the dehydrogenation reaction, and the coupling
partners employed must not interfere with the
preceding dehydrogenation step, we began an
extensive investigation into potential coupling
partners that could be compatible with the
dehydrogenation reaction. We discovered that,
if well-documented bromoalkynes were used as
coupling partners to form complexg-alkylidene
butenolides ( 27 ), a cascade reaction was
possible. The development of synthetic meth-
ods for the construction of such scaffolds has
been ongoing for decades as a result of the
ubiquity of butenolides in natural products and
bioactive molecules ( 28 – 31 ). However, existing
methods invariably require multiple synthetic
steps stemming from conventional retro-synthetic approaches. The method presented
herein, based on an unconventional C−H
dehydrogenation-alkynylation-cyclization cas-
cade with aliphatic carboxylic acids, offers a
retrosynthetic disconnection for one-step con-
struction ofg-alkylidene butenolides.
A series of bidentate, six-membered chelat-
ing pyridine-pyridone ligands (L5andL20to1284 3 DECEMBER 2021•VOL 374 ISSUE 6572 science.orgSCIENCE
Fig 3. Substrate scope for
butenolide formation.Reaction
conditions: 3 or 6 (0.1 mmol),
4 (2.0 equiv), Pd(OAc) 2 (10 mol %),
ligand (18 mol %), Ag 2 CO 3
(2.0 equiv), Li 2 CO 3 (2.0 equiv),
NaOAc (0.5 equiv), 1,4-dioxane
(0.2 mL),t-BuOH (0.8 mL),
under argon at 100°C for 16 h.
Isolated yields are reported.
TIPS, triisopropylsilyl; TBDPS,
tert-butyldiphenylsilyl; TBS,
tert-butyldimethylsilyl. *Methylene
activation product observable by
(^1) H NMR. Conditions for further
derivatizations of butenolide product:
(a) Tetrabutylammonium fluoride
(TBAF); (b) (N-iodosuccinimide) NIS,
Ag 2 CO 3 ; (c) NaOH; (d) N 2 H 4.
See supplementary materials
for details.
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