Organic Letters
Letter
a
major isomer (ratio of 9:1). Fortunately, changing the catalyst
to Pd(dba)2/dppp led to further improvement of the yield and
complete E selectivity of the desired product 4aa (Table 1,
entry 5, dba = dibenzylideneacetone, dppp = 1,3-bis(diphenyl-
phosphanyl)propane). Again adding 10 mol % of CuI afforded
the coupling product in 59% yield (Table 1, entry 6). The use
of dppe (1,2-bis(diphenylphosphanyl)ethane) or dppf (1,1′-
bis(diphenylphosphino)ferrocene) slightly decreased the yield
(Table 1, entries 7, 8, and 11). The best result was obtained by
performing the reaction with potassium fluoride instead of
cesium fluoride in the presence of 18-crown-6 (18C6) affording
4aa in 73% yield (Table 1, entry 9). In the absence of the
palladium complex the hydroalkynylation product was detected
as the sole product (Table 1, entry 13).
Scheme 2. Scope with Respect to Alkyne
With the optimized reaction conditions in hand we started to
examine the reaction scope (Scheme 2). In total, we subjected
14 different alkyne derivatives to the reaction conditions.
Various electron-donating and electron-withdrawing aryl
acetylenes were exposed to the reaction. The electron-donating
methoxy group attached to the aryl moiety improved the yield
to 79% (4ab). Methyl substituents in meta- and para-positions
to the alkyne provided 4ac and 4ad in 66% and 62% yields,
respectively. Also electron-withdrawing alkynes such as 1-
ethynyl-4-nitrobenzene and 4-ethynylbenzonitrile afforded 4ae
and 4af in 60% and 57% yields. The coupling with 3-ethynyl
thiophene, a heterocyclic alkyne, proceeded smoothly in 76%
yield (4ag). Besides aryl acetylenes, we also employed weakly
electron-donating aliphatic groups. 1-Hexyne and the sterically
encumbered 3,3-dimethylbut-1-yne reacted to afford 4ah and
4ai in 64% and 65% yield, respectively.
It is literature-known that primary and secondary alcohols
react with arynes to produce aryl ethers.12 Nevertheless, in our
case the use of 4-pentyn-1-ol showed only coupling at the
terminal alkyne to form a new C−C bond. The corresponding
primary alcohol 4aj was obtained in 69% yield. Also nitrile and
phthalimide derivatives delivered the corresponding products in
yields of 76% (4ak) and 62% (4am). Even diyne units were
tolerated; phenyldiacetylene afforded the desired product 4an
in 61% yield. The installation of an electron-withdrawing group
such as an ester directly attached to the alkyne moiety strongly
reduces the nucleophilicity of the acetylide. As a result, the C−
C coupling was completely prevented and 4al was not obtained.
Afterward, we extended the scope of the three-component
reaction with respect to the aryne (Table 2).
Gratefully, a broad spectrum of arynes including electron-
rich, electron-deficient and arynes with extended π-systems
could be transformed. The indane aryne precursor 1b and the
3,4-dimethoxy derivative 1c accomplished 4ba and 4ca in 76%
and 70% yields, respectively. Naphthalene precursor 1d led to
the corresponding coupling product 4da in 58% yield (Table 2,
entry 3). Unfortunately, when using the aryne precursor 1e
bearing two fluorine substituents the desired coupling product
4ea was obtained in only 11% yield (Table 2, entry 4) although
1e was entirely consumed. In addition, when unsymmetrical
aryne precursors were employed regioisomeric mixtures
resulted in 50% up to 78% yields (Table 2, entries 5−8).
Noteworthy, in the case of 1f the chlorine substituent has a
strong electronic influence on the aryne system leading to a
regioisomeric ratio of 5:1. In contrast, we did not observe any
regioselective preference in the formation of 4ha with a methyl
group at the same position.13
a
Conditions: 1a (204 μmol), 2 (136 μmol), 3 (177 μmol), Pd(dba)2
(13.6 μmol), dppp (13.6 μmol), KF (408 μmol), 18C6 (408 μmol),
MeCN (4 mL) at 50 °C for 16 h; all yields represent isolated coupling
products.
coupling (Scheme 3). Initially, copper acetylide 2a′ is generated
by deprotonation of the terminal alkyne 2a using CsF and CuI.
Acetylide 2a′, acting as a nucleophile, couples to the in situ
generated benzyne 1a′ affording the highly nucleophilic copper
intermediate 5. Simultaneously, vinyl cyclopropane 3 is
activated by the Pd(0) catalyst to form π-allyl palladium
complex 3′. This complex is intercepted by the nucleophilic
intermediate 5 at the least hindered carbon of 3′ to form
complex 4aa′. The regeneration of the active palladium catalyst
closes the catalytic cycle and affords the desired coupling
product 4aa.
On the basis of these results, we propose a possible
mechanism for the palladium-catalyzed three-component
B
Org. Lett. XXXX, XXX, XXX−XXX
Garve, Lennart K. B.
