.
Angewandte
Communications
Table 1: Substrate scope: variation of iodonium salts.
the first time the data obtained was used to rationally design
a more complex molecule that predictably underwent a highly
chemo- and regioselective reaction under the reported
conditions.
Using our previously reported reaction conditions as
a starting point,[14] we were delighted to discover that 2-n-
butylthiophene (1a) and [Ph2I]BF4 (2a) gave 2-n-butyl-4-
phenylthiophene (4a). Control experiments indicated that
neither CuCl nor base were necessary and that reactivity was
observed at room temperature. Of the heterogeneous cata-
lysts screened, only Pd catalysts were reactive. Some homo-
geneous Pd catalysts also gave 4a, though with much lower
conversion. Standard screening of solvents, catalyst loading,
temperature, and ratio of reagents established the optimized
conditions to be 5 mol% Pd/C in EtOH at 608C and 1a and
2a in a ratio of 1:1.4. No product formed in a control reaction
conducted without Pd/C. Additional experiments showed that
reaction with 2 mol% Pd/C gave similar conversion, though
an elevated temperature of 808C was required to avoid
extended reaction time. Triflate counterions (2b) were
tolerated, and the use of the unsymmetrical iodonium salt
[PhI(TRIP)]OTf (3a) (TRIP = 2,4,6-triisopropylphenyl) gave
4a in comparable yield without transfer of the TRIP group.
Consequently, TRIP can be used as a cheap nontransferable
dummy group instead of a potentially expensive second
equivalent of arene as is the case with symmetrical aryliodo-
nium salts. The yield did not change when absolute EtOH or
an argon atmosphere were used. The addition of 50 equiv of
water resulted in only a minor decrease in yield to 72%,
which is likely due to poor dispersion of the catalyst.[18] We
employed commercial Pd/C from Heraeus for our study,
though Pd/C from other common suppliers was also reactive.
See the Supporting Information for all optimization data.
Having established the reaction conditions, we explored
General conditions: 1a (0.300 mmol), 3b–j (1.4 equiv), Pd/C (5 mol%),
EtOH (1.5 mL), 22 h. Yields refer to isolated products. C3/C2 ratios
determined by GC–MS analysis of the crude reaction mixture.
[a] 1a/3j=3:1; 4j and 4k are products of the same reaction.
tolerated; these results extend the scope of our reaction
beyond that of all other methods.[12]
Our method also proved applicable to benzo[b]thio-
phenes, giving the desired products with complete selectivity
(Table 3).[20] The reactivity of other heterocycles was also
explored. The reactions of benzofuran and 1H-indole with 2a
gave the corresponding C2-arylated products in 77% and
40% yield, respectively (6d and 6e). 2-n-Butylfuran was also
found to be a suitable substrate when an electron-deficient
aryliodonium salt was employed (6 f). Reaction of 2-n-
butylfuran with 2a resulted in decomposition of the starting
materials. To demonstrate the scalability of the reaction, the
standard reaction was performed on a 5 mmol scale yielding
4a in an excellent 89% yield. The recycling of Pd/C was also
investigated, though a decrease in yield was observed for the
second (64%) and third (48%) cycle. We used the surfactant
Brij 35 so that reactions in both EtOH/H2O mixtures and pure
H2O proceeded with synthetically useful yields of up to 61%
(see the Supporting Information).
Prior to exploring the substrate scope we applied the
optimized reaction conditions in a robustness screen (see the
Supporting Information).[17] The screen predicted the toler-
ance of the reaction to aryl and alkyl halides, aromatic esters,
tertiary amides, and primary alcohols. Primary and aromatic
amines, as well as alkenes and alkynes that are likely oxidized
under the reaction conditions, were predicted to be unsuitable
substrates. These results were validated when we explored the
scope.
the scope of unsymmetrical iodonium salts 3 (Table 1).[19]
A
broad range of functionalized arenes could be coupled with
1a giving the expected products in good to excellent yields.
Electron-poor, electron-rich, and sterically encumbered
arenes were well tolerated. The coupling of heterocyclic
iodonium salts (thiophene derivative) should be highlighted
(4j, 4k), and enabled the preparation of the all-C3-connected
terthiophene 4k.
We subsequently explored the scope of the thiophenes.[20]
In general, alkyl-substituted thiophenes reacted irrespective
of their substitution pattern to give the expected products in
typically excellent yields (Table 2, 4a, 4l–4n). Notably,
tetrasubstituted thiophenes (4o) can be prepared. The
completely selective C3-arylation of unsubstituted thiophene
is particularly noteworthy (4p), and when an excess of 2a was
used, only the 3,4-diarylated product was observed (4q).
Substrates with aryl and halide substituents (no proto-
dehalogenation observed) in the C2- or C3-position gave
the desired products. Strongly electron-donating or electron-
withdrawing groups (OMe, C(O)NMe2, CO2H) were toler-
ated only in the C3-position. A catalyst loading of 10 mol%
Pd/C and a reaction temperature of 808C were employed with
non-alkyl C3-substituted thiophenes to maintain a reaction
time of 22 h. Significantly, for the first time, unprotected
alcohols, amides, and carboxylic acids (esterified in situ), were
The screen indicated that heterocycles including pyrroles,
indoles, furans, and benzofurans are reactive under the
standard conditions. As the screen determines the yield of
1810
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Angew. Chem. Int. Ed. 2014, 53, 1809 –1813