.
Angewandte
Communications
Table 2: Scope of palladium-catalyzed alkyl-Heck-type cross-couplings
use of inorganic bases instead of Cy2NMe (Table 1, entries 1
and 3), with K3PO4 most effective. We determined that the
use of solvents that lack abstractable hydrogen atoms limited
the production of by-product 2, and PhCF3 was found to be
a suitable choice. Lowering the reaction temperature to 808C
resulted in a marked decrease in reaction efficiency (Table 1,
entry 4). A slight excess of acrylonitrile was preferable in this
cross-coupling (1.5 equiv), however, reactions using a slight
excess of alkyl iodide proceeded in lower yield (Table 1,
entry 5). Other palladium-based catalytic systems, including
[Pd(PPh3)4], which we used in our previous studies, were
inferior to [PdCl2(dppf)] (Table 1, entry 6–8). The combina-
tion of Pd(OAc)2 (10 mol%) and dppf (20 mol%) was
a suitable substitute for [PdCl2(dppf)] (10 mol%; Table 1,
entry 9). No product was formed in the absence of [PdCl2-
(dppf)] (Table 1, entry 10), and the reaction proceeded in the
dark (entry 11). The success of this cross-coupling is partic-
ularly intriguing with regard to the potential for an undesired
polymerization of acrylonitrile.[8]
with respect to the alkene.[a]
Upon the identification of a viable reaction system, we
first surveyed the cross-coupling of a variety of alkenes. As
with acrylonitrile cross-coupling (Table 1), the use of [PdCl2-
(dppf)] was crucial to obtain a high yield. An electronically
diverse set of styrenes, including those with base- and
nucleophile-sensitive functionality, are viable coupling part-
ners (Table 2, entries 1–9). In styrenyl cross-couplings,
Cy2NMe was used as base, because reductive by-products
were not problematic. 2-Vinyl pyridine participates in the
cross-coupling, albeit in modest yield (Table 2, entry 10).
Electron-poor alkenes, such as methyl vinyl ketone (Table 2,
entry 11) and acrylonitrile (entries 12 and 13), afforded the
products in moderate to good yields. In the case of the highly
polymerizable methyl vinyl ketone, substitution of [PdCl2-
(dppf)] for [{Pd(allyl)Cl}2] (5 mol%) and PPh2tBu (40 mol%)
was required. We studied the reaction of trans-2-(tert-
butyldimethylsilyloxy)-1-iodocyclohexane in order to probe
the diastereoselectivity of the reaction with simple cyclic
substrates (Table 2, entry 13). The cross-coupling of this
substrate with acrylonitrile delivered the product with
a 50:50 ratio of cis- and trans-substituted cyclic diastereomers.
Alkenes containing substituents in the b position also react
efficiently (Table 2, entries 14–16) with either cyclohexylio-
dide or the heterocyclic 4-iodo-1-tosylpiperidine as coupling
partners. In analogy to the standard Heck reaction using aryl
electrophiles, the cross-couplings of b-substituted alkenes
gave mixtures of geometric isomers as products, with the
predominate isomer containing the incoming alkyl electro-
phile and the electron-withdrawing group in trans position to
each other.[9] In the cross-couplings of b-disubstituted alkenes,
we determined that [Pd(PPh3)4] was superior to [PdCl2(dppf)]
as catalyst.
[a] Reactions run using 1.0 equiv alkyl iodide and 1.5 equiv alkene 0.5m
in PhCF3 at 1008C in the presence of 10 mol% [PdCl2(dppf)] and
2.0 equiv Cy2NMe for 14 h. [b] Yields of isolated product. [c] Product
ratios were determined by 1H NMR spectroscopy of crude reaction
mixtures. [d] Yield calculated by 1H NMR spectroscopy of the crude
reaction mixture using an internal standard. [e] 2.0 equiv K3PO4 used as
base. [f] 5 mol% [{Pd(allyl)Cl}2] and 40 mol% PPh2tBu used as catalyst,
5 h. [g] 10 mol% [Pd(PPh3)4] used as catalyst. [h] 2.0 equiv alkyl iodide
and 1.0 equiv enone. [i] 3.0 equiv crotononitrile. TBS=tert-butyldime-
thylsilyl, Ts=toluene-p-sulfonyl.
the reactions of 1-iodooctane and 2-iodononane (Table 3,
entries 4 and 5). Sterically congested 6-iodo-1,4-dioxaspiro-
[4.5]decane was an excellent substrate, and coupled with
styrene in 79% yield (Table 3, entry 6). The reactions of alkyl
iodide substrates containing nucleofuges in the a position are
À
We next examined the scope of the reaction with a variety
of alkyl iodides using styrene as the coupling partner
(Table 3). Cyclopentyl and cycloheptyliodide reacted with
similar efficiency to cyclohexyl iodide (Table 3, entries 1 and
2).[10] The cross-coupling of exo-2-norbornyl iodide provided
the styrylation product with high diastereoselectivity (> 95:5
d.r.; Table 3, entry 3). The cross-coupling is also applicable to
acyclic primary and secondary iodides, as demonstrated by
also useful intermolecular C C bond-forming transforma-
tions, as demonstrated by the reactions of an iodo-g-lactone
and enantiopure TBS-protected (S)-1-iodododecan-2-ol
(Table 3, entries 7 and 8). With regard to the array of useful
methods for the asymmetric synthesis of such substrates,[11] we
view this as a particularly attractive approach to the
enantioselective preparation of highly functionalized small
molecules.
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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