Organic Letters
Letter
regioisomer 14′ in 22% yield. Further attempts to improve the
yields by lowering the temperature (80 °C; 14 (53%) and 14′
(15%)) and decreasing the Rh catalyst amount (1 mol %; 14
(40%) and 14′ (12%)) were unsuccessful.
Scheme 7. Control Experiments and Plausible Reaction
Pathway
When salicylaldehyde was reacted with 1,4-hydroquinone
(2a′) instead of 1,4-benzoquinone (2a), xanthone formation
was not observed. However, when silver(I) oxide was added,
3a was generated in 74% yield. The versatility of this protocol
with 1,4-hydroquinone was tested (Scheme 6) with salicy-
Scheme 6. Reaction with 1,4-Hydroquinones
1,2-benzoquinone, catechol, or 1,2-naphthoquinone (instead of
1,4-benzoquinone), no annulation product was observed.
These substrates are likely to bind rhodium in a bidentate
chelating mode; therefore, olefinic coordination is improbable,
and the desired catalysis cannot proceed. When the reaction
was performed at high temperature (e.g., 130 °C), xanthone
was still obtained as the only product, and decarbonylation or
any other side product(s) was not observed.
Based on the experimental observations and literature
reports,15−18 a plausible mechanism for this protocol is
outlined in Scheme 7c. An active rhodium catalyst I is
generated in the presence of CsOAc, which undergoes C−H
metalation with 1a to form five-membered rhodacycle
intermediate II through hydroxyl-directed aldehydic C−H
bond activation. The coordination of quinone with II generates
intermediate III, which produces a seven-membered rhoda-
cycle intermediate IV via migratory insertion. Next, Rh
complex IV undergoes reductive elimination and aromatization
to afford the final product V and Rh(I) catalyst. Rh(I) is
oxidized to the active Rh(III) catalyst by air in combination
with benzoquinone and AcOH. The regenerated Rh(III)
catalyst is further used to catalyze the next catalytic cycle.20
Regiocontrol in unsymmetrically substituted 1,4-benzoqui-
nones is governed by the stereoelectronic characteristics of the
substituent, which in turn dictate the mode of migratory
insertion.
laldehyde bearing electron-donating (3b and 3c), electron-
withdrawing (3i and 3k), and other types of substituents (3q,
4e, and 4i). Interestingly, 1,4-hydroquinone was successfully
employed for the late-stage functionalization of estrone (6)
and by using substituted 1,4-hydroquinone (5a and 5l).
To gain insights into the reaction mechanism, 1a was treated
with 1, 2, and 4 equiv of CD3OD in 1,2-DCE under standard
conditions; this treatment showed the deuteration of aldehydic
C−H bond at 5, 8, and 10%, respectively (Scheme 7a). The
competitive reaction between 1a and 1a-D was carried out in
equimolar quantities. The unreacted mixture of 1a-D and 1a
showed a ratio of 1.32 based on the 1H NMR analysis (Scheme
7b).21
The combination of 2-methoxybenzaldehyde (or benzalde-
hyde) and 1,4-benzoquinone under standard conditions
remained unreacted even after 16 h, indicating the importance
of the ortho hydroxyl group. The more electron-deficient 2-
(methoxycarbonyl)-1,4-benzoquinone or 2-(methoxycarbon-
yl)-1,4-hydroquinone did not provide the annulation product
with salicylaldehyde. Similarly, 1,4-naphthoquinone, which is
significantly electron deficient compared to 1,4-benzoquinone,
did not undergo effective olefin coordination, resulting in no
annulation reaction. When salicylaldehyde was reacted with
In conclusion, one-step synthesis of diverse multihydroxy-
lated xanthone derivatives is developed via Rh(III)-catalyzed
double C−H/O−H annulation of the salicylaldehydes with
1,4-benzoquinones or 1,4-hydroquinones. This redox-neutral
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Org. Lett. 2021, 23, 2465−2470