Palladium-catalysed arylation of sulfonamide stabilised enolates

Article abstract of DOI:10.1016/j.tetlet.2005.01.096

α-Arylation of methanesulfonamides using palladium catalysis is described. For example, treatment of N-benzyl-N-methylmethanesulfonamide with catalytic Pd(OAc)₂ in the presence of sodium tert-butoxide, triphenylphosphine and toluene afforded N-

Full text of DOI:10.1016/j.tetlet.2005.01.096

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1597–1599
Palladium-catalysed arylation of sulfonamide stabilised enolates
Jacob G. Zeevaart,a Christopher J. Parkinsona,* and Charles B. de Koningb
aCSIR Bio/Chemtek, Speciality and Fine Chemicals Programme, Modderfontein, South Africa
bMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, WITS, 2050 South Africa
Received 24 November 2004; revised 10 January 2005; accepted 19 January 2005
Available online 1 February 2005
Abstract—a-Arylation of methanesulfonamides using palladium catalysis is described. For example, treatment of N-benzyl-N-
methylmethanesulfonamide with catalytic Pd(OAc)2 in the presence of sodium tert-butoxide, triphenylphosphine and toluene afforded
N-benzyl-N-methylphenylmethanesulfonamide in 66% yield.
Ó 2005 Elsevier Ltd. All rights reserved.
Since the early breakthroughs of 1997, palladiumcata-
lysed enolate arylation has become a reliable and widely
applicable reaction. The methodology has been devel-
oped in research programmes pioneered by Hartwig
and Buchwald (amongst others) and now accom-
modates a wide variety of stabilised carbanions with a
degree of rational prediction as to the required base
and ligand to facilitate the reaction.1
the acidity of the subject sulfonamide through the gener-
ation of a b-cyanosulfonamide. The relatively acidic
2-[N-(benzyloxymethyl)-N-methylaminosulfonyl]cyano-
acetate (1) was coupled with aryl iodide 2a using
tetrakis(triphenylphosphine)palladium(0) as catalyst
and sodiumhydride as base ( Scheme 1) to afford 2b.
Similar reactions have previously been performed by a
SRN1 type reaction involving potassiumand liquid
ammonia chemistry.9
It has been demonstrated that sulfones also undergo the
same type of arylation reaction. Intermolecular enolate
arylation of substituted methylphenylsulfones (YCH2-
SO2Ph, Y = electron withdrawing group) with aryl
iodides using CuI/NaH has been reported by Suzuki2
and Gorelik et al.3 while the use of a palladiumcatalyst
in this transformation was published by Kondo and co-
workers.4 Ciufolini has also reported one example of an
intramolecular version of this type of reaction.5 In addi-
tion, Beletskaya and co-workers have recently published
several examples of palladium catalysed intermolecular
couplings of sulfone stabilised enolates with aryl bro-
mides.6 N-Substituted methylphenylsulfoximes have
also been demonstrated to proceed in intramolecular
versions of this coupling reaction mediated by a palla-
dium/BINAP catalyst.7
The preparation of compounds such as 1, containing
both a sulfonamide and a cyano substituent to enhance
the acidity of the protons between both functional
groups, is relatively cumbersome. In cases where the a-
aryl methanesulfonamide is required as in the target
compound, such electron-withdrawing groups have to
be removed after coupling with the aryl halide. The
preparation of methanesulfonamides, on the other hand,
is extremely simple through the reaction of methane-
sulfonyl chloride and the appropriate amine. It has,
ArI
O
O
O
O
S
CN 10% Pd(PPh3)4
S
CN
N
N
NaH
Ph
I
Ar
Ph
O
1
O
2b
Only one example of an arylation reaction is found
where the nucleophile is a sulfonamide.8 However, the
success of this procedure required an enhancement of
ArI =
Cl
NHMe
Keywords: Palladiumcatalysis; Sulfonaimde stabilised enolates;
Arylation.
2a
Scheme 1. Palladiumcatalysed arylation of a b-cyanosulfonamide.
Cl
*
Corresponding author. Tel.: +27 11 6052601; fax: +27 11 6083200;
e-mail: cparkinson@csir.co.za
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.096

1598
J. G. Zeevaart et al. / Tetrahedron Letters 46 (2005) 1597–1599
however, previously been reported that highly nucleo-
philic carbanions (stabilised by only one electron-with-
drawing group) such as those derived from
methylphenylsulfone and methylphenylsulfoxide are
unreactive in arylation chemistry.6,10,11 We found this
fact surprising since the arylation of the closely related
methylphenylsulfoximes has been demonstrated by
Bolmet al. 7 and other systems with high pKa values such
as acetamides, acetonitrile and acetic acid esters
(pKa ꢀ 31–3512) have been used successfully in enolate
arylation reactions.13–17 Therefore, in this letter we wish
to communicate the successful enol arylation reaction of
methanesulfonamides with aryl halides using palladium
catalysts.
sulfonamide enolate would necessitate the use of a
stronger base as has been observed for substrates like
aliphatic amides and esters13,17,16 with similar pKa
values. Initial attempts with the stronger NaHMDS base
were, however, unsuccessful. Identical conditions used
for the substrate 3, however, resulted in the formation
of the desired arylated product 6a from 5a, albeit in
low yield (ꢀ10% yield by GLC). Unlike the clean reac-
tion observed for substrate 3, biphenyl was formed as
a by-product (ꢀ20%). Under the same conditions a
moderate yield (51%) of 6a was obtained with iodo-
benzene as the aromatic substrate in the reaction. The
successful utilisation of bromobenzene as the aromatic
partner in the same reaction, however, was realised by
increasing the reaction temperature (entry 7). Contrary
to the improved yield obtained with the PtBu3 ligand
for the arylation reaction with 3, the yield of 6a was
poor when attempted with the methanesulfonamide
substrate 5a (entry 8). The use of K3PO4 as base was
unsuccessful (entry 9) with substrate 5a (Scheme 2).
Following the reported successful arylation of an a-
cyano methanesulfonamide,8 we prepared a similar sub-
strate 3. It was found that 3 could be arylated with
iodobenzene using a Pd(OAc)2/PPh3 catalyst in a tolu-
ene solution at 70 °C with NaOtBu as base (Table 1, en-
try 1) to give the desired arylated product 4 in 63% yield.
The same reaction with bromobenzene was performed at
110 °C and gave the product in 77% yield (entry 2).
Incomplete conversion of both starting materials was
observed, presumably due to the enhanced thermody-
namic acidity of the product and the subsequent coordi-
nation of the resultant anion to the catalyst generating
an intermediate with geometry unsuitable for further
reaction.
Following these investigations the nature of the sulfon-
amide was the subject of further studies. The N,N-diiso-
propyl methanesulfonamide 5b (Scheme 3, Table 2) was
employed in our next study. Besides the formation of
moderate yields (9–46% for bromobenzene) of the de-
sired mono-arylated product 6b from 5b by utilising a
number of phosphine ligands, diarylation to give 7b
was observed in varying amounts (Table 2). BINAP
was more selective towards mono-arylation than triphen-
ylphosphine (see entries 1 and 3). The ligands PCy3 and
PtBu3 behaved very differently in this transformation
with PCy3 leading preferentially to the diarylated prod-
uct 7b while PtBu3 was the most selective ligand for
mono-arylation (entries 4 and 5). Cyclohexyl JohnPhos
8 gave moderate activity (similar to triphenylphosphine)
with high mono-selectivity (entry 9). The use of a lower
palladium loading (1 mol %) while maintaining a high
Turning our attention to the use of alternative ligands
and bases it was found that the use of the highly versa-
tile PtBu3 ligand (entry 3)18 led to a higher yield in the
conversion of 3 to 4 albeit in a more complex product
matrix. It was also demonstrated that K3PO4 could be
used as base in the presence of a small amount
of N,N-dimethylacetamide as co-solvent (entry 4).
Yields were, however, inferior to that obtained by using
NaOtBu as the base in the reaction.
O
O
O
O
PhX
S
CN
S
CN
Motivated by the successful arylation of 3, we reasoned
that the arylation of the methanesulfonamide substrate,
lacking the extra stabilising substituent, for example, 5a
might be feasible. It was thought the higher pKa (be-
tween 32 and 35)12,13 of the mono-stabilised methane-
8% Pd(OAc)2, L
N
N
Ph
Base
Ph
Ph
3
4
PhX
O
O
O
O
S
S
8% Pd(OAc)2, L
N
N
Table 1.
Ph
Base
Ph
Ph
Entry
X
I
Yield Biphenyl Base 1.75 Ligand °C
5a
6a
(%)a
(%)
equiv
L 22%
Scheme 2. Arylation of N-benzyl-N-methyl sulfonamidoacetonitrile
and N-benzyl-N-methyl methanesulfonamide (see Table 1 for condi-
tions and yields).
1
2
3
4
5
6
7
8
9
3
3
3
3
63
0
NaOtBu
NaOtBu
NaOtBu
PPh3
PPh3
70
110
110
100d
70
Br 77
Br 81
0
b
0
PtBu3
c
I
41
0
K3PO4
PPh3
PPh3
PPh3
PPh3
5a Br ꢀ10
5a 51
ꢀ20
5
NaOtBu
NaOtBu
NaOtBu
NaOtBu
I
75
PhBr
O
O
O
O
O
O
R1
S
Ar
5a Br 66
5a Br 28
6
110
110
110
R1
S
Ar
R1
S
Pd(OAc)2 / L
NaOtBu
PtBu3
b
N
N
<1–10
ꢀ10
N
+
c
5a
I
0
K3PO4
PPh3
Ar
R2
7b-e
R2
6b-e
R2
5b-e
a Yield determined by GC with 2-methoxynaphthalene as internal
standard.
b 5 mol % PdOAc2 and 7.5 mol % PtBu3 were used.
c 2.3 M equiv base was used.
d N,N-Dimethylacetamide as co-solvent.
Scheme 3. Reagents and conditions: 2 mmol aryl bromide, 2.2 mmol
sulfonamide, 3.5 mmol NaOtBu, 5 mL toluene, 1–8% Pd(OAc)2,
ligand, 110 °C, 15 h (see Table 2 for ligand and yields).

J. G. Zeevaart et al. / Tetrahedron Letters 46 (2005) 1597–1599
1599
Table 2.
Entry Methanesulfonamide 5
ArBr
Pd(OAc)2 Ligand (mol %)
(mol %)
6 Yield (%) 7 Yield (%) Biphenyl yield (%)
1
2
3
4
5
6
7
8
5b R1 = R2 = iPr
5b R1 = R2 = iPr
5b R1 = R2 = iPr
5b R1 = R2 = iPr
5b R1 = R2 = iPr
5b R1 = R2 = iPr
5b R1 = R2 = iPr
5b R1 = R2 = iPr
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
Bromobenzene
2-Bromotoluene
4-Bromoanisole
8
8
5
4
5
1
8
8
PPh3 (23)
PoTol3 (15)
BINAP (7.5)
PtBu3 (8)
6b, 34
6b, 9
7b, 14
7b, 0
7b, 9
15
3
6b, 45
6b, 46
6b, 14
6b, 34
6b, 50
6b, 52
6
7b, 4
<1
0
PCy3 (10)
PPh3 (23)
PPh3 (23)
PPh3 (23)
7b, 25
7b, 29
7b, 10
7b, 2
<1
Nd
3
9
5b R1 = R2 = iPr
4-Bromoanisole
Bromobenzene
5
6b, 34
7b, <1
3
Cy2P
8 (10)
PPh3 (23)
PPh3 (23)
PPh3 (23)
10
11
12
5c R1–R2–(CH2)4–
8
8
8
6c, 35
6d, 60
6e, 34
7c, 6
7d, 5
7e, 4
9
5d R1–R2 = –(CH2)2O(CH2)2– Bromobenzene
5
14
5e R1 = Me, R2 = Ph
Bromobenzene
4. Sakamoto, T.; Katoh, E.; Kondo, Y.; Yamanaka, H.
Chem. Pharm. Bull. 1990, 38, 1513.
5. Ciufolini, M. A.; Qi, H.-B. J. Org. Chem. 1988, 53, 4149.
6. Kashin, A. N.; Mitin, A. V.; Beletskaya, I. P.; Wife, R.
Tetrahedron Lett. 2002, 43, 2539.
PPh3 loading did not lead to lower arylation activity but
instead led to the formation of similar amounts of the
mono- and di-arylated products 6 and 7 and suppression
of biphenyl formation (entry 6).
7. Bolm, C.; Hiroaki, H.; Verrucci, M. J. Organomet. Chem.
2003, 687, 444.
Using the more sterically hindered 2-bromotoluene in-
stead of bromobenzene in the enolate arylation reaction
with 5b also led to a marginal increase in selectivity of
the product ratios of 6b and 7b, while the unhindered
and electron-rich 4-bromoanisole led to almost exclu-
sively the mono-arylated product (entries 8 and 9).
These results indicate that not only steric factors, but
also electronic factors are important in determining
the selectivity and yield of this reaction.
8. Middleton, D. S.; Stobie, A. 1,2,3,4-Tetrahydro-1-naph-
thalenamine Compounds Useful in Therapy, Chem. Abstr.
133:222454, WO 00/51972; Pfizer Limited, 2000.
9. Skorcz, J. A.; Suh, J. T.; Germershausen, R. L. J.
Heterocycl. Chem. 1974, 11, 73.
10. Mitin, A. V.; Kashin, A. N.; Beletskaya, I. P. J. Organo-
met. Chem. 2004, 689, 1085.
´
11. Rodrıguez, N.; Cuenca, A.; Ramırez De Arellano, C.;
Medio-Simon, M.; Asensio, G. Org. Lett. 2004, 5, 1705.
´
´
12. Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
13. Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J.
Org. Chem. 1998, 63, 6546.
14. Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
15. Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
9330.
The problems concerning diarylation of the N,N-diiso-
propyl substituted sulfonamide 5b proved to be less
apparent on less sterically hindered sulfonamides. For
example, treatment of substrates 5c–e under the same
conditions used in entry 1 in Table 2 led to ratios of
the monoarylated product 6c–e to the diarylated prod-
ucts 7c–e exceeding 10:1 where the major side product
was biphenyl (entries 10–12).
16. Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc.
2001, 123, 8410.
17. Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
123, 7996.
t
18. Fuꢀs highly stable Bu3PÆHBF4 salt was used (available
fromStremChemicals); Netherton, M. R.; Fu, G. C. Org.
Lett. 2001, 3, 4295.
In conclusion, we have shown the first examples of the
a-arylation of methanesulfonamides under palladium,
catalysis conditions using phosphine ligands and sodium
t-butoxide as a base.19 The outcome of this reaction is
apparently governed by a mixture of steric and elec-
tronic effects, with the major by-products being biphenyl
and diarylation of the methanesulfonamide. Both aryl
bromides and iodides are active participants in this cou-
pling reaction.
19. General experimental procedure: A screw-capped Pyrex
tube (50 mL) was charged with sodium tert-butoxide
(3.5 mmol), 10 mL dry toluene (distilled from sodium),
methanesulfonamide 5 (2.2 mmol), and aryl bromide
(2.0 mmol). A warmed (ꢀ60 °C for 1 min) suspension of
Pd(OAc)2 (36 mg, 0.16 mmol, 8 mol %), triphenylphos-
phine (120 mg, 0.46 mmol, 23 mol %), 2-methoxynaphtha-
lene (an accurately weighed amount as internal standard)
and toluene (3 mL) were added. The tube was flushed with
nitrogen and heated to 100–110 °C in a Robosynthon
multireactor for 15–20 h. The conversion of the methane-
sulfonamide and aryl bromide was determined by GLC
analysis based on internal standard calculation. After a
total reaction time of 15–20 h the reaction mixture was
cooled and quenched by addition of water and dilute
hydrochloric acid followed by extraction into ethyl
acetate. After solvent removal, the residue was purified
by column chromatography to afford the products.
References and notes
1. For a review on this topic see: Culkin, D. A.; Hartwig, J.
F. Acc. Chem. Res. 2003, 36, 234.
2. Suzuki, H.; Yi, Q.; Inoue, J.; Kusume, K.; Ogawa, T.
Chem. Lett. 1987, 887.
3. Gorelik, M. V.; Titova, S. P.; Kanor, M. A. J. Org. Chem.
USSR (Engl. Transl.) 1992, 28, 1852.