Palladium-catalyzed Negishi α-arylation of alkylsulfones

Article abstract of DOI:10.1016/j.tetlet.2009.12.035

A general, mild catalytic system for α-monoarylation of various alkyl sulfones is described that utilizes palladium-catalyzed Negishi cross-coupling approach.

Full text of DOI:10.1016/j.tetlet.2009.12.035

Tetrahedron Letters 51 (2010) 939–941
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed Negishi a-arylation of alkylsulfones
*
Gang Zhou , Pauline C. Ting, Robert G. Aslanian
Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A general, mild catalytic system for a-monoarylation of various alkyl sulfones is described that utilizes
palladium-catalyzed Negishi cross-coupling approach.
Received 20 November 2009
Revised 7 December 2009
Accepted 8 December 2009
Available online 26 December 2009
Published by Elsevier Ltd.
The sulfone is an important organic structural motif in the total
synthesis of natural products and biologically active compounds.1
The sulfonyl group can facilitate the deprotonation of a neighbor-
ing carbon atom and the corresponding carbanion can then be used
for a variety of transformations. Afterwards, the auxiliary sulfonyl
group can be easily removed by reductive desulfonylation.1b
Although several synthetic routes to arylmethylsulfones have been
reported,1c these routes are complex multi-step procedures which
have limited use in sulfone synthesis.
Using methylphenylsulfone 1 as a model sulfone and bromo-
benzene as a typical aryl halide, we optimized the reaction condi-
tions by varying the ligands (Table 1, entries 3–6). Under these
conditions, LHMDS was used as the base and arylzinc reagent
was prepared in situ by the reaction of aryllithium with anhydrous
ZnCl2. The reactions proceeded smoothly with bromobenzene and
the best yield of monoarylated sulfone 2 was obtained with X-Phos
as ligand (Table 1, entry 6).7 Using ligands Dave-Phos or S-Phos
also gave monoarylated sulfones 2 but in relatively lower yield (Ta-
ble 1, entries 3 and 5).
While many reports dealing with a
-arylation of ketones exist,2
there are few reports concerning C-arylations of alkyl sulfone
derivatives. To our knowledge, only a single literature reference
has studied the C-arylations of methanesulfone derivatives in
Table 1
Arylation of methylphenylsulfone 1
which the
a-H acidity is enhanced by activating groups (e.g.,
NO2, CN, and CO2R).3
O
O
S
condition
Br
According to Beletskaya and co-workers, a-functionalized (e.g.,
S Me
NO2, CN or CO2R) sulfones can be monoarylated by a Pd-catalyzed
reaction with a conventional PPh3 ligand.3 However, in the case of
arylation of simple methylphenylsulfone 1 without an activating
group, these reaction conditions are ineffective despite the use of
NaH or NaOtBu as base (Table 1, entries 1 and 2). The lack of reac-
O
O
1
2
Entry
Conditiona
Yieldb (%)
1
2
3
4
5
6
NaH, Pd2dba3, CHCl3, PPh3, dioxane, 70 °C, 3 h
NaOtBu, Pd(OAc)2, PPh3, toluene, 110 °C, 12 h
LHMDS, ZnCl2, Pd(OAc)2, S-Phos, THF, 65 °C, 5 h
LHMDS, ZnCl2, Pd(OAc)2, Ru-Phos, THF, 65 °C, 5 h
LHMDS, ZnCl2, Pd(OAc)2, Dave-Phos, THF, 65 °C, 6 h
LHMDS, ZnCl2, Pd(OAc)2, X-Phos, THF, 65 °C, 5 h
0
5
20
0
62
85
tivity was thought to be due to the higher pKa of the sulfonyl a-CH-
acid (pKa 29)4, however, the stronger base n-BuLi could not affect
this transformation.3
Recently we have reported a mild palladium-catalyzed aryla-
tion reaction which couples aryl halides with in situ prepared sul-
fonamide zinc reagents.5 The ligand plays a critical role in the
success of this arylation reaction.6 A set of sterically hindered
and electron-rich phosphines were screened and only the bulky
monodentate ligands X-Phos and Dave-Phos, as shown in Figure 1,
proved to be applicable for this coupling. Herein, we extend the
utility of this system and apply it to the synthesis of benzylsulfones
a
Reactions were conducted with aryl bromide (0.7 mmol), substrate
(1.0 mmol).
1
b
Isolated yield based on bromobenzene.
PCy2
PCy2
NMe2
PCy2
iPr
PCy2
OMe
iPr
i-PrO
Oi-Pr
by palladium-catalyzed
a-arylation of the related alkylsulfones
MeO
with aryl halides (Table 1).
iPr
X-Phos
Ru-Phos
Dave-Phos
S-Phos
* Corresponding author. Tel.: +1 908 740 3740; fax: +1 908 740 2252.
E-mail address: gang.zhou@spcorp.com (G. Zhou).
Figure 1. Representative ligand structures.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.12.035

940
G. Zhou et al. / Tetrahedron Letters 51 (2010) 939–941
Table 2
Table 3
Arylation of methylphenylsulfone 1 with various halidesa
Arylation of sulfone substrates via the palladium-catalyzed Negishi couplinga
O
S
O O
O
2) Pd(OAc)2
X-Phos
1) LHMDS
ZnCl2
Ar
1) LHMDS
ZnCl2
2) Pd(OAc)2
X-Phos
O
Me
O
S
R2
S
R1
S
R2
R1
O
1
O
3
Br
4
5
Entry Aryl halide
Time
Product
Yieldb
(h)
(%)
Entry
1
R1
R2
H
Time (h)
3
Product
Yieldb (%)
60
O
S
O
Cl
S
1
10
20
Me
O
O
O
Me
Me
O
Cl
OMe
Me
S
2
10
10
10
6
65
90
82
98
63
S
2
3
Et
Me
Me
10
12
52
68
O
OMe
O
O
S
Me
O
Br
3
S
Ph
O
Me
F
Me
O
F
O
S
O
O
S
4
Br
O
4
Ph
Ph
24
82
S
O
Br
OMe
CN
5
O
S
O
O
OMe
CN
5
6
–CH2R2
Ph
–CH2CH2–
CN
12
6
53
72
O
S
Br
6
12
CN
O
O
S
O
O
S
Br
CO2Et
7
12
6
74
94
62
68
54
O
S
7
Ph
CO2Et
6
70
O
O
S
O
Br
8
a
Reactions were conducted with aryl halides (0.7 mmol), substrate 4 (1.0 mmol),
LHMDS (1.5 mmol), ZnCl2 (1.5 mmol), Pd(OAc)2 (0.04 mmol) and X-Phos
OMe
O
O
S
OMe
(0.08 mmol) in THF (2 mL) at 65 °C.
Br
Br
N
b
Isolated yield based on bromobenzene.
9
10
11
18
5
N
O
O
While the arylation reactions described in Table 2 employed
various substituted aryl halides with methylphenylsulfone 1, addi-
tional alkylsulfones 4 were also subjected to arylation under our
optimized reaction conditions (Table 3). The reactions of a variety
of sulfones 4 with bromobenzene were generally complete at 65 °C
and consistently afforded mono-arylated products 5 in moderate
to good yields (Table 3, entries 1–7) along with a minor amount
of the bisarylation side products (<20%).
In conclusion, we have developed an efficient method for the
synthesis of functionalized benzylic sulfones, using the palla-
dium-catalyzed Negishi coupling reaction of various alkylsulfones
and aryl halides.
S
O
O
S
Br
5
O
a
Reactions were conducted with aryl halides (0.7 mmol), substrate 1 (1.0 mmol),
LHMDS (1.5 mmol), ZnCl2 (1.5 mmol), Pd(OAc)2 (0.04 mmol) and X-Phos
(0.08 mmol) in THF (2 mL) at 65 °C.
Isolated yield based on halide.
b
With this optimized condition in hand, we further investigated
this sulfone arylation by coupling a variety of aryl and vinyl halides
with methylphenylsulfone 1 (Table 2). Aryl bromides or chlorides
were employed as the electrophilic partner. Substituted aryl bro-
mides smoothly gave the desired monoarylation products (Table 2,
entries 3, 4 and 7) while the aryl chlorides showed relatively lower
reactivity (Table 2, entries 1 and 2). The electronic properties of the
reactants also influenced the reaction. Electron-rich aryl halides
are good substrates under our coupling conditions, exemplified
by 4-chloroanisole, 4-bromoanisole, and 6-bromo-2-methoxyl-
naphthalene (Table 2, entries 2, 5 and 8). However, aryl bromide
Acknowledgments
We would like to thank our colleagues at the Kenilworth site of
Merck Research Laboratories. Mr. Ibrahim Daaro for mass spec-
trometry assistance, Dr. Xiaolei Gao for proofreading, and Dr. Mal-
colm MacCoss for support of this program.
References and notes
1. (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford, 1993;
´
(b) Najera, C.; Yus, M. Tetrahedron 1999, 55, 10546; (c) Houben-Weyl. In
components with electron-withdrawing groups resulted in
a
Methoden Der Organic Chemie; Georg Thieme: Stuttgart, New York, 1985; E11.
2. (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
1360; (b) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996; (c)
Jørgensen, M.; Lee, S.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
12557; (d) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330.
3. Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R. Tetrahedron Lett. 2002, 43,
2539.
mono-arylated product with moderate yield (Table 2, entries 6).
A heterocyclic halide such as 4-bromopyridine is also tolerated in
this system (Table 2, entry 9). Vinyl bromides such as bromosty-
rene and bromo-2-methylpropene can be used to generate the cor-
responding a-vinylation products (Table 2, entries 10 and 11).

G. Zhou et al. / Tetrahedron Letters 51 (2010) 939–941
941
4. Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 4641.
À20 °C. The reaction mixture was slowly warmed from À20 °C to room
temperature over 60 min then bromobenzene (0.70 mmol, 0.7 equiv) and a
solution of the ligand (0.08 mmol, 11.4 mol %) with Pd(OAc)2 (0.04 mmol,
5.7 mol %) in THF (0.5 mL) were added successively. The solution was then
degassed under vacuum for 20 min and recharged with nitrogen. The resulting
reaction mixture was heated in an oil bath at 65 °C for the stated time, cooled to
room temperature, quenched with aqueous NH4Cl (1 mL) and 1 N HCl (0.5 mL)
then extracted with CH2Cl2 (3 Â 10 mL). The organic phase was dried over
MgSO4, filtered and concentrated under reduced pressure. The crude product
was purified by silica gel chromatography with an eluant of hexanes/ether
(20:1) to afford the desired product 2 as a white solid (138 mg, 85%); 1H NMR
(500 MHz, CDCl3): d 7.61–7.66 (m, 3H, Ar–H), 7.55–7.57 (m, 1H, Ar–H), 7.47 (t,
J = 7.5 Hz, 2H, Ar–H), 7.33–7.36 (m, 1H, Ar–H), 7.29 (t, J = 6.0 Hz, 2H, Ar–H), 7.10
(d, J = 7.5 Hz, 1H, Ar–H), 4.34 (s, 2H, CH2); 13C NMR (125 MHz, CDCl3): d 134.1,
131.2(2C), 130.4, 129.3 (2C), 129.2, 129.1 (3C), 128.9 (2C), 63.3; HRMS (EI) calcd
for [C13H12NaO2S] ([M+Na]+): 255.0456; found 255.0695.
5. Zhou, G.; Ting, P.; Aslanian, R.; Piwinski, J. J. Org. Lett. 2008, 10, 2517.
6. The chosen catalysts have proven reactivity in other arylation reactions, see: (a)
Hamada, T.; Chieffi, A.; Ahman, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
1261; (b) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett. 2002, 4, 4053; (c)
Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976; (d) Yin, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043; (e) Wu, L.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 15824; (f) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F.
J. Org. Chem. 1998, 63, 6546; (g) Campos, K. R.; Klapars, A.; Waldman, J. H.;
Dormer, P. G.; Chen, C. J. Am. Chem. Soc. 2006, 128, 3538; (h) Huang, J. K.; Bunel,
E.; Faul, M. M. Org. Lett. 2007, 9, 4343.
7. General experimental procedure for compound 2: To
a stirred solution of
methylphenylsulfone 1 (1.0 mmol, 1.0 equiv) in THF (0.5 mL) at À20 °C in a
sealed tube under nitrogen was added a solution of LiHMDS (1.5 mL, 1.5 equiv,
1.0 M in THF). After stirring for 30 min at room temperature, a freshly prepared
solution of ZnCl2 (0.206 g, 1.5 mmol, 1.5 equiv) in THF (0.5 mL) was added at