.
Angewandte
Communications
an intermolecular domino reaction of an aryl iodide. These
positions react selectively in a sequence of carbopalladations
À
and cross C H activations, furnishing complex fused biaryls
(Scheme 1c). Our interest in this particular area was driven
by recent studies on the Pd0-catalyzed carboiodination
reaction.[13] We initially set out to capture intermediate E
with an alkyl iodide,[14] however, we observed the formation
of the dimerization product 6a (see Scheme 4) in modest
yields. Intrigued by the complexity of this product we set out
to investigate the transformation in detail.
Upon optimization,[15] synthetically useful levels of dimer
6a could be obtained. However, a by-product (7a) remained
an issue and indicated the presence of an additional and
competing reaction pathway.[16] Interestingly, the extent of by-
product formation depended on the nature of the base, the Pd
source, and the ligand.[15] By using Buchwaldꢀs palladacycle
precatalyst Pd-1 (Scheme 3) and Cs2CO3 in DMF, the highest
selectivity for 6a:7a was 7:1, and 6a was isolated in 68%
yield. With the optimized reaction conditions in hand, we
began to explore the scope of the transformation.
Scheme 4. Substrate scope of the dimerization of 3.[a] [a] When R1, R2,
or R3 were H, they were omitted for clarity in the table. Yields are
reported with respect to 0.30 mmol of 3. Conditions: 0.60 mmol
scale.[17] Pd-1 or Pd-2 (1.5 mol%), 3 (1.0 equiv), Cs2CO3 (2.5 equiv),
DMF (0.4m), 1008C, 18–22 h. [b] Yields of isolated products. [c] Ratio
1
determined by H NMR analysis of the crude reaction mixture.
[d] 2.45 mmol scale (0.60 mmol scale resulted in 67% yield of 6b).
[e] Isolation of clean 7b failed because of coeluting impurities [f] Com-
bined yield of 6g and 7g.
synthetically useful yields (9i, 9k). Aryl iodides substituted
with sterically different groups on the meta position gave
divergent selectivity. More sterically demanding electron-
À
withdrawing groups, such as CF3 (9l), favored the C H
activation in the para position (HA, Scheme 5), whereas
Scheme 3. Privileged Pd precatalysts.
À
a meta-fluoro substituent allowed the final C C formation at
À
When the aromatic ring contained either an electron-
donating or an electron-withdrawing group, a marginal
impact on the yield was observed and yields higher than
50% were typically obtained (entries b–d, Scheme 4). The
effect of varying the alkyl chain was also investigated. Both
ethyl and butyl groups were tolerated, giving the correspond-
ing products 6e and 6 f in 59% and 61% yield, respectively;
however, the application of Pd-2 was necessary to achieve
good selectivities in these cases (Scheme 4). The selectivity of
the reaction (6 vs. 7) ranged between 5:1 and 7:1, and by-
products 7a–f were generally obtained in 8–9% yield
(Scheme 4).
We next studied a heteroaryl cross-coupling (Scheme 5).
We successfully obtained the desired product 9, accompanied
by smaller amounts of the dimerization product 6a. The
highest yields were obtained using Cs2CO3 in DMF, however,
efficient suppression of 6a was only observed when palladium
precatalyst Pd-3 was used.[15] An increase in the reaction rate
was observed when a catalytic amount of CsOPiv was added,
even with a catalyst loading of 3 mol%.[18]
Under the optimized reaction conditions, para-substituted
aryl iodides formed the desired products in up to 71% yield.
In general, electron-donating substituents on the aryl iodide,
such as alkoxy groups, protected amines, or acetals, resulted in
higher yields compared to their electron-deficient counter-
parts (Scheme 5). In the case of the electron-withdrawing
CF3-containing substrate, it was necessary to increase the
catalyst loading to 6 mol%. Bis-meta-substituted aryl iodides
were also tolerated and the products were afforded in
the C HB position with a regioselectivity of 8:1 (9n).
Although, substituents at the ortho position generally gave
poor results,[20] a fluoro group at the ortho position was
tolerated and the corresponding product 9p and by-product
9n were afforded in 56% and 6% yield, respectively.
Variations on the aromatic ring of the methallyl ether
were also studied (Scheme 5). The reaction of methyl- and
dioxolane-substituted methallyl ethers with para-methoxy
iodobenzene furnished products 10a and 10c in yields of 58%
and 56% yield, respectively. Additionally, a fused bipyridyl
structure was accessible by the reaction of electron-deficient
pyridyl-substituted methallyl ether 3g with the 4-iodopyri-
dine, and 10 f was isolated in 64% yield. However, the
introduction of 3g enhanced both the by-product formation
(up to 10%) and the dimerization process (up to 20%).
Substitution of the vinylic methyl group with longer alkyl
chains did not seem to affect the reaction. Similarly high
yields of 70% and 69% were observed for both the ethyl- and
the butyl-substituted systems (10h and 10i). In order to have
a handle for post-synthesis modification, a silyl ether was
subjected to the reaction conditions and 10k was obtained in
47% yield after 21 hours.
The scalability of the heterodimerization reaction was
demonstrated for the reaction of 6a with 4-methyl iodoben-
zene. When run on a 3.7mmol scale, the desired product 9b
was obtained in 72% yield.
On the basis of these preliminary results, a proposed
mechanism is outlined in Scheme 6, in which two reaction
pathways (A: PdIV versus B: PdII–PdII) are considered in
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!
Sickert, Marcel
