Angewandte
Chemie
cupration of the diene with the copper hydride species
generated by b-hydrogen elimination of alkyl copper inter-
mediates.[12,13] A labeling experiment using CD3CD2MgBr
indicated that the KIE of this reaction is 1.6.[14,15]
To shed light on the active species of the hydrocupration,
we conducted stoichiometric reaction with the copper hydride
complex 6 [Eq. (3)].[16,17] Although no hydrocupration of 6
A plausible reaction pathway for this catalytic hydro-
alkylation is shown in Scheme 2. Catalytically active copper
hydride ate complexes (10), probably generated by b-hydro-
with the neutral conjugated dienes proceeded at room
temperature, the addition of 1 equivalent of a Grignard
reagent did accelerate the reaction, dramatically, to give
reduced olefins in 70% overall yield after aqueous work up.
These results may suggest that the active species of hydro-
[18]
À
cupration are ate complexes having a Cu H moiety.
When the alkyl fluoride 1u was used, the corresponding
product 2u was obtained in 72% yield and any cyclized
products, that can be formed by radical cyclization, were not
observed [Eq. (4)].[19] This result may rule out a possibility of
alkyl radical intermediates which might be possibly generated
in situ from alkyl fluorides.
Scheme 2. Plausible reaction pathways.
gen elimination of the diethyl cuprate 9, add to 1,3-butadiene
to form the allyl cuprates 11 and/or 12,[20] although the
detailed structure of the copper species generated by pre-
treatment is not clear yet. Then the resulting allyl cuprates, or
the corresponding allylic Grignard reagent 13 derived from
the allyl cuprates,[21] react with alkyl fluorides in an SN2-type
mechanism[7] at the g-carbon atom of the allyl cuprates or
allylic Grignard reagents, selectively,[22] to give the 1,2-
addition product and regenerate the ethyl copper complex 8.
We then performed kinetic studies using isoprene (4a),
nOct-F (1b), EtMgCl, and CuCl2,[10] and found that the
reaction obeyed zero-order kinetics with respect to 1b and 4a,
As we reported previously, copper catalyzes the cross-
coupling of alkyl fluorides with alkyl Grignard reagents in the
presence of 1,3-butadiene at 258C.[7a] This outcome is differ-
ent to that of the current results, that is, cross-coupling versus
reductive alkylation, and arises from pre-treatment of
a copper salt with a Grignard reagent in the presence of 1,3-
dienes (Table 1, entries 1–3). When EtMgCl was added to
CuCl2 in THF including 1,3-butadiene, a yellow solution,
which is effective for cross-coupling reaction, is formed
quickly. This solution gradually turns to a dark-reddish brown
suspension on stirring at 508C and reductive alkylation begins
to proceed. This observation implies the generation of a new
active copper species. We then examined the reaction of
nOctBr, which is more reactive than alkyl fluorides, in these
solutions to probe the activities of the coppper species. When
we mixed CuCl2 (5 mol%), EtMgCl in THF, 1,3-butadiene,
and nOctBr in this order at À788C and the obtained yellow
solution was stirred at 508C, nOctBr coupled with EtMgCl in
82% yield as reported previously.[7a] In contrast, when nOctBr
was added to a THF solution after 10 minutes of stirring at
508C, no coupling product was obtained, thus indicating that
an active catalytic species for cross-coupling transmuted
completely to the other species [Eq. (5)].[10]
À
thus indicating that C F bond cleavage is relatively fast in the
current reaction despite the large bond dissociation energy of
[8]
À
C F bonds. In contrast, the reaction obeyed first-order
kinetics with respect to CuCl2 and EtMgCl. These kinetic
studies and the observed KIE may suggest the rate-limiting
step to be diethyl cuprate formation from ethyl copper and
EtMgCl or the subsequent b-H elimination.
In conclusion, we have developed the hydroalkylation of
1,3-butadiene using unactivated alkyl fluorides as electro-
philes. The present reaction provides a new method for the
À
synthesis of alkylated terminal alkenes through C C bond
formation between an internal carbon atom of 1,3-diene and
an sp3-carbon fragment. The current copper catalysis has
several features, including hydrocupration of neutral conju-
gated diene, selective hydroalkylation of 1,3-dienes over
À
alkenes and alkynes, catalytic cleavage of C F bond, and
À
selective C C bond formation at the relatively congested
internal carbon center of dienes. Alkyl fluorides are inert
À
toward various reagents because of the strong C F bonds.
This feature will allow us to create a new synthetic route by
Angew. Chem. Int. Ed. 2015, 54, 9347 –9350
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim