesis; University Pierre et Marie
Curie: Paris, 2001.
(7) Madec, D.; Prestat, G.; Martini, E.; Fristrup, P.; Poli, G.;
Norrby, P.-O. Org. Lett. 2005, 7, 995.
6
7
8
5c
5d
5e
COMe
CN
6¢c
6¢d
6¢e
CONPh2
(8) (a) This substrate was prepared by oxidation of the
corresponding thioether (see ref. 8b) with Oxone® and wet
alumina (see ref. 8c). (b) Babin, D.; Demassey, J.; Demoute,
J.-P.; Dutheil, P.; Terrie, I.; Tessier, J. J. Org. Chem. 1992,
57, 584. (c) Greenhalgh, R. P. Synlett 1992, 235.
(9) For generalities on phase transfer catalysis, see:
(a) Demlow, E. V.; Demlow, S. S. Phase Transfer Catalysis,
3rd ed.; VCH: Weinheim, 1993. (b) Goldberg, Y. Phase
Transfer Catalysis: Selected Problems and Applications;
Gordon and Breach Science Publ.: Reading, 1992.
(c) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase Transfer
Catalysis: Fundamentals, Applications, and Industrial
Perspectives; Chapman and Hall: New York, 1994.
(10) For a review on the effect of halides in transition-metal
catalysis see: Fagnou, K.; Lautens, M. Angew. Chem. Int.
Ed. 2002, 41, 26.
a Reagents and conditions: substrate (1 equiv), H5IO6 (2.1 equiv),
CrO3 (10 mol%), EtOAc–CH3CN (2:1), –35 °C.
b Yields are given for isolated products.
c The oxidized products were isolated as a 1:1 mixture of diastere-
omers.
In summary, we have reported a new and operationally
very simple protocol for the palladium-catalyzed allylic
alkylation of a-sulfinyl carbanions, a transformation not
satisfactorily achievable under classical conditions. The
new reaction conditions allow the allylation of the tested
precursors in good yields and with milder reaction condi-
tions than previously reported. Extension to intramolecu-
lar and/or asymmetric variants of the present method is
currently under investigation.
(11) General Procedure for Palladium-Catalyzed Allylic
Allylation of a-Sulfinyl Activated Carbanions under
Biphasic Conditions.
To a solution of [Pd(C3H5)Cl]2 (2 mol%) in CH2Cl2 (500 mL)
dppe (5 mol%) was added. After 5 min stirring at r.t., the
allyl acetate (1 mmol), a CH2Cl2 (4.5 mL) solution of the
sulfoxide (1.1 mmol), H2O (5 mL), and KOH (50% aq
solution, 2 mmol) were successively added. The resulting
biphasic system was vigorously stirred at r.t. for the
indicated reaction time. The aqueous phase was extracted
three times with CH2Cl2. The collected organic phases were
dried over MgSO4 and the solvent was removed in vacuo.
The crude product was purified by flash chromatography.
(12) Nokami, J.; Kataoka, K.; Shiraishi, K.; Osafune, M.;
Hussain, I.; Sumida, S.-I. J. Org. Chem. 2001, 66, 1228.
Acknowledgment
The support and sponsorship concerted by CNRS and COST Action
D24 ‘Sustainable Chemical Processes: Stereoselective Transition
Metal-Catalyzed Reactions’ are kindly acknowledged.
Synlett 2006, No. 7, 1055–1058 © Thieme Stuttgart · New York

1058
G. Maitro et al.
LETTER
(13) Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.;
Wakabayashi, S. J. Am. Chem. Soc. 1984, 106, 7890.
(14) This substrate has been prepared by oxidation of the
corresponding thioether with Oxone® and wet alumina (see
ref. 8).
(15) Brebion, F. PhD Thesis; Université Pierre et Marie Curie:
Paris, 2004.
(16) (a) Jarvis, B. B.; Fried, H. E. J. Org. Chem. 1975, 40, 1278.
(b) Kunieda, N.; Nokami, J.; Kinoshita, M. Bull. Chem. Soc.
Jpn. 1976, 49, 256.
(17) Barluenga, J.; Martinez-Gallo, J. M.; Najera, C.; Frananas,
F. J.; Yus, M. J. Chem. Soc., Perkin Trans. 1 1987, 2605.
(18) Mikolajczyk, M.; Perlikowska, W.; Omelanczuk, J.; Cristau,
H.-J.; Perraud-Darcy, A. J. Org. Chem. 1998, 63, 9716.
(19) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc.
1976, 98, 4887.
(20) For pKa values of compounds strictly related to 1f and 1h
see: http://www.chem.wisc.edu/areas/reich/pkatable/.
(21) Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2003, 68,
5388.
Synlett 2006, No. 7, 1055–1058 © Thieme Stuttgart · New York