Sequential Energy Transfer Catalysis: A Cascade Synthesis of Angularly-Fused Dihydrocoumarins

Article abstract of DOI:10.1021/acs.orglett.9b03882

An operationally simple one-pot protocol has been developed to enable the conversion of diversely substituted cinnamic acid derivatives into angularly-fused dihydrocoumarins (up to 94%). Inspired by coumarin biosynthesis, this reaction cascade harnesses photochemical E → Z alkene isomerization enabled by energy transfer catalysis using inexpensive thioxanthen-9-one (TX) under irradiation at 402 nm. Subsequent lactonization generates the heterocyclic core prior to a second photosensitization event to induce a [2 + 2] cycloaddition, again mediated by TX. The tetracyclic products are generated efficiently, and proof of the structure was established by X-ray crystallography. Mechanistic investigations, including structural probes and NMR reaction monitoring, support the postulated order of events. The study underscores the synthetic value of inexpensive small-molecule organic photocatalysts in the generation of structural complexity via sequential ?€-bond activation.

Full text of DOI:10.1021/acs.orglett.9b03882

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sequential Energy Transfer Catalysis: A Cascade Synthesis of
Angularly-Fused Dihydrocoumarins
́
̌
́
Tomas Nevesely, Constantin G. Daniliuc, and Ryan Gilmour*
̈
̈
̈
̈
Organisch Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, 48149 Munster, Germany
S
* Supporting Information
ABSTRACT: An operationally simple one-pot protocol has been developed to enable the conversion of diversely substituted
cinnamic acid derivatives into angularly-fused dihydrocoumarins (up to 94%). Inspired by coumarin biosynthesis, this reaction
cascade harnesses photochemical E → Z alkene isomerization enabled by energy transfer catalysis using inexpensive
thioxanthen-9-one (TX) under irradiation at 402 nm. Subsequent lactonization generates the heterocyclic core prior to a second
photosensitization event to induce a [2 + 2] cycloaddition, again mediated by TX. The tetracyclic products are generated
efficiently, and proof of the structure was established by X-ray crystallography. Mechanistic investigations, including structural
probes and NMR reaction monitoring, support the postulated order of events. The study underscores the synthetic value of
inexpensive small-molecule organic photocatalysts in the generation of structural complexity via sequential π-bond activation.
Scheme 1. Cascade Route to Angularly-Fused
Dihydrocoumarins via Sequential Energy Transfer Catalysis
he functional versatility and structural tenacity of
Tcoumarins has led to their privileged status in
biomedicine and materials science1 and continues to fuel the
development of innovative strategies to facilitate their
construction.2 In addition to the venerable Pechmann
condensation,3 the contemporary repertoire of synthetic
approaches includes transition metal4 and Lewis acid5
catalyzed processes, variations of the Knoevenagel reaction,6
and photochemical strategies.7 In this diverse arsenal,
bioinspired strategies that translate the conceptual simplicity
of coumarin biosynthesis to a laboratory paradigm remain
elusive. Inherent to this process is a geometrical E → Z
isomerization of coumaric acid glycosides,8 which facilitates
rapid lactonization to generate the heterocyclic core (Scheme
1, top).9 Given the renaissance of contra-thermodynamic
alkene isomerization enabled by selective energy transfer
catalysis,10 mechanistic constructs that emulate the first two
steps of coumarin biosynthesis9a might also be extended to
generate structural complexity. This laboratory recently
reported the direct photocatalytic conversion of simple
cinnamic acids to coumarins to enable a sequential selective
energy transfer−single electron transfer cascade (Scheme 1,
center).11 However, efforts to induce a subsequent energy
transfer event under the auspices of flavin catalysis were
unsuccessful. By re-engineering the transformation to more
accurately reflect the biosynthetic precursor, the photoinduced
SET step would be circumvented,12 thereby potentially
allowing two sequential energy transfer events to be coupled
(Scheme 1, bottom). It was envisaged that appropriately
substituted cinnamic acid precursors would respond to
sequential energy transfer activation to generate additional
complexity with high atom economy.13
To validate the notion of sequential energy transfer in
enabling a bioinspired coumarin synthesis, substrate I bearing a
Received: October 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
pendent alkene unit was conceived. Efficient photosensitized E
→ Z isomerization would generate cis-cinnamic acid II with
concomitant lactonization (III). Since the terminal alkene is
predisposed to undergo a [2 + 2] cycloaddition with the
coumarin core via a second energy transfer process,14 the
angularly fused dihydrocoumarin scaffold IV would result. This
would validate the conceptual framework of using sequential
energy transfer events to generate structural complexity.
Collectively, this bioinspired cascade15 would enable angularly
fused coumarins such as 4 to be generated using a single
photocatalyst. In identifying a suitable photosensitizer to
enable successive activation via energy transfer, (−)-riboflavin
was considered.16 Previous studies from this laboratory have
demonstrated that photoexcited (−)-riboflavin effectively
isomerizes activated alkenes embedded in the cinnamoyl
motif.17 Although isomerization and in situ cyclization were
observed, the [2 + 2] cycloaddition presented a challenge (see
Table 1, entry 6). Given the high triplet energy of coumarin
(ET = 261 kJ/mol)18 it was reasoned that thioxanthen-9-one
(ET = 265 kJ/mol)19 would be a prudent replacement for
(−)-riboflavin (ET = 209 kJ/mol).18
Scheme 2. Exploration of the Substrate Scope
Initially, the conversion of substrate 1 to tetracycle ( )-2
was investigated using TX under irradiation at 402 nm using a
violet LED (Table 1). Reactions were performed at 50 °C
a
Table 1. Reaction Optimization Using TX
b
entry
t [h]
T [°C]
solvent
yield [%]
1
2
3
4
5
24
14
24
24
24
24
50
50
20
50
50
50
MeCN
MeCN
MeCN
MeOH
PhCF3
MeCN
91
77
28
81
86
c
d
6
<5 (67)
a
Reactions were carried out on a 0.05 mmol scale in 1 mL of degassed
b
solvent under an argon atmosphere with irradiation at 402 nm. NMR
yields using 1,3,5-trimethoxybenzene as the internal standard. (−)-
Riboflavin (5 mol %) was used instead of TX. Only the lactonized
c
d
product was observed (e.g., III in Scheme 1).
a
Reactions were carried out on a 0.1 mmol scale in 2 mL of degassed
MeCN under Ar with irradiation at 402 nm for 24 h. Isolated yields
are shown.
under an inert atmosphere to mitigate any effects of oxygen on
the efficiency of the energy transfer process. Gratifyingly, the
initial reaction in acetonitrile at 50 °C furnished the expected
product ( )-2 in 91% yield (entry 1). Reducing the reaction
time had a detrimental effect on the yield (entry 2), as did
lowering the temperature to 20 °C (entry 3). Changes to the
reaction medium were tolerated, albeit with slight reductions
in yield (81 and 86%; entries 4 and 5).
For the purposes of scope expansion, a series of structurally
modified substrates were prepared and exposed to TX (5 mol
%) in acetonitrile (50 °C) under irradiation at 402 nm
(Scheme 2). This one-pot protocol enabled the formation of
parent coumarin 2 in 80% yield. The trifluoromethyl substrate
required 36 h to reach completion to generate compound 3 in
61% yield, and the most efficient example in the study arose
from the introduction of an ether side chain (4; 94%). The π-
extended examples 5 and 6 were furnished in respectable yields
of 83% and 86%, respectively, and the bromo derivative 7
provides a building block for subsequent derivatization.
Switching the pendent alkene from the β- to the α-position
allowed the isomeric coumarin scaffold 8 to be accessed.
Finally, α,β-disubstitution was tolerated, as exemplified by
scaffold 9 (75%). The relative stereochemistry of the racemic
1
products was established by detailed H NMR analysis, and it
was possible to grow crystals of 7 that were suitable for X-ray
crystallographic analysis (CCDC 1960689; see the inset at the
bottom of Scheme 2 and the Supporting Information).
A process of reaction deconstruction was then conducted to
independently investigate the two energy transfer processes.
To that end, the starting material was simplified and the
alkenyl side chain was truncated to explore the isomerization/
lactonization (Table 2, 10 → 11). Control reactions confirmed
B
DOI: 10.1021/acs.orglett.9b03882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
isomerization, lactonization and finally cycloaddition, the
MOM-protected substrate 13 was examined (Scheme 3).
Table 2. Study of the Isomerization/Lactonization Step
Scheme 3. Probing the Order of Energy Transfer Events
b
entry
variation
t [h]
conv. [%]
yield [%]
1
2
3
4
5
6
no light
no TX
MeCN
MeCN
MeOH
PhCF3
24
24
14
24
24
24
<5
<5
86
>95
>95
>95
0 (0)
0 (0)
66 (12)
53 (30)
0 (71)
0 (79)
This would prevent lactonization from occurring and thereby
enable a competition between isomerization and [2 + 2]
cycloaddition. Under the standard reaction conditions, only
the Z-configured product 14 was generated, in line with the
working hypothesis. Additional support for this order of events
was obtained from the NMR time course shown in Scheme 4.
a
Reactions were carried out on 0.1 mmol scale in 2 mL of degassed
b
solvent under Ar with irradiation at 402 nm. NMR yields using 1,3,5-
trimethoxybenzene as the internal standard. Values in parentheses are
the yields of the coumarin dimer.
Scheme 4. NMR Time Course
the requirement of both light and photocatalyst for cyclization
(entries 1 and 2). Inspection of the UV−vis spectrum of 10
indicates a lack of absorption at 402 nm (see the Supporting
Information), thereby accounting for the exceptionally
inefficient alkene isomerization observed. Exposing 10 to the
reaction conditions reported above led to the formation of 11,
albeit with competing coumarin dimerization that proved to be
solvent-dependent20 (entries 3 and 4, yields given in
parentheses). This is in line with the observation that TX
induces both energy transfer events (Table 1). Switching the
solvent from acetonitrile to methanol or trifluorotoluene
(entries 5 and 6, respectively) led to exclusive formation of
the dimer, which prompted a closer inspection of the
cycloaddition event.
To that end, compound 12 was prepared, and the efficiency
of the final step of the reaction cascade was interrogated
(Table 3). Control reactions once again established the
Table 3. Investigation of the [2 + 2] Cycloaddition with
a
TX
From this analysis, it is possible to observe the initial
isomerization after 1 h by virtue of the signals I (E, 3.04
ppm) and II (Z, 2.44 ppm). Moreover, the signal for the EtOH
released during lactonization is visible at δH = 3.54 ppm.
In conclusion, an operationally simple one-pot conversion of
cinnamic acids to angularly fused dihydrocoumarins is
reported. This biomimetic strategy emulates the contra-
thermodynamic alkene isomerization/lactonization sequence
inherent to the natural product biosynthesis and extends the
sequence to further photocycloaddition. Enabled by sequential
energy transfer events using a single organic photocatalyst, this
approach underscores the value of inexpensive small-molecule
photosensitizers such as thioxanthen-9-one in generating
structural complexity by π-bond activation.
b
entry
variation
t [h]
conv. [%]
yield [%]
1
2
3
4
5
6
no light
no cat.
MeCN
MeCN
MeOH
PhCF3
24
24
24
1
1
1
<5
7
>95
>95
>95
>95
<5
7
87
96
96
97
a
Reactions were carried out on a 0.1 mmol scale in 2 mL of degassed
solvent under Ar with irradiation at 402 nm. NMR yields using 1,3,5-
trimethoxybenzene as the internal standard.
b
ASSOCIATED CONTENT
■
S
* Supporting Information
importance of the photon source and the TX photocatalyst
for efficient cyclization (entries 1 and 2). Reducing the
reaction time from 24 to 1 h improved the yield (entries 3 and
4), and the transformation was tolerant of changes in the
solvent (entries 5 and 6). Finally, to provide experimental
support for the postulated sequence of events involving
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03882.
Experimental protocols and NMR and X-ray data (PDF)
C
DOI: 10.1021/acs.orglett.9b03882
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
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CCDC 1960689 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
■
Corresponding Author
*ryan.gilmour@uni-muenster.de
ORCID
Ryan Gilmour: 0000-0002-3153-6065
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from the WWU Mu
and the CiM-IMPRS Graduate School (fellowship to T.N.).
■
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nster
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