Dearomative Cascade Photocatalysis: Divergent Synthesis through Catalyst Selective Energy Transfer

Article abstract of DOI:10.1021/jacs.8b03302

The discovery and application of dearomative cascade photocatalysis as a strategy in complex molecule synthesis is described. Visible-light-absorbing photosensitizers were used to (sequentially) activate a 1-naphthol derived arene precursor to divergently form two different polycyclic molecular scaffolds through catalyst selective energy transfer.

Full text of DOI:10.1021/jacs.8b03302

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Communication
Dearomative Cascade Photocatalysis: Divergent
Synthesis through Catalyst Selective Energy Transfer
Michael J. James, Jonas Luca Schwarz, Felix Strieth-Kalthoff, Birgit Wibbeling, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Jul 2018
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Dearomative Cascade Photocatalysis: Divergent Synthesis
through Catalyst Selective Energy Transfer
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Michael J. James, Jonas L. Schwarz, Felix StriethꢀKalthoff, Birgit Wibbeling, and Frank Glorius*
OrganischꢀChemisches Institut, Westfälische WilhelmsꢀUniversität Münster, Corrensstraße 40, 48149 Münster, Germany
Supporting Information Placeholder
Scheme 1. (a) Previous UV-light-promoted [2 + 2] dearomati-
zation reactions. (b) This work: Divergent synthesis through
dearomative cascade photocatalysis.
ABSTRACT: The discovery and application of dearomative
cascade photocatalysis as a strategy in complex molecule syntheꢀ
sis is described. Visibleꢀlightꢀabsorbing photosensitizers were
used to (sequentially) activate a 1ꢀnaphthol derived arene precurꢀ
sor to divergently form two different polycyclic molecular scafꢀ
folds through catalyst selective energy transfer.
Cascade reactions, processes in which multiple chemical bonds
are formed and cleaved in a oneꢀpot operation via a wellꢀ
understood mechanistic sequence, provide an attractive solution to
minimize labor and time inputs in the synthesis of complex organꢀ
ic molecules.1 The efficiency of cascade reactions is perhaps most
elegantly demonstrated in nature, where multiple complex natural
products are often assembled from a single intermediate in diverꢀ
gent enzymatic cascades.2 Unsurprisingly, attempts to mimic
nature in this regard have inspired the development of multiple
methodologies and their application in total synthesis.3,4
In a complementary fashion to cascade reactions, dearomatization
reactions offer another promising strategy to minimize synthetic
costs by utilizing abundant and inexpensive twoꢀdimensional (2D)
industrial feedstocks to directly form highly complex threeꢀ
dimensional (3D) molecular scaffolds.5 Moreover, dearomatizaꢀ
tion strategies utilizing visibleꢀlight, as another abundant natural
resource, offer further benefits regarding cost and environmental
sustainability.6 A prominent recent example of such an approach
can be found in the elegant work of Sarlah and coꢀworkers, who
utilized visibleꢀlight absorbing arenophiles to enable the twoꢀstep
dearomative functionalization of simple benzenoid arenes.7
Our studies began by examining the reactivity of naphtholꢀ
derivative 1a under visibleꢀlight photocatalytic conditions (Table
1, entries 1–3).11 Pleasingly, a number of iridiumꢀbased photoꢀ
catalysts were found to efficiently promote the expected cycloadꢀ
dition to form styrene 2a. Intriguingly, we also observed the
formation of a second product 3a with an exotic 6/4/6/5 ring
system (whose structure was unambiguously confirmed by Xꢀray
crystallographic analysis, Figure 1).12 Further screening studies
(entries 4–8) revealed that either product 2a or 3a could be selecꢀ
tively prepared in excellent yield by reaction with PC II (1 mol%)
in MeOH (0.02 M) or PC III (1 mol%) in 1,4ꢀdioxane (0.04 M)
respectively. We were further intrigued by these observations
when we began to suspect that benzocyclobutene 3a was formed
via a photocatalytic rearrangement of styrene 2a, which would
constitute an unusual and synthetically powerful photocatalytic
dearomative cascade reaction.
Herein, we describe a combination of the aforementioned reaction
classes,8 whereby visibleꢀlightꢀmediated photocatalysis was used
to promote and control a dearomative cascade reaction process.
This approach was inspired by the pioneering work of Wagner
and coꢀworkers, who used UVꢀlight to induce the cycloaddition of
alkenes to triplet benzenes.9 In particular, our work focused on the
underexplored photochemical reactivity of 1ꢀnaphthol arenes,
which have previously been shown to undergo [2 + 2] cycloaddiꢀ
tions under irradiation with UVꢀlight (3 examples, Scheme 1a). In
our approach, a variety of simple 2D naphthol arenes were seꢀ
quentially activated with a visibleꢀlightꢀabsorbing photosensitizer
to directly prepare natural productꢀlike 3D molecular scaffolds10
with defined contiguous stereocenters, in a single operation
(Scheme 1b). Furthermore, through careful choice of photosensiꢀ
tizer and conditions, we report to the best of our knowledge, the
first known example of divergent synthesis using catalyst selecꢀ
tive energy transfer (EnT).
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with the known photophysical properties of PC I–III (Scheme
Table 1. Reaction discovery and optimization studies
2.3),13 it became evident that there was no feasible correlation
between the oxidation or reduction potentials of the photocatalysts
and the formation of 2a and 3a, suggesting that a photoinduced
single electron transfer (SET) oxidation or reduction process was
not in operation for either step. However, a clear correlation was
observed between photocatalyst triplet energy and the selective
formation of 2a and 3a.14 Selectivity in this instance would then
presumably be controlled by the relative rates of EnT. Considerꢀ
ing this, SternꢀVolmer quenching studies were then performed to
illustrate the relative rates of EnT (Scheme 2.4); these studies
showed that while both photocatalysts were readily quenched by
naphthol 1a, only PC III was effectively quenched by styrene 2a,
suggesting that there is insufficient spectral overlap for efficient
EnT with PC II (for evidence in support of this, see the supportꢀ
ing information). Further control experiments also precluded the
possibility that these reactions were promoted in a nonꢀ
photocatalytic thermal pathway.11 Considering these studies, we
propose the following mechanistic pathway for the formation of
both products (Scheme 2.5). First, irradiation of the IrIII photosenꢀ
sitizer produces its longꢀlived triplet excited state, which activates
naphthol 1a via EnT (both PC II and PC III), to afford triplet
intermediate 1a*. The triplet naphthalene species 1a* then engagꢀ
es in an intramolecular dearomatizing [2 + 2] cycloaddition with
the pendant alkene to afford styrene 2a.15 Following this dearomaꢀ
tization step, the remaining πꢀsystem of styrene 2a is selectively
activated by PC III via another energy transfer event to form 2a*.
The triplet styrene 2a* then undergoes a vinyl cyclobutane rearꢀ
rangement,16 whereby the C–C bond of the adjacent cyclobutane
ring is fragmented to form diradical intermediate 4, which followꢀ
ing intersystem crossing and radicalꢀradical recombination affords
benzocyclobutene 3a.
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Yield (%)b
2a
Entry
Catalysta
Solvent
3a
42
1
2
3
4
5
6
7
8
MeCN
58
PC I
MeCN
67
21
45
64
93
19
15
30
79
53
36
7
PC II
PC III
PC II
PC II
PC II
PC III
PC III
MeCN
1,4ꢀdioxane
DCE
MeOHc
DCE
81
85
Having concluded mechanistic studies, we sought to examine and
establish the generality of this dearomative cascade photocatalysis
strategy. Thus, a variety of naphthol arenes 1a–m were readily
prepared and reacted under both sets of the optimized reaction
conditions on a larger synthetic scale (Scheme 3). First, we examꢀ
ined naphthols bearing primary and secondary aliphatic acyclic
substituted ketones (1a–c), which were all converted into the
desired products in good to excellent yield. Next, cyclic substitutꢀ
ed ketones (1d–f) were examined, which again were all wellꢀ
tolerated under both sets of conditions. Similarly, naphthols bearꢀ
ing alkyl (1g), aryl (1h) and benzyl esters (1i) also afforded the
desired products in typically excellent yield, which could all be
readily used to make derivatives of these complex scaffolds.
However, it should be noted that no reaction was observed in the
absence of a carbonylꢀbased electron withdrawing group, which is
presumably necessary to lower the triplet energy of the aromatic
system.11 Next, naphthols with substituents and functional group
handles installed on the naphthalene rings were studied to illusꢀ
trate the ability of this method to access highly challenging strucꢀ
tural motifs. For example, 4ꢀMe substituted naphthol 1j was
readily converted into benzocyclobutene 3j, which possess conꢀ
tiguous quaternary stereocenters, with perfect diastereoselectivity.
The bromide substituted naphthol 1k, which could also enable the
diversification of these complex scaffolds, was converted into
both of the desired products in excellent yield. Next, 6,7ꢀ
disubstituted naphthols (1l,m) were then readily prepared and
converted into the desired products in modest to good yield. Unꢀ
fortunately, whilst substrates bearing substituted alkenes readily
engaged in the [2 + 2] photocycloaddition step with PC II, they
failed to cleanly form the corresponding benzocyclobutene prodꢀ
ucts with PC III. This limitation is tentatively attributed to changꢀ
es in radical stability, which may enable competitive ringꢀ
opening/fragmentation pathways from the triplet styrene intermeꢀ
1,4ꢀdioxane
a Reactions performed with 0.1 mmol of 1a and catalyst in the
stated solvent (0.04 M) under irradiation with blue LEDs (λmax
=
455 nm); b Determined by 1H NMR spectroscopy against an internal
standard (1,3,5ꢀtrimethoxybenzene); c 0.02 M.
Figure 1. Crystal structures of 2a and 3a (thermal ellipsoids
shown at 15% probability)
2a
3a
(X-ray)
(X-ray)
To confirm our suspicions we monitored the formation of both
1
products under the optimized conditions by H NMR spectroscoꢀ
py. Using PC II, only the gradual formation of styrene 2a was
observed for the first 18 h, after which the yield was diminished
by low levels of conversion into benzocyclobutene 3a (Scheme
3.1a). However, as suspected, when using PC III the simultaneꢀ
ous and rapid conversion of naphthol 1a into styrene 2a, and
styrene 2a into benzocyclobutene 3a, was immediately observed
(Scheme 2.1b). To decipher potential modes of photocatalyst
activation (electron or energy transfer) for each step, computaꢀ
tional studies were performed to calculate the physical properties
of 1a and 2a (Scheme 2.2). From the comparison of these results
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diates (evidence in support of this and discussions of other limitaꢀ
tions can be found within the supporting information).
the controlled photosensitized rearrangement of other styrenyl
substituted ring systems. More generally, we envision the applicaꢀ
tion of this synthetic strategy to other arene systems utilizing
other photocatalytic activation modes and cyclization processes.19
Overall, we believe that this work will inspire and enable the
photochemical synthesis of other complex molecular frameworks
with unprecedented levels of selectivity.
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In summary, we have reported the discovery and application of
dearomative cascade photocatalysis as a strategy in complex
molecule synthesis. Simple naphthol arenes were selectively and
divergently converted into complex stereodefined polycyclic
products using catalyst selective energy transfer.17 We hope that
the individual elements of this work will serve to inform several
lines of future research, such as potential asymmetric variants18 or
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Scheme 2. Mechanistic studies: (1) Reaction monitoring by 1H NMR with a) PC II and b) PC III. (2) DFT calculated physical prop-
erties. (3) Summary of photocatalyst photophysical properties. (4) Stern-Volmer quenching studies with 1a, 2a and a) PC II and b)
PC III. (5) Proposed reaction mechanism for the divergent reaction protocols
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Scheme 3. Substrate scope of the divergent reaction protocols
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dation (J.L.S., F.SꢀK.) and the Deutsche Forschungsgemeinschaft
(Leibniz Award and SFB858). We thank Dr Z. Nairoukh, A.
TlahuextꢀAca and M. Teders (all WWU) for helpful discussions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
REFERENCES
Experimental and computational details (PDF)
Crystallographic Data for 2a and 3a (CIF)
AUTHOR INFORMATION
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Corresponding Author
*glorius@uniꢀmuenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the Alexander von Humboldt Founꢀ
dation (M.J.J.), the Alfried Krupp von Bohlen and Halbach Founꢀ
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(11) For further information on optimization, mechanistic and scoping
studies, see the Supporting Information.
(12) CCDC 1831750 (2a) and 1831751 (3a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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