Angewandte
Chemie
1008C, the major product was that resulting from aldol
condensation/dehydration of the starting aldehyde. After
some experimentation, it was found that a catalyst composed
of rac-binap and Pd(OAc)2 in dioxane (0.25m) at 808C
provided the best results, affording the desired a-aryl
aldehyde in excellent yield (Table 1, entry 7). Substitution of
Cs2CO3 with other bases (Table 1, entries 8–10) or dioxane
with other solvents (entries 11–14) resulted in lower yields of
product.[11] The inclusion of molecular sieves in the reaction
mixture had a deleterious effect, affording exclusively prod-
ucts derived from dehydration of the aldol products (Table 1,
entry 15). In contrast, the addition of water (10 mol%)
resulted in the formation of the desired a-aryl aldehyde in
84% yield (Table 1, entry 16).[12] On the basis of these results,
we believe that the key to the success of the reaction was
determining conditions under which the aldol product can
form rapidly, in a reversible manner (further evidence is
provided below in Scheme 3).
Encouraged by these initial findings, we decided to
examine the reaction with the less reactive aryl chlorides,
which are more abundant as well as less expensive than their
corresponding iodides, bromides, or fluorides (Figure 1).
Based on our own experience in cross-coupling reactions, a
bulkier and more electron-rich biaryl ligand was expected to
be crucial by using aryl chlorides as coupling partners. Indeed,
ligands L1–L3 were found to be particularly effective while L8–
L10 provided only trace amounts of the desired cross-coupling
product. The use of bidentate ligands, such as xantphos (L11)
or rac-binap (L12), afforded the desired product only in
moderate yield. The best results were finally obtained by
using L5 [13] at 1008C, with 1.5 equivalents of aldehyde under
otherwise similar reaction conditions for the corresponding
aryl bromides.
With the optimal reaction conditions established for the
Pd-catalyzed a-arylation of aliphatic linear aldehydes, we
turned our attention to the scope of this reaction (Table 2).
With regard to the aryl halide, both electron-rich and
electron-deficient aryl halides were equally efficient. A
variety of functional groups were tolerated in either coupling
partner, including silyl groups (Table 2, entries 1 and 4), esters
(entries 2 and 4), ethers (entries 2, 3, and 6), acetals (entries 1,
5, and 10), alkenes (entry 9), aryl halides (entries 5 and 7), and
heterocyclic moieties (entries 8, 9, and 10). Although b-
substituents on the aldehyde (Table 2, entry 7) or ortho
substituents in the aryl moiety (entries 5 and 6) did not
hinder the reaction, these substrates required a longer
reaction time. While the use of aryl bromides proved to be
general, the coupling of 3-chloro-pyridine (Table 2, entry 9)
or ortho-chlorofluorobenzene (entry 5) was unsuccessful,
leading to decomposition. At present we do not have an
explanation for this result.
An interesting reaction outcome was observed when
changing the solvent to DMF (Table 2, entries 11 and 12).
In the first case, the product presumably arises from an
aldol dimerization–dehydration, followed by a selective g-
arylation.[14] In contrast, the reaction of 2-bromoaniline did
not afford the a-arylation nor the g-arylation product, but
the 3-substituted indole derivative in excellent yield
(Table 2, entry 12).[15,16] In a process closely related to the
Merck indole synthesis,[17] we believe that this reaction
proceeds through the intermediacy of an aldimine, which
tautomerizes to the enamine and undergoes an intra-
molecular arylation and subsequent isomerization to afford
the 3-substituted indole.[18,19] Although not yet investigated
in detail, a-arylations also occurred with lower catalyst
loadings (Table 2, entries 1 and 12).
The formation of all-carbon quaternary centers
remains a great challenge in organic synthesis.[20] To further
extend the scope of our methodology, the a-arylation of a-
branched aldehydes was evaluated (Table 3). While the
reaction conditions were essentially identical to those
described for Figure 1, the use of L2 [21] provided superior
results when using aryl bromides. As with unbranched
aldehydes, the process shows a high degree of functional-
group compatibility, leaving silyl groups (Table 3, entry 1),
esters (entries 2 and 5), alkenes (entries 5 and 6), acetals
(entry 6), aryl tosylates (entry 3), ketones (entry 4), ethers
(entry 7), and heterocycles intact (entry 8).
To lend support for our hypothesis of a reversible aldol
process, we independently prepared the aldol product I (as
a mixture of diastereomers) from the self-condensation of
hexanal (4:1 anti/syn).[22] The reaction of I (0.60 equiv) with
methyl 3-bromobenzoate provided the a-arylated com-
pound in a similar yield and took place at essentially the
same rate as the corresponding reaction with hexanal
Figure 1. Screening the effect of ligandson the a-arylation of hexanal with
aryl halides. For GC yields dodecane was used as internal standard.
X=Br: aldehyde (1.20 equiv) in dioxane (0.25m) at 808C for 3 h; X=Cl:
aldehyde (1.50 equiv) in dioxane (0.125m) at 1008C for 8 h.
Angew. Chem. Int. Ed. 2007, 46, 7236 –7239
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7237
Martin, Ruben
