Ligand-enabled γ-C-H olefination and carbonylation: Construction of β-quaternary carbon centers

Article abstract of DOI:10.1021/ja501689j

Monoselective γ-C-H olefination and carbonylation of aliphatic acids has been accomplished by using a combination of a quinoline-based ligand and a weakly coordinating amide directing group. The reaction provides a new route for constructing richly functionalized all-carbon quaternary carbon centers at the β-position of aliphatic acids.

Full text of DOI:10.1021/ja501689j

Communication
pubs.acs.org/JACS
Ligand-Enabled γ‑C−H Olefination and Carbonylation: Construction
of β‑Quaternary Carbon Centers
Suhua Li, Gang Chen, Chen-Guo Feng, Wei Gong, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
β-C−H functionalizations of aliphatic acids using directed
ABSTRACT: Monoselective γ-C−H olefination and
carbonylation of aliphatic acids has been accomplished
by using a combination of a quinoline-based ligand and a
weakly coordinating amide directing group. The reaction
provides a new route for constructing richly functionalized
all-carbon quaternary carbon centers at the β-position of
aliphatic acids.
metalation have been extensively investigated and reported over
the past decade.4,5 In contrast, however, corresponding γ-C−H
functionalizations remain largely underdeveloped.6,7 Further-
more, the development of sp3 C−H olefination reactions in
general remains a challenge, with relatively few examples having
been reported in recent years.8 This is not surprising
considering the known difficulties in developing the Heck
reaction using alkyl halides.9 Thus, in order to establish a
versatile platform for constructing β-quaternary carbon centers
via γ-C−H activation, we sought to address these specific
challenges. Encouraged by the recent observation that pyridine-
or quinoline-based ligands can promote the β-C−H arylation of
aliphatic amides,10 we surmised that further optimization of
these ligands could enable an unprecedented γ-C−H
functionalization .
mong the many potential applications of C−H activation
A
reactions in synthesis, functionalizing abundant, yet
underutilized starting materials at strategic positions to
construct common and synthetically enabling synthons has
emerged as an attractive, achievable goal.1 In this context, a
wide range of sp2 C−H activation reactions of benzoic acids,2
phenyl acetic acids and hydrocinnamic acids3 have been
developed. These transformations have greatly enriched the
diversity of structurally limited but readily available bulky
chemicals as building blocks. In parallel, we are also
investigating the possibility of establishing a platform for the
construction of α-quaternary carbon centers from pivalic acid,
the success of which will be critically dependent on the
continued development of diverse racemic and asymmetric β-
C−H functionalizations (eq 1).4 However, to extend this
Our initial studies were guided by reaction parameters that
were found to be optimal for β-sp3 C−H olefinations.8a
Unfortunately, substrate 1a (derived from 3,3-dimethylbutanoic
acid) failed to react with ethyl acrylate under these conditions.
To our dismay, we found that tuning of various reaction
parameters proved largely unsuccessful. We next tested a series
of pyridine- and quinoline-based ligands, including 2-
alkoxylquinoline L1, which was found to be extremely effective
for promoting the β-arylation of sp3 C−H bonds.10 However,
these efforts were also met without success (eq 3).
approach toward the construction of β-quaternary carbon
centersanother major class of versatile synthonsγ-C−H
functionalizations also need to be fully investigated and
developed (eq 2). Specifically, it would be advantageous to
install functional groups at the γ-position that are amenable for
further transformations in order to construct synthetically
useful intermediates. Herein we report our initial progress
toward this goal through the monoselective γ-C−H olefination
and -carbonylation of a variety of β-quaternary amides. We
found that the use of a newly developed quinoline-based ligand
was essential to allow for these unprecedented transformations.
Following these fruitless attempts, we decided to focus on
the development of new ligands, beginning with tricyclic ligand
L2, which contains a dihydropyran ring. We reasoned that by
restraining the conformational freedom of the 2-alkoxy motif,
one of the oxygen lone pairs would be constrained to a plane
parallel to the π-system of the quinoline ring.11 This would in
Received: February 17, 2014
Published: March 26, 2014
© 2014 American Chemical Society
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Communication
turn result in a more electron-rich ligand, potentially affecting
the reactivity of the Pd(II) catalyst. As such, extensive screening
of oxidants and bases was carried out with L2 as our ligand (see
Supporting Information). We were pleased to find that C−H
olefination of amide 1a with ethyl acrylate in the presence of 10
mol % Pd(OAc)2, 20 mol % L2, 2.0 equiv of AgOAc, and 1.1
equiv of K2HPO4 in C6F5CF3 provided the desired lactam 2a
(formed after subsequent intramolecular hetero-Michael
addition) in 45% yield (eq 3). However, further tuning of the
reaction parameters at this stage failed to improve the yield.
To investigate the impact of ligand structure on reaction
efficiency, we revisited the use of pyridine- and quinoline-based
ligands L3−L6 under these newly established conditions. The
consistently poor yields obtained with these ligands suggest that
the pyran structural motif is crucial for the observed reactivity
with L2 (Table 1). We therefore prepared analogues L7−L15
moiety with the Pd(II) center, we focused on the introduction
of noncoordinative electron-donating substituents (L13−L15).
Gratifyingly, we found that the use of ligand L15, bearing a tert-
butyl group at the C-7 position, afforded lactam 2a in 62%
yield. Substitution of the dihydropyran ring with dihydrofuran
decreased the yield (L16, 40%) indicating that the orientation
of the lone pair on the oxygen is vital. Additionally, we also
found that increased ligand loadings (40 mol %) improved the
yield to 71%. Through further screening, it was discovered that
by performing the reaction under an oxygen atmosphere and
introducing 10 mol % co-oxidant TEMPO4d and 2 equiv of
NaHCO3 we could increase the yield of 2a to 95% (see
Supporting Information). We also tested other amide directing
groups derived from different amines including aniline, albeit
leading to a significant decrease in yields (see Supporting
Information).
With these optimized conditions in hand, we proceeded to
survey the scope of the reaction with substrates derived from β-
quaternary center-bearing aliphatic amides (Table 2). Replacing
one or two methyl groups with ethyl substituents decreased the
isolated yields from 87% to 68% and 70%, respectively (2a−c).
Substrates incorporating benzyl and cyclopentyl functional
a
Table 1. Ligand Development
a
Table 2. Scope of Substrates
a
Reaction conditions: 0.1 mmol of substrate, 50 μL of ethyl acrylate,
0.01 mmol of Pd(OAc)2 (10 mol %), 0.02 mmol of Ligand, 0.2 mmol
of AgOAc, 0.11 mmol of K2HPO4, 1 mL of C6F5CF3, 50 mL sealed
tube, 120 °C (oil), 20 h. Yield was determined by the 1H NMR
b
spectroscopy using CH2Br2 as the internal standard. 40 mol % L15,
10 mol % TEMPO, O2 (1 atm), and 0.2 mmol of NaHCO3 were used.
and investigated their use as ligands for this reaction. Taken
together with the results obtained with ligand L2, ligands L7−
L9 suggest that incorporation of electron-donating groups at C-
7 and C-9 of the quinoline ring decreases the effectiveness of
the ligand. In contrast, the yield was improved to 56% when a
methoxy group was positioned at C-8 in L9. Addition of the
electron-withdrawing trifluoromethyl or fluoro group (L10−
L12) had significant detrimental effects on the observed
reactivity. Mindful of the potential coordination of the methoxy
a
Reaction conditions: 0.1 mmol of substrate, 50 μL of ethyl acrylate,
0.01 mmol of Pd(OAc)2 (10 mol %), 0.04 mmol of Ligand, 0.01 mmol
of TEMPO, 0.2 mmol of AgOAc, 0.11 mmol of K2HPO4 and 0.2
mmol of NaHCO3, 1 mL of C6F5CF3, O2 (1 atm), 50 mL sealed tube,
120 °C (oil), 20 h. Isolated yield.
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Communication
groups at the β-position are olefinated to give the desired
lactams in moderate yields (2d, 2e). Both γ- and δ-methoxy
groups as well as γ-esters are tolerated, leading to moderate and
synthetically useful yields (2f−h). Interestingly, cyclic sub-
strates work well and provide the desired spiral lactams in 66−
83% yield (2i−l). To our satisfaction, we found that both
tetrahydropyran and piperidine structural motifs are also
compatible with this olefination protocol (2k, 2l).
Although this method is currently limited to the mono-
functionalization of all-carbon β-quaternary carbon centers, we
envision that sequential C−H functionalizations at the γ-carbon
would provide a novel disconnection for the construction of
richly functionalized all-carbon β-quaternary carbon centers. To
this end, we developed a γ-carbonylation protocol utilizing
ligand L15 (for ligand screening and optimization of
conditions, see Supporting Information). The use of oxidant
tert-butyl peroxide increased the NMR yield from 37% to 67%.
The reaction was also successfully performed in 1 g scale to give
4a in 61% isolated yield (Scheme 3). The monoselectivity was
We also investigated the use of a variety of activated olefins
as coupling partners (Table 3). Olefination of 1a with benzyl
a
Table 3. Scope of Olefins
Scheme 3. Sequential C−H Functionalizations
ensured through intermediate formation of imide 4a, which is
then converted to amide 5a, a suitable substrate for our newly
developed olefination reaction.4d 5a is subsequently subjected
to ethyl acrylate in the presence of Pd(II) and ligand L15 to
yield lactam 2h, which can in turn be opened to provide amide
6a. Omission of the ester forming step in the ring-opening
process ensured formation of the amide such that the four
carbons on the quaternary center would be distinct.
In summary, we have developed the first example of γ-
C(sp3)−H olefination, which provides a novel disconnection
for the preparation of γ-olefinated aliphatic acids. The use of a
newly developed quinoline-based ligand is crucial for realizing
this transformation. This ligand also enables a sequential and
monoselective γ-carbonylation/olefination procedure to afford
highly functionalized all-carbon quaternary centers.
a
Reaction conditions: 0.1 mmol of substrate, 0.4 mmol of alkenes, 15
mol % Pd(OAc)2, 50 mol % Ligand, 0.015 mmol of TEMPO, 0.2
mmol of AgOAc, 0.11 mmol of K2HPO4 and 0.2 mmol of NaHCO3, 1
mL of C6F5CF3, O2 (1 atm), 50 mL sealed tube, 130 °C (oil), 20 h.
b
Isolated yield. 10 mol % Pd(OAc)2 and 40 mol % Ligand used.
acrylate yielded 2aa in 77% yield. α,β-Unsaturated ketones and
nitriles, however, proved less efficient. Thus, the catalyst
loading was increased to 15 mol % Pd(OAc)2 in order to
improve the yields (2ab−d, 64−73% yield).
We also prepared lactam 2a on gram scale in order to
demonstrate the robustness of this newly developed trans-
formation (Scheme 1). Furthermore, to render this reaction
Scheme 1. Gram-Scale Synthesis
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
Notes
even more synthetically useful, we developed a one-pot
deprotonation/ring-opening procedure to convert 2a into γ-
olefinated ester 3a, which can be used as a synthon for a variety
of further elaborations (Scheme 2).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge The Scripps Research Institute and
the NIH (NIGMS, 2R01GM084019) for financial support.
■
Scheme 2. Deprotection
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