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lower yield (entry 11), and the reaction did not happen
under low temperature (entry 12). Significantly, the
yield of 3aa was reduced to 27% in the absence of
prestirring of the aldehyde with the copper complex
(entry 13), and no product was isolated without slow
addition of the diazo substrate (entry 14). Control
experiment without copper catalyst yielded no product
(entry 15). It is noteworthy that the carboxylic acid
ligands of rhodium catalysts have obvious effect on the
stereochemistry, which demonstrates that a Rh-ligated
ylide intermediate is probably formed; while different
copper catalysts with or without chiral ligands have no
influence on the stereochemistry indicating that the
reaction might take place via a metal-free ylide under
copper catalysis (Supporting Information). It is pro-
posed that the steric effect for the free carbonyl ylide
resulted better diastereoselectivity, while the steric
effect and ligated-metal for the metal-ligated carbonyl
ylide would make the reaction complex with poor
diastereocontrol.
With the optimal reaction conditions in hand,[12] we
next set out to investigate the scope of diazo
compounds (Table 2). Varying the ester group of diazo
compounds to bulky ethyl or benzyl substitutent gave
lower yields (3aa–ca). Then, the reaction of aldehyde-
tethered-cyclohexadienone 2a with different substi-
tuted aryl diazoacetates bearing electron-donating or
Scheme 1. Previous Reports and Our Strategy.
and in continuation with our interest in catalytic electron-withdrawing substituents at the para- and
copper-carbene transformations for developing novel meta-position of the aryl moiety all proceeded
methodologies on polycyclic skeleton synthesis,[9] smoothly to furnish the desired products (3da–oa),
herein, we report a novel copper-catalyzed tandem while the yield sharply decreased for ortho-substituted
intermolecular ylide formation/intramolecular 1,3-di- diazo compounds, indicating that the steric effect is
polar cycloaddition of diazo compounds and aldehyde- more significant than the electronic factor for this
tethered-cyclohexadienones to access various oxapoly- reaction (3pa–qa). Additionally, different di-substi-
cyclic systems with excellent chemo- and diastereose- tuted phenyl diazoacetates and bulky naphthyl diazo-
lectivities and moderate to excellent yields under mild acetate were also well tolerated for the reaction (3ra–
conditions (Scheme 1e).
ua). When 3-diazo-oxindole substrate was applied to
We first utilized phenyl diazoacetate 1a and the reaction, an interesting spiro-oxindole fused hex-
aldehyde-tethered-cyclohexadienone 2a as model sub- acyclic framework was obtained in one step (3va–wa),
strates to optimize the reaction conditions (Table 1). which is attractive for medicinal chemistry.[13] More-
When the reaction was performed in methylene over, because the structure of diazo compound has a
dichloride (CH2Cl2) at room temperature with large impact on the reaction outcome,[14] other types of
Rh2(OAc)4 as the catalyst, the desired product 3aa was diazo compounds were further tested for this reaction.
obtained in 36% yield with moderate diastereoselectiv- Gratifyingly, dimethyl 2-diazomalonate was suitable
ity (entry 1).[10] The reaction was highly sensitive to for this reaction, affording the desired product 3xa in
moisture, and no desired product was detected without 47% yield. However, no target product 3ya was
4 Å MS (entry 2). Inspired by Muthusamy’s report,[7] detected from the reaction mixture when (1-diazoethyl)
copper catalysts were extensively investigated, and benzene was utilized. The structure and relative stereo-
gratifyingly, Cu(COD)(hfac) has been proven to be the chemistry of 3aa were unambiguously confirmed by
best catalyst, affording the desired product 3aa in 34% X-ray diffraction analysis.[15]
yield as single diastereomer (entries 3–5). Next, differ-
Next, various substituted aldehyde-tethered-cyclo-
ent solvents were screened. (Trifluoromethyl)benzene hexadienone substrates were subjected to the optimized
(PhCF3) was the best choice, and the alternative reaction conditions and generally showed somehow
aromatic solvents including toluene, xylenes, and lower efficiency (Table 3). The influence of the R
chlorobenzene (PhCl) gave moderate yields,[11] whereas substituent was first investigated. Changing the R
the other solvents were not suitable for the reaction group of cyclohexadienones from methyl to ethyl or
(entries 6–10). Moreover, high temperature led to a acetyl group had adverse effect on the reaction,
Adv. Synth. Catal. 2021, 363, 1–7
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