L39; table S8) were prepared for the exami-
nation of this cascade reaction. We observed that
bidentate ligands bearing electron-withdrawing
substituents such asL33andL39were superior,
providing the butenolide product5ain 68 and
57% yields, respectively. As expected, the use of
five-membered chelating ligands such asL8only
provideda,b-unsaturated acids as products, and
extensive modification of reaction conditions
in an attempt to coax this ligand to enable the
desired reactivity proved futile. This stark
contrast in reactivity between the five- and
six-membered chelating ligands further high-
lights how a simple design element—the
ligand bite angle—could result in distinct
chemical reactivities.
With optimal conditions and effective ligands
in hand, we next examined the substrate scope
of this cascade reaction (Fig. 3). Simple linear
aliphatic carboxylic acids were found to be
compatible with the current conditions, pro-
viding theb-substitutedg-alkylidene buteno-
lide products in up to 70% yield (5ato5s).
Among them, 3-cyclopentylpropionic acid3g
and 3-cyclohexanepropionic acid3hboth
afforded their corresponding butenolides in
lower yields (5gand5h), presumably as a
result of unfavorable steric hindrance at their
b-positions. Carboxylic acid substrates with
an ester moiety gave 66 to 67% yield of the
b-substitutedg-alkylidene butenolide prod-
ucts (5kand5l). Fatty acids were also found
to be compatible with this transformation,
providing theg-alkylidene butenolide prod-
ucts in up to 54% yields, with the remaining
starting materials mostly recovered (5rand
5s). The reaction also proved effective in the
formation of fused butenolides, affording prod-
ucts5tto5yin moderate yields. Notably,
the transformation was found to be compa-
tible with substrates of various ring sizes
(5tand5w), substitutions (5uand5v), and
saturated heterocycles (5xand5y). Various
bromoalkynes (5zand5aa) were briefly eva-
luated as coupling partners; both gave the
correspondingg-alkylidene butenolide prod-
ucts in synthetically useful yields.a-Quaternary
substrate 1-propylcyclohexane-1-carboxylic acid
was also compatible, although it gave a lower
yield (5ab).
Next, branched aliphatic carboxylic acids
containingb-methyl C–H bonds were exam-
ined. These substrates also proved to be re-
active under similar reaction conditions, and
ligandL39was identified as the optimal
ligand for these substrates. With this new set
of reaction conditions, isobutyric acid was
found to provide thea-substitutedg-alkylidene
butenolide product7ain 82% yield. For sub-
strates that possessed bothb-methyl andb-
methylene C–H bonds, preferential butenolide
formation at the methyl C–H bond was ob-
served. For example, with 2-methylbutyric acid
as the substrate,a-substitutedg-alkylidene
butenolide7bwas formed as the major product,
instead of thea,b-disubstitutedg-alkylidene
butenolide7b. Substrates with alkyl (7cand
7d), aryl (7eto7i), heteroatoms (7hto7j),
and saturated heterocycle (7j)sidechainswere
foundtobecompatiblewiththereaction
conditions, and provided their corresponding
g-alkylidene butenolides in moderate to high
yields. This cascade reaction ensured exclusive
monoselectivity in the presence of multiple
b-C−H bonds.
Because butenolide natural products are
often bioactive, our method for the con-
struction ofg-alkylidene butenolides from
aliphatic carboxylic acids presented herein
could potentially allow for late-stage intro-
duction of butenolide moieties into complex
natural products and drug molecules and thus
provide access to hitherto-unknown hybrid
molecules with potential biological activities.
To illustrate the feasibility of this transfor-
mation, the antiasthmatic drug seratrodast
was subjected to the standard reaction con-
ditions and the corresponding butenolide
hybrid5abwas obtained in 42% yield. The
success with two more examples (7land7m)
further demonstrates the compatibility of
this reaction with complex molecules.
Theg-alkylidene butenolide5twas briefly
investigated for further derivatization (Fig. 3).
The desilylation of the triisopropylsilyl (TIPS)
protecting group was carried out by tetrabu-
tylammonium fluoride (TBAF), affording 8 in
67% yield. Butenolide5treadily underwent
iododesilylation to afford vinyl iodide product
9 in 73% yield, which could be further de-
rivatized by cross-coupling reactions. Alkaline
hydrolysis of5tprovided a 1,4-dicarbonyl
compound 10 in 66% yield. Treatment of5t
with hydrazine in methanol at room temper-
ature converted theg-alkylidene butenolide
into pyridazine 11 in 81% yield.
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Pd-catalyzed dehydrogenation reactions that
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eithera,b-unsaturated acids org-alkylidene
butenolides. The design of bidentate pyridine-
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ACKNOWLEDGMENTS
We thank S. Chan for proofreading and S. Chan and D. Strassfeld
for helpful suggestions in preparing the manuscript. Z.W. thanks
P. Wang for help with ligand synthesis. We also thank the X-ray
Crystallography Facility (UCSD) for x-ray crystallography.
Funding:We acknowledge The Scripps Research Institute,
NIH (NIGMS, 2R01GM084019), and Bristol-Myers Squibb for
financial support. We acknowledge the Ghadiri Lab and the
High Performance Computing Facility at Scripps Research
for providing computational resources.Author contributions:
J.-Q.Y. conceived the concept. Z.W. developed the ligands
and the dehydrogenation reaction. L.H. developed the butenolide
formation reaction. N.C. carried out computational modeling
and analysis. J.X.Q. participated in substrate scope survey
and discussions and also provided substrates for late-stage
functionalization. J.-Q.Y. directed the project.Competing interests:
J.-Q.Y., Z.W., and L.H. are inventors on a patent application
related to this work (US Patent Application 63/203,241) filed by
The Scripps Research Institute. The authors declare no other
competing interests.Data and materials availability:Metrical
parameters for the structures of ligand/Pd complexes (see
supplementary materials) are available free of charge from the
Cambridge Crystallographic Data Centre under reference
numbers CCDC-2062539 and CCDC-2062540. All other data
are in the supplementary materials.SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abl3939
Materials and Methods
Figs. S1 to S3
Tables S1 to S13
References ( 32 – 56 )
X-ray Crystallographic Data
Computational Data and Analysis
NMR Spectra10 July 2021; accepted 1 September 2021
Published online 11 November 2021
10.1126/science.abl3939SCIENCEscience.org 3 DECEMBER 2021•VOL 374 ISSUE 6572 1285
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