Organic Letters
Letter
substrate 5j to catalyst 6 illustrates the suggested binding
situation. Direct excitation of quinolones 5 is impossible with
the chosen light source due to the absence of any absorbance at λ
> 360 nm. The substrates require an energy transfer from the
thioxanthone to engage in a consecutive [2 + 2] photo-
cycloaddition. Upon excitation of thioxanthone 6, the
population of its triplet state occurs within picoseconds,12 and
the close proximity to the quinolone facilitates a rapid energy
transfer. The quinolone triplet, in turn, undergoes C−C bond
formation by addition to the internal carbon atom of the olefin
to a 1,4-diradical, which after ISC generates the product. A high
enantioface differentiation is guaranteed as the top face of the
quinolone is shielded by the thioxanthone chromophore.
Recently, the use of ruthenium and iridium complexes has
been advertised as an alternative to organic triplet sensitizers.13
The disadvantage of their high molecular weight (MW > 500
Da) is compensated by the fact that they can be used in low
quantities (<2 mol %) and that they exhibit high photostability.
The present intramolecular [2 + 2] photocycloaddition of
quinolones appeared as a suitable reaction to evaluate the
photostability and efficiency of catalyst 6. Quinolone 5n was
chosen as the test substrate (Scheme 3).
cycloaddition could be initiated by catalyst 6 at λ = 420 nm
even at low temperature and that product 9 was obtained in 72%
yield with significant enantioselectivity (81% ee).
In two additional sets of experiments, allenes were studied as
potential reaction partners in the enantioselective [2 + 2]
photocycloaddition. Despite the high synthetic utility of allene
photocycloaddition products,15 this substrate class has received
little attention in the context of enantioselective photo-
chemistry.16 The first set of allenes (compounds 10) was linked
via an ethylene tether to the oxygen atom at carbon C4 of the
quinolone. The time required to achieve full conversion in their
reaction varied slightly, but in all cases, the desired products 11
were obtained in high yields and with excellent enantioselectiv-
ity (Scheme 5). A single regioisomer was obtained with an
exocyclic double bond that invites further functionalization.
Scheme 5. Enantioselective Intramolecular [2 + 2]
Photocycloaddition of 3-Alkyl-4-(penta-3,4-dienyloxy)-
quinolones 10
Scheme 3. Enantioselective [2 + 2] Photocycloaddition of
Substrate 5n to Cyclobutane 7n: Efficiency of Sensitizer 6 at
Low Catalyst Loadings
Quinolones 12, in which an unsubstituted allene was linked
only by a methylene linker to the oxygen atom, reacted also with
high regio- and chemoselectivity to a single product. The
addition product 13a of 6-chloroquinolone 12a could be readily
isolated and fully characterized (Scheme 6). The addition occurs
in this instance to the terminal double bond of the allene, and the
remaining double bond is embedded into a dihydrofuran ring as
part of a 4,5,5a-trihydrocyclobuta-2H-furan core. The strained
enol ether is prone to ring opening, and the photocycloaddition
products of other allenes 12 turned out to be less stable than
product 13a. Traces of acid (e.g., 0.5 mol % of H2SO4) led to
ring opening, which is presumably initiated by protonation at the
quinolone C2 oxygen atom (structure 13).17 Fragmentation of
the cyclobutane ring leaves a positive charge in the allylic
position, which is released by deprotonation to form a furan ring.
As the fragmentation occurs via a ketene hemiaminal, which
subsequently tautomerizes, the only remaining stereogenic
center within the newly formed azocinone ring does not retain
its configuration, and products 14 were racemic. One of the
fragmentation products (X = H) was isolated and fully
characterized (see the SI for further details). Terminal dimethyl
substitution at the allene revealed that a second enantioselective
reaction pathway is accessible beyond the [2 + 2] photo-
cycloaddition. Upon irradiation of substrate 15 in the presence
of catalyst 6, cyclobutane 16 was formed in 50% yield with high
enantioselectivity (98% ee). In addition, the formation of diene
18 was observed,18 and the latter compound was isolated in 47%
yield. It seems likely that the product stems from the same 1,4-
diradical precursor 17 as cyclobutane 16. The additional methyl
groups open an alternative reaction pathway to intermediate 17,
allowing for intramolecular hydrogen abstraction19 from the
radical at atom C3 of the quinolone ring. The first C−C bond
formation step within the complex of compound 15 to sensitizer
Under standard conditions with 10 mol % of catalyst 6, its [2 +
2] photocycloaddition to product 7n proceeded in 99% yield
(99% ee). Lowering the catalyst loading to 1.0 mol % led to a
minimal decrease in enantioselectivity, and even at a catalyst
loading of 0.5 mol %, the yield and the enantioselectivity
remained high. Turnover numbers achieved with catalyst 6 thus
exceed 200, and given its low molecular weight (MW = 432.5
Da), minimal quantities are sufficient not only to facilitate a
visible-light-mediated reaction but also to maintain a high
enantioselectivity.
The electronic limits of the alkene part involved in the
catalytic intramolecular [2 + 2] photocycloaddition were probed
by employing electron-deficient 4-(3,4,4-trifluorobut-3-eny-
loxy)-3-methylquinolone (8) (Scheme 4). Trifluorinated olefins
have, to the best of our knowledge, not yet been employed in
visible-light-mediated [2 + 2] photocycloaddition reactions.14 It
was therefore gratifying to note that a successful photo-
Scheme 4. Intramolecular [2 + 2] Photocycloaddition of
Electron-Deficient 4-(3,4,4-Trifluorobut-3-enyloxy)-3-
methylquinolone (8) (HFX: Hexafluoro-m-xylene)
C
Org. Lett. XXXX, XXX, XXX−XXX