Letter
Synthesis of Benzo-Fused Cyclic Ketones via Metal-Free Ring
Expansion of Cyclopropanols Enabled by Proton-Coupled Electron
Transfer
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ABSTRACT: The metal-free ring expansion of cyclopropanols
containing a pendant styrene moiety was successfully achieved
using a proton-coupled electron transfer enabled by an organic
photoredox catalyst. Through this, variants of 1-tetralone and 1-
benzosuberone bearing a substituent at the benzylic position were
selectively obtained through the regioselective ring closure of alkyl
radical intermediates depending on the substitution pattern of the
alkene moiety.
1-Tetralones and 1-benzosuberones are broadly found in
natural products such as Hamigeran A, Merochlorin B, and
Parviflorol (Figure 1a).1 In addition, they have been used as
versatile building blocks in the synthesis of complex
molecules.2 Accordingly, considerable effort has been devoted
to achieve efficient construction of these benzo-fused ketone
frameworks.3−5 However, metal-free catalytic methods for the
synthesis of 1-tetralones and 1-benzosuberones bearing
substituents at the benzylic position are underdeveloped.6
The radical-mediated ring enlargements, such as the
Beckwith−Dowd ring-expansion reaction, are powerful tools
in organic synthesis as they provide efficient access to cyclic
ketones via alkoxy radical intermediates.7 In particular, readily
available cycloalkanols can be used as convenient precursors
for the synthesis of cyclic ketones because the single-electron
oxidation of cycloalkanols generates reactive carbon-centered
radicals via β-scission of cycloalkoxy radical intermediates. For
example, both Zhu et al. and Gong et al. independently
reported the radical ring expansion of 1-arylcyclobutanols
mediated by AgI or CeIV to prepare 1-tetralone derivatives
(Figure 1b).8,9 However, these transformations require a noble
metal-based catalyst or a transition metal oxidant, leading to
metal waste after completion of the reaction. In addition, the
products obtained from these reactions are limited to
variations on 1-tetralone that have unsubstituted γ-positions.
Recently, more attention has been paid to proton-coupled
electron transfer (PCET) as it enables redox-neutral and highly
atom-economical transformations.10 In their pioneering work,
Knowles et al. developed the PCET-initiated ring expansion of
5−7-membered cyclic alcohols using an Ir-based photoredox
catalyst to selectively afford 6−9-membered cyclic ketones
bearing substituents at the α- and/or β-positions (Figure 1c).11
Although transition metal oxidants were unnecessary in this
method, the cyclic alcohol substrates were limited to
heterocycles or carbocycles with a tertiary center that produces
stabilized α-amino, α-alkoxy, or tertiary alkyl radical inter-
mediates after ring opening. Therefore, a new strategy is
required to synthesize benzo-fused ketones using PCET-
initiated ring expansion: we designed a novel cyclopropanol
substrate 1 with a pendant styrene moiety with the expectation
that the strained cyclopropanol obviates the need for radical
stabilizing groups (Figure 1d).12 The required substrate 1 was
readily prepared from commercially available 2′-iodoacetophe-
none using Simmons−Smith cyclopropanation and well-
established cross-coupling reactions (see the Supporting
Information for details). Herein, we report our study along
this line to establish the efficient synthesis of γ-substituted 1-
tetralones and δ-substituted 1-benzosuberones. To the best of
our knowledge, this is the first example of using PCET for the
ring expansion of cyclopropanols.10,11
We began a preliminary study using 1a as the model
substrate (Table 1). Several photoredox catalysts were first
assessed under blue-light irradiation in the presence of a
commercially available base PnBu3Et+(EtO)2POO−. The
reaction of 1a in the presence of [Ir(dF(CF3)ppy)2(dtbbpy)]-
PF6 (A) [E1/2(*P/P−) = 1.21 V vs SCE in MeCN]13 yielded
33% of the desired 1-tetralone 2a, although 4a, the
stereoisomer of 1a, was obtained in 8% yield (entry 1). The
use of 4DPAIPN (B) [E1/2(*P/P−) = 1.10 V vs SCE in
MeCN]14 increased the yield of 4a, while the yield of 2a
decreased (entry 2). These results suggest that photocatalysts
Received: April 27, 2021
Published: June 1, 2021
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4710−4714
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