the PFP-sulfonate esters are often crystalline in nature and
are significantly less reactive to nucleophiles than their
sulfonyl chloride counterpart. We have demonstrated that
the Suzuki-Miyaura reaction can be performed in the
presence of the PFP-sulfonate ester moiety in good yield,
thereby providing a convenient route to the synthesis of
biaryl and heterobiaryl sulfonate esters. The resulting
biaryl product should impart the desired stability, ease of
handling, and simple activation for the preparation of
sulfonamides.
robenzene boronic acid (3a) and the 4-bromobenzene-PFP-
sulfonate ester (2) (see Table 1). A variety of palladium
catalysts were tested such as Pd(PPh
Pd (dba) , Pd(OAc) , Pd(PPh , Herrmann’s PdPC21
PdCl (dppf), PdCl (CH CN), and PdCl [P(CH . From
the screening experiments, the catalyst that gave the best
results was found to be PdCl (PPh (Table 1, entry 7).
3 4 2 3 2
) , PdCl (PPh ) ,
2
3
2
3
)
4
20
H ,
2
2
3
2
3 6 4 3 2
C H ) ]
2
3 2
)
The reactions were carried out in a variety of refluxing
solvents (DME, DMF, THF, toluene, and dioxane) and also
in single combinations of these solvents with EtOH. In fact,
the reaction does not occur without some ethanol being
present (Table 1, entries 1, 2, 6, 7). In general, the best results
were found with various combinations of dioxane and EtOH
The PFP-sulfonate ester (2) was prepared from 4-bro-
mobenzenesulfonyl-chloride (1) in excellent yield, following
the conditions reported in Scheme 1. Complete esterification
(Table 1, entry 7).
As the cross-coupling reaction only occurs in the presence
of a moderately strong base, a number of bases were screened
for their ability to promote the desired cross-coupling
Scheme 1. Pentafluorophenyl Sulfonate Esterification of
4-Bromobenzenesulfonyl Chloride (1)
reaction, e.g., K
NaF, NaOTf, NaCF
thy that under similar reaction conditions, sodium carbonate
Table 1, entry 2) was infinitely better than potassium
2
CO
3
, Cs
2
CO
3
, Li
2
CO
3
, Na
2
3 3
CO , NaHCO ,
3 2 3 2 4 7
CO , Et N, and Na B O . It is notewor-
(
carbonate (Table 1, entry 5) in the C-C cross-coupling
reaction. Although these two bases would appear to have
similar basicities, the presence of a potassium cation appears
to significantly accelerate the rate of hydrolysis of the PFP-
sulfonate ester (2) and presumably any of the desired cross-
coupling products (4-8) shown in Scheme 3. A small but
consistent improvement in yield was also observed when the
reactions were carried out using conventional heating (Table
was observed after 1 h at room temperature. This product
was then used as a substrate to prepare 4-biaryl- and
1
, entry 2) rather than using microwave heating (Table 1,
entry 3). Moreover, we were delighted to discover that the
use of anhydrous sodium tetraborate (Na ), a reasonably
4
-heterobiaryl-PFP-sulfonate esters (4-8) using the C-C
Suzuki-Miyaura cross-coupling reaction.
Scheme 2 illustrates the general synthetic strategy used
to prepare 3′,4′-dichlorobiphenyl-4-sulfonic acid pentafluo-
2 4 7
B O
inexpensive and mild base, resulted in a significant improve-
ment in the isolated yield of the target biaryl and heterobiaryl-
PFP-sulfonate esters (4-8) (e.g., Table 1, entry 7). One very
notable feature of the employment of this base over sodium
carbonate was a significant reduction in the formation of
unwanted byproducts derived from bis-boronic acid coupling,
reduction of the aryl bromide (2), or hydrolysis of the PFP-
sulfonate ester (2).
Scheme 2. Synthesis of 3′,4′-Dichlorobiphenyl-4-sulfonic
Acid Pentafluorophenyl Ester (4)
In attempting to analyze the effects of different bases in
the cross-coupling reaction, there is a balance between
promoting the desired cross-coupling reaction and causing
undesirable hydrolysis of the PFP-sulfonate ester. The base
2 3 2 3
K CO , and to a lesser extent Na CO , was found to promote
hydrolysis of the PFP-sulfonate ester. The use of Na
2 4 7
B O
not only promoted the cross-coupling reaction but also
minimized the formation of all unwanted side reactions,
allowing much easier isolation of the products (4-8) (see
Scheme 3).
Scheme 3 illustrates the general synthetic strategy used
to prepare both 4-biaryl-PFP-sulfonate esters (4-6) and
rophenyl ester (4) from the 4-bromobenzene-PFP-sulfonate
ester (2) in the presence of PdCl (PPh ) .
2 3 4
In our search for optimal conditions, we explored the C-C
cross-coupling between the electron-deficient, 3,4-dichlo-
4
-heterobiaryl-PFP-sulfonate esters (7, 8) from the 4-bro-
mobenzene-PFP-sulfonate ester (2) using methods A and D.
A variety of boronic acids were chosen to determine the
scope of the reaction from an electron-deficient example,
3,4-dichlorophenyl boronic acid (3a), through more electron-
(9) Caddick, S.; Wilden, J. D.; Wadman, S. N.; Judd, D. B. Org. Lett.
2
002, 4, 2549.
rich examples, including para-tolyl boronic acid (3b) and
844
Org. Lett., Vol. 7, No. 5, 2005
Avitabile, Barbara G.
