ACS Catalysis
Letter
(3e−g), as did heteroaryl chloride electrophiles based on
quinaldine, quinoline, and benzothiophene core structures
(3h−l). Conversely, no conversion was achieved in reactions
that employed 2-chloroanisole, 2-chlorobenzotrifluoride, or 6-
chloroindole. Control experiments confirmed that the
uncatalyzed background reactivity (e.g., SNAr) contributes
negligibly to the observed yields herein, except for the
formation of 3i where a 30% conversion to product was
observed in the absence of C4.
by any base-metal catalyst system. Competition experiments
highlight important selectivity differences between Ni catalysts
supported by this new ligand and other DalPhos ligands (e.g.,
PhPAd-DalPhos), thereby suggesting that CgPhen-DalPhos
may offer unique catalytic performance in other sought-after
cross-couplings. Future work will involve exploring the
mechanism of these and related Ni-catalyzed transformations
to gain insights into the role of the ligand structure in enabling
transformations of the type presented herein.
The feasibility of employing tert-butanol and tert-amyl
alcohol, as well as the bulky secondary substrate 2-
adamantanol, in Ni-catalyzed C−O cross-couplings with
(hetero)aryl electrophiles (Cl, Br, OMs, and OPiv) using C4
was also demonstrated, leading to 4a−i (Figure 4B). In this
chemistry, quinoline and quinoxaline heteroaryl electrophiles,
as well as aryl chlorides featuring alkenyl, nitrile, and methoxy
substitutions, proved to be effective reaction partners.
Although not the primary focus of the present study, C4 can
also be employed successfully in conceptually related C−N
cross-couplings involving bulky alkylamines (including 1-
adamantylamine, t-butylamine, and cumylamine) in combina-
tion with (hetero)aryl chlorides (90−110 °C, leading to 5a−f;
Scheme S1).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
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sı
Synthetic protocols and product characterization data,
including NMR spectra (PDF)
X-ray crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
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Mark Stradiotto − Department of Chemistry, Dalhousie
University, Halifax, Nova Scotia B3H 4R2, Canada;
Competition experiments were conducted to establish the
preferred reactivity of C4 (Figure 5) in terms of C−O versus
C−N cross-couplings of comparably sized nucleophiles as well
as C−O cross-couplings of aliphatic alcohols that differ in size.
While C4 proved to be capable of effecting both C−N and C−
O cross-coupling involving sterically demanding aliphatic
nucleophiles (vide supra), a clear preference for cumylamine
to give 5f over tert-butanol to give 4a (20:1) was observed in
competitions involving 6-chloroquinoline (Figure 5A). This is
in keeping with the common trend of C−N cross-coupling
being favored over analogous C−O cross-couplings, as is
reflected in the preference of C1 for the cross-coupling of
octylamine over a structurally related primary aliphatic
alcohol.8a Conversely, when the contending nucleophiles 1-
adamantanol and tert-butylamine were explored in cross-
couplings of 7-chlorquinaldine that led to 3h and 5a,
respectively, C4 exhibited a preference for C−O cross-coupling
(2.5:1), while C2 displayed a clear selectivity for C−N cross-
coupling (Figure 5B). These observations underscore that C4
is well-matched to the C−O cross-coupling of tertiary aliphatic
alcohols relative to C1 or C2, especially when the 1-
adamantanol nucleophile is involved. In a competition between
tert-butanol and 2-adamantanol when C4 and 6-chloroquino-
line were employed, which led to 4a and 4g, respectively, a
clear selectivity for the secondary alcohol was observed (Figure
5C). Similarly, methanol outpaced 1-adamantanol as a
nucleophile in the formation of 6a over 3l (Figure 5D).
These latter two observations establish that while C4 can
promote the C−O cross-coupling of tertiary aliphatic alcohols
as demonstrated in this report, primary and secondary aliphatic
alcohols are preferred substrates. On this basis, we anticipated
that it should be possible to selectively O-arylate the primary
aliphatic position in 3-(hydroxymethyl)-1-adamantanol; this
indeed proved to be the case when 3-X-anisole electrophiles
were used (X = Cl or Br), leading to the formation of 6b
(Figure 5E).
Authors
Kathleen M. Morrison − Department of Chemistry, Dalhousie
University, Halifax, Nova Scotia B3H 4R2, Canada
Ryan T. McGuire − Department of Chemistry, Dalhousie
University, Halifax, Nova Scotia B3H 4R2, Canada
Michael J. Ferguson − X-Ray Crystallography Laboratory,
Department of Chemistry, University of Alberta, Edmonton,
Complete contact information is available at:
Notes
The authors declare the following competing financial
interest(s): Dalhousie University has filed patents on the
DalPhos ancillary ligands and derived nickel pre-catalysts used
in this work, from which royalty payments may be derived.
ACKNOWLEDGMENTS
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We are grateful to the NSERC of Canada (Discovery Grant for
M.S. RGPIN-2019-04288, PGS-D for K.M.M., and CGS-D for
R.T.M.), the Killam Trusts, and Dalhousie University for their
support of this work. Solvay is thanked for the donation of
phosphatrioxaadamantane. We also thank Dr. Michael
Lumsden and Mr. Xiao Feng (Dalhousie) for technical
assistance in the acquisition of NMR and MS data.
REFERENCES
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In summary, a Ni precatalyst featuring the new ligand
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aliphatic alcohols and (hetero)aryl electrophiles, with a
substrate scope that has not previously been demonstrated
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