Organic Letters
Letter
a
nones in moderate yields (4v and 4w). α,β-Disubstituted
acrylic acids, typically more reactive compared to their mono-α-
substituted counterparts, were found to successfully engage in
this transformation to provide the corresponding cyclo-
pentenones (Scheme 3, 4x−4z). Cyclopentene-1-carboxylic
acid failed to produce the desired cyclopentenone but
delivered the alkylated product, presumably due to the high
ring strain (Scheme 3, 4af).19 In contrast, cyclohexene-1-
carboxylic acid was active to generate hexahydro-1H-inden-1-
one products with different malonates (Scheme 3, 4aa−4ae).
Cinnamic acid is inactive under reaction conditions, and the
experiment with other aromatic or aliphatic aldehydes failed.
This transformation could be carried out on a larger scale (1
mmol) to give 4aa in 70% yield. The structure of cyclo-
pentenone 4r was explicitly characterized by single-crystal X-
ray diffraction.
Scheme 4. Synthesis of 5-Alkyated Cyclopentenones
5-Substituted cyclopentenones are key prevalent motifs of
natural products and biologically active drugs. In general, the
5-alkylation of cyclopentenones can be achieved only by using
a kinetic base such as LDA. During our studies, we detected
the formation of trace 5-monoester-substituted cyclopente-
nones, which should be produced from a cyclopentenone 4.
We envisioned that the subsequent alkylation of 5-
monoester-substituted cyclopentenones might drive the
reaction to formation of a 5-alkylated product. To our delight,
5-alkylated cyclopentenones were successfully obtained
directly when a variety of alkyl halides were treated with 5,5-
diester cyclopentenone 4 with 1 equiv of Na2CO3 in MeOH
(Scheme 3, 5a−5z). Benzyl bromides were active in reacting
with as-prepared 5,5-diester cyclopentenones smoothly to give
the diverse 5-benzyl-substituted cyclopentanones (Scheme 3,
5a−5l). Benzyl bromides with both electron-donating and
-withdrawing groups in the aryl ring carried out the reaction
fast, and the steric hindrance had little effect on the alkylation.
Allylic and propargyl bromides showed equal reactivity
(Scheme 3, 5m−5u). Alkyl bromides showed poor reactivity.
However, a variety of alkyl iodides were compatible with the
method to give the 5-alkylated cyclopentenones in moderate
yields (Scheme 3, 5v−5z). The ester group in cyclopentenone
4 and cyclopentenone 5 could be easily removed by
decarboxylation (Scheme 3, 6a−6e and 7a−7h).
a
Reactions were performed on a 0.2 mmol scale. See the Supporting
b
Information for experimental details. Isolated yields. On a 1 mmol
scale.
On the basis of this efficient three-component cyclization,
the reaction to the multicomponent reaction was extended by
the addition of excess formaldehyde and malonates to afford 5-
alkylated cyclopentenones as shown in Scheme 4. With the
optimal reaction conditions, cyclopentenone 8v was isolated in
65% yield using NaOAc as a base in hexafluoroisopropanol
(HFIP) (Scheme 4, 8v). This reaction exhibited a broad
substrate scope. α-Aryl-substituted acrylic acids participated in
the reaction very well to give the desired cyclopentenones
smoothly (Scheme 4, 8a−8i). Electronic and steric effects of
the aryl ring almost did not influence the reaction, and fluoro,
chloro, and bromo groups were tolerated. A range of α-alkyl-
substituted acrylic acids, including methyl, ethyl, butyl,
phenylethyl, cyclopentyl, cyclohexyl, and benzyl, were
compatible, producing the expected 5-alkylated cyclopente-
nones in good yields (Scheme 4, 8j−8p). α,β-Disubstituted
acrylic acids presented good reactivity, furnishing the
polysubstituted cyclopentenones fast (Scheme 4, 8q−8u).
Cyclohexene-1-carboxylic acid reacted well with various
malonates to afford hexahydro-1H-inden-1-one products
(Scheme 4, 8v−8y).
To elucidate the pathway of this multicomponent reaction,
several control experiments were conducted (see the
In conclusion, a novel protocol for the rapid synthesis of
cyclopentenones from a Rh-catalyzed three-component cycli-
zation involving vinylic C−H cleavage has been developed.
The readily available starting materials (acrylic acids, form-
aldehyde, and malonates) are precisely assembled in order to
afford the cyclopentenones in one reaction vessel. It should be
emphasized that the carboxyl directing group subsequently
participates in the reaction, supplying one carbon to cyclo-
pentenone products. A variety of 5-alkylated cyclopentenones
were smoothly obtained by the exposure of a mixture of as-
prepared cyclopentenones to various alkyl halides in a
Na2CO3/MeOH solution. A multicomponent reaction oc-
curred after the modification of the reaction conditions to give
the multisubstituted cyclopentenones in one pot with excessive
formaldehyde and malonates. This protocol provides a highly
efficient synthesis of cyclopentenones from abundant starting
materials without the use of toxic carbon monoxide and
therefore complements the existing synthetic methods. Addi-
5057
Org. Lett. 2021, 23, 5054−5059