Angewandte
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Chemie
(Scheme 4). Importantly, 1a–1n were all prepared from the
corresponding amines in one step and used without further
purification, thus representing a significant advantage from
a practical standpoint. As becomes evident from the results
3
compiled in Scheme 4, our synergistic C(sp )ÀN cleavage/CO
2
insertion reaction was largely insensitive to electronic
changes on the aromatic ring and could perfectly accommo-
Scheme 3. Screening of reaction conditions. Reaction conditions: 1a
(
(
0.20 mmol), NiBr ·diglyme (10 mol%), ligand (26 mol%), Mn
2
0.40 mmol), CO (1 atm) in DMF (0.40m) at 908C for 72 h. [a] Yields
2
determined by HPLC using anisole as internal standard. [b] Yield of
isolated product. [c] L4 (10 mol%).
Scheme 4. Carboxylation of primary ammonium salts. Reaction condi-
tions: as for Scheme 3, entry 1; yields of isolated products are given as
an average of at least two independent runs. [a] 1a (1.0 mmol),
employed for other benzyl electrophiles (Scheme 1, path
[
5e,f]
3
b),
indicating that the activation of C(sp )ÀN bonds would
be more problematic than anticipated. After a judicious
2
NiBr ·diglyme (5 mol%). Bn=benzyl; TBDPS=tert-butyldiphenylsilyl.
[15]
screening of all reaction parameters, NiBr ·diglyme and L4
2
(
Scheme 3), a bench-stable ligand preparable in one step and
[15]
on a multigram scale,
reducing agent in DMF to afford 2a in 81% yield (entry 1).
were combined with Mn as the
[16]
[21]
date non-extended p systems.
Similarly, the inclusion of
Importantly, no traces of homodimerization products were
detected in the crude reaction mixtures, in direct contrast to
ortho substituents posed no problems (2i–2k). The reaction
showed an excellent chemoselectivity profile, with ammoni-
um salts containing various functional groups, such as esters
(1h), fluorides (1c), silyl ethers (1g), or acetals (1m), being
easily accommodated. Although one might argue that the
inclusion of thioethers might be problematic due to the strong
[5e,f]
related carboxylation techniques (Scheme 1, path b).
II
While other Ni sources provided lower yields (entries 2
and 4), we found that Ni(COD) (COD = 1,5-cyclooctadiene)
2
was not a suitable precatalyst, suggesting that COD might
[17]
[22]
compete with substrate binding (entry 3).
As shown in
binding affinity of sulfur atoms to Ni centers, we found that
entries 5 and 6, the use of the structurally related solvent
dimethylacetamide (DMA), Zn as reducing agent, or the
such motifs did not interfere with the formation of 2j.
Likewise, the presence of heteroaryl rings could be tolerated
with equal ease (2n). This operationally simple procedure was
also found to be scalable, and catalyst loadings could be
decreased to 5 mol% without significant erosion in yield (2a;
70% yield).
Prompted by the inherent limitations posed by the
available catalytic reductive carboxylation techniques for
the synthesis of a-substituted phenylacetic acids (Scheme 1),
we wondered whether our procedure could be extended to
secondary benzyl ammonium salts possessing b-hydrogen
atoms (Scheme 5). Although parasitic homodimerization or
b-hydride elimination pathways could be anticipated, an issue
previously observed in a myriad of cross-electrophile reac-
[18]
inclusion of MgCl as an additive had a deleterious effect.
2
As anticipated, subtle differences in the ligand backbone
exerted a profound influence on the reaction outcome.
Specifically, we found an increased reactivity of 1,10-phenan-
throlines over bipyridines or terpyridines, presumably due to
their significant backbone rigidity compared to nonfused
analogues. Although speculative, we believe that the greater
activity of L4 over the L1–L6 series is attributed to an
intimate interplay of electronic and steric effects of the
substituents on the 1,10-phenanthroline backbone, thus
increasing the robustness, reactivity, and stability of the
0
[19]
propagating Ni L species.
As expected, control experi-
n
ments revealed that all reaction parameters were critical for
success (entry 15).
tions of benzyl derivatives, this was not the case, and we found
[
15,20]
[23,24]
that a NiCl /L6 regime afforded 4a in 93% yield.
As for
2
With these conditions in hand, we focused our attention
on the preparative scope of our Ni-catalyzed direct carbox-
ylation reaction of primary benzyl ammonium salts with CO2
Scheme 4, we found that catalyst loadings could be decreased
to 5 mol% without deterioration in yield at a large scale.
Importantly, a number of substrates possessing b-hydrogen
5
054
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Angew. Chem. Int. Ed. 2016, 55, 5053 –5057