Organic Letters
Letter
a
Scheme 2. Scope of the Branched-Selective Alkylation by SPO-Nickel Catalysis
a
Branched/linear selectivities in parentheses.
a
Scheme 3. C−O Alkylation by SPO-Nickel Catalysis
commonly obtained Ziegler alkylation at the more acidic α-
position to the heteroatom.18 Finally, also an electron-rich N-
protected aniline derivative was converted successfully yielding
4na in good yield and selectivity.
Based on the outstanding selectivity within the linear
alkylation, we became interested in the considerably more
challenging alkylation with secondary alkylmagnesium halides.
We initiated our studies here again with 1a as the model
substrate and sec-butylmagnesium chloride (2f) as the
alkylation reagent (Table 2 and Table S4 in the Supporting
Information). Communally used nickel precursors with
established phosphine ligand failed to facilitate the envisioned
transformation (entries 1−2). In contrast, the well-defined
catalyst 3a proved to be suitable, yielding desired product 4af
in moderate yield and selectivity (entry 3). Further
optimization showed that biomass-derived 2-MeTHF is also
suitable for this transformation (entry 4).19 A slightly increased
temperature is needed for a higher conversion and better
selectivity (entry 6). The high reactivity of catalyst 3a toward
unactivated C−F bonds was further reflected by a high TOF,
yielding 4af in 77% yield after only 0.5 h (entry 7).
Under the optimized reaction conditions, various acyclic
secondary Grignard reagents, such as s-BuMgCl (4af), (4-
phenylbutan-2-yl)magnesium bromide (4ag), and i-PrMgCl
(4bk), were successfully converted by the SPO-nickel catalyst
3a (Scheme 2). All secondary alkylating reagents delivered the
coupling product with excellent selectivities and good yields.
Furthermore, cyclic secondary Grignard reagents, such as a
bulky bicycle- (4ah), cyclpropyl- (4ai), and cyclopentyl (4aj−
4bj) -magnesium halide, were also suitable coupling partners
with excellent yields and high levels of selectivity without
observable ring opening.20 The use of para-substituted arenes
did not influence the reaction (4cf−4ef), and indeed C−O
bonds stay intact during the course of the reaction (4ff). In
a
Linear/branched selectivities in parentheses.
form a nickel/magnesium bimetallic catalytic species that
carries out push−pull cooperative activation of the aryl
fluoride.5i,m,16 Lowering the reaction temperature and
changing the solvent to THF improves the yield and
suppresses the formation of 5 (entry 8). Subsequently, we
explored the catalyst’s versatility, with respect to the viable
structures of fluoroarenes 1 and alkyl nucleophiles 2. Notably,
a wide range of fluoroarenes 1 and alkylmagnesium bromides 2
were converted in an efficient manner to provide the
corresponding products 4 in excellent yield (Scheme 1). The
C(sp2)−C(sp3) bond formation of arylfluoride 1a was
successful performed with different alkylmagnesium reagents,
delivering the corresponding products 4aa−4ba in up to 82%
yield. The tether had no major influence (2b−2d). In addition,
also the branched reagent 2e delivered 4be selectively without
isomerization. The variation with respect to fluoroarene 1 was
not limited to naphthalene derivatives. Indeed, also structural
motifs such as phenyl (4ca), biphenyl (4ea), and pyrene (4ga)
were efficiently transferred. To our delight, the C−O bond
successfully survived under the reaction conditions (4fa),
without interference, indicating notable innate chemoselectiv-
ity. Finally N-protected indoles (4ha, 4he, and 4ja) show high
catalytic performance yielding otherwise difficult to synthesize
motifs that were studied in C−H transformations.17 In
addition, pyridines (1k−m) are tolerated by the SPO-nickel
regime, showing no deactivation of catalyst 3a by potentially
coordination, generating (4ka−4ma) in good yield without
C
Org. Lett. XXXX, XXX, XXX−XXX