Visible-Light-Enabled Paternò-Büchi Reaction via Triplet Energy Transfer for the Synthesis of Oxetanes

Article abstract of DOI:10.1021/acs.orglett.0c02316

One of the most efficient ways to synthesize oxetanes is the light-enabled [2 + 2] cycloaddition reaction of carbonyls and alkenes, referred to as the Paternò-Büchi reaction. The reaction conditions for this transformation typically require the use of hig

Full text of DOI:10.1021/acs.orglett.0c02316

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Letter
̀
Visible-Light-Enabled Paterno−Buchi Reaction via Triplet Energy
̈
Transfer for the Synthesis of Oxetanes
Katie A. Rykaczewski and Corinna S. Schindler*
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ABSTRACT: One of the most efficient ways to synthesize oxetanes is the light-enabled [2 + 2] cycloaddition reaction of carbonyls
̀
and alkenes, referred to as the Paterno−Bu
̈
chi reaction. The reaction conditions for this transformation typically require the use of
high energy UV light to excite the carbonyl, limiting the applications, safety, and scalability. We herein report the development of a
̀
visible-light-mediated Paterno−Buchi reaction protocol that relies on triplet energy transfer from an iridium-based photocatalyst to
̈
the carbonyl substrates. This mode of activation is demonstrated for a variety of aryl glyoxylates and negates the need for both
visible-light-absorbing carbonyl starting materials and UV light to enable access to a variety of functionalized oxetanes in up to 99%
yield.
xetanes are four-membered oxygen-containing hetero-
Ocycles that have emerged as important scaffolds in drug
design and development over the past decade. The
incorporation of oxetanes into active pharmaceuticals is
particularly attractive and was shown to have a positive impact
on their physiochemical and biochemical properties.1 Specif-
ically, these four-membered heterocycles profoundly impact
the aqueous solubility, lipophilicity, metabolic stability, and
conformational preference of molecules, lending themselves as
alternative scaffolds for geminal dimethyl substituents or
carbonyl groups.2 Several strategies for the synthesis of
functionalized oxetanes have been advanced including intra-
molecular etherification via nucleophilic substitution (1),3
epoxide ring opening and closing (2),4 ring contraction of
carbohydrates (3),5 and electrophilic halocyclization of
alcohols (4)6 (Figure 1A). Arguably, while each of these
methods offer unique benefits to oxetane synthesis, the direct
light-induced [2 + 2] cycloaddition between carbonyls and
alkenes (5) represents a highly efficient method and the most
direct approach toward these heterocycles. These [2 + 2]
̀
cycloadditions are referred to as Paterno−Buchi reactions and
̈
allow for a variety of substitution about the heterocycle and a
convergent synthesis, while requiring minimal prefunctionali-
zation.7
Figure 1. (A) Select strategies to access oxetanes. (B) Traditional
̀
Paterno−Buchi reaction design. (C) Proposed energy transfer
̈
mechanism for excitation of carbonyls.
̀
Traditionally, the Paterno−Buchi reaction proceeds via an
̈
excitation of the carbonyl moiety (6) under UV light
irradiation (7), which then engages from either the singlet or
triplet excited state with an alkene (8) to form an oxetane (9)
Received: July 11, 2020
̀
(Figure 1B). Recent advances in Paterno−Buchi reactions have
̈
lent themselves to the synthesis of new and structurally
complex oxetanes, but still require the use of high-energy UV
https://dx.doi.org/10.1021/acs.orglett.0c02316
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© XXXX American Chemical Society
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Letter
light.7 This prerequisite for UV light is often associated with
challenges in the scalability of these transformations and
significant safety concerns due to possible UV radiation
exposure. Despite these drawbacks, complementary visible-
light-induced processes are significantly less advanced,
although the milder reaction conditions are expected to
significantly increase the functional group tolerance, scalability,
̀
and safety of these Paterno−Buchi reactions. Importantly, two
̈
successful examples of these [2 + 2] cycloadditions relying on
visible light irradiation have recently been reported by the
groups of Dell’Amico and Ouyang.8,9
Although an important advancement, these reactions are
inherently limited to starting materials that exhibit the required
photophysical features for direct excitation (Figure 1B). We
envisioned that a potentially more general synthetic approach
Figure 2. Evaluation of photocatalysts in visible-light-enabled
̀
Paterno−Buchi reactions. Reactions were performed with 12 (0.05
̈
mmol), alkene 13 (10 equiv), and photocatalyst (2.5 mol %) in
MeCN (0.1 M) under blue LED irradiation (465 nm) at ambient
temperature (fan cooling) for 0.5 h. aYield determined by quantitative
1H NMR analysis from the crude mixture using an internal standard.
̀
to visible-light-enabled Paterno−Buchi reactions could rely on
̈
utilizing a photocatalyst (10) to be the primary excited state
species in solution to ultimately generate the desired excited
state carbonyl (7) via triplet energy transfer (Figure 1C). In
related efforts, our lab has recently demonstrated that triplet
energy transfer can efficiently activate functionalized imines to
enable the synthesis of similarly strained four-membered
loading, and alkene equivalents (see Supporting Information
for additional details). The reaction was determined to
proceed in good yields of up to 75% relying on 1,2-
dichloroethane, methylene chloride, acetone, toluene, ethyl
acetate, methanol, and acetonitrile as reaction solvent. Catalyst
loadings as low as 0.5 mol % of 15 and equimolar amounts of
alkene 13 proved to be sufficient in forming oxetane 14 in up
to 70% yield.
̀
nitrogen-containing heterocycles in aza Paterno−Buchi re-
̈
actions.10 This transformation relies on a visible-light-
absorbing iridium photocatalyst to access the corresponding
excited state of the substrate via triplet energy transfer. We
envisioned a similar design principle to be applicable to
̀
carbonyl activation in a visible-light enabled Paterno−Buchi
̈
Next, we set out to investigate the scope of this visible-light-
reaction protocol.11 In this reaction platform, the photocatalyst
(10) is expected to absorb visible light, resulting in population
of the triplet excited state (11), followed by subsequent energy
transfer to the carbonyl (6), producing the reactive triplet
̀
enabled Paterno−Buchi reaction (Figure 3). Specifically, a
̈
variety of aryl glyoxylates and different alkene reaction partners
were investigated upon their ability to undergo the desired
transformation. Methyl, ethyl, adamantyl, and tert-butyl esters
all provided good to excellent yields of oxetanes 16−19 of up
to 99%. Interestingly, direct irradiation of ethyl benzoylformate
without photocatalyst or alkene showed complete decom-
position. We were pleased to see that, under our standard
conditions, rapid conversion to oxetane 17 was observed (see
Supporting Information for details). Additionally, both
electron-donating and -withdrawing groups on the aromatic
ring resulted in the formation of the desired oxetane products.
The anisole derivative 21 was obtained in 72% yield, while the
electron-withdrawing para-nitrile provided oxetane 20 in 66%
yield. Interestingly, an additional ester present on the aromatic
ring was tolerated under the optimal reaction conditions as
shown in the formation of oxetane 22 in 91% yield.
Furthermore, the para-bromo aromatic glyoxylate was
evaluated and proceeded in 77% yield to result in oxetane
23. Further efforts centered on the investigation of alkene
reaction partners showed that di-, tri-, and tetrasubstituted
alkenes undergo the desired transformation providing oxetanes
14 and 24−28 in yields ranging from 46% to 83%. Specifically,
cyclohexene as an alkene partner successfully formed the
bicyclic oxetane 25 in a good yield of 65%. Moreover, aromatic
alkenes like benzofuran and furan gave the cycloadducts 26
and 27 in 64% and 46% yield, respectively. Additionally, an
acyclic vinyl ether was able to provide oxetane 28 in 68% yield.
Mechanistic investigations were subsequently initiated to
gain additional insights into the controlling features of this
̀
energy state (7) allowing for efficient Paterno−Buchi reactions
̈
(Figure 1C). Importantly, this mode of activation negates the
need for visible-light-absorbing carbonyls, instead requiring
that their triplet energy (ET) lies close enough to that of the
photocatalyst. Based on their low triplet energy (approximately
60 kcal mol−1), we hypothesized that glyoxylate derivatives
could be a good starting point for the development of a visible-
̀
light-enabled Paterno−Buchi reaction relying on triplet energy
̈
transfer.12
Our initial investigations into the development of a mild
̀
protocol for visible-light-enabled Paterno−Buchi reactions was
̈
focused on methyl benzoylformate (12), due to its superior
stability compared to other glyoxylate substrates. Specifically,
Norrish type II reactivity is a known competing reaction path
for glyoxylate substrates under irradiation with UV light (see
Supporting Information for details).13 When glyoxylate 12 and
alkene 13 were converted with catalytic amounts of [Ir(dF-
(Me)ppy)2(dtbbpy)]PF6 upon irradiation with 456 nm light in
acetonitrile for 0.5 h, the formation of oxetane 14 was observed
in 72% yield (entry 1, Figure 2). A selection of photocatalysts
varying in their triplet energies was subsequently evaluated
(entries 2−6, Figure 2). Ultimately, photocatalyst 15 was
identified as optimal due to its established reactivity and high
yield of oxetane 14 (entry 2, Figure 2), while photocatalysts of
similar triplet energies compared to 15 were found equally
sufficient in catalyzing the transformation. Importantly,
catalysts of lower triplet energy failed to provide the desired
oxetane product 14, which is consistent with a reaction
mechanism relying on an energy transfer mechanism (entries
4−6, Figure 2). Subsequent efforts focused on additional
reaction optimization, including varying the solvent, catalyst
̀
visible-light-enabled Paterno−Buchi reaction. Specifically, we
were interested in investigating the difference between a
possible direct excitation of the carbonyl and our proposed
triplet energy transfer process. When glyoxylate 12 and alkene
13 were irradiated with UV-A light, the formation of oxetane
̈
B
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Letter
was observed within 0.5 h of irradiation (entry 2, Figure 4).
After 16 h at 456 nm, a 25% yield of oxetane 14 was observed
(entry 3, Figure 4). Upon heating 12 and 13, without
photocatalyst and light no reactivity was observed (entry 5,
Figure 4). These results suggest that the reactivity observed
under our optimal reaction conditions (entry 4, Figure 4) does
not stem from direct excitation of the carbonyl, and instead
indicate that the photocatalyst has a significant impact on the
reactivity by greatly accelerating the desired transformation.
Demonstration of this reactivity suggests that other carbonyls
which do not absorb visible light will be able to be sensitized
with visible light in combination with a suitable photocatalyst,
given that the triplet energy is low enough for an energetically
favorable energy transfer process. Furthermore, a Stern−
Volmer quenching study was completed which showed a
quenching interaction between glyoxylate 12 and photocatalyst
(15) (see Supporting Information for details). We postulate
that a photoredox process is unlikely under the optimized
reaction conditions, as the excited state redox potentials of 15
(IrIII*/II = +1.21 V versus SCE; Ir IV/III* = −0.89 V versus
SCE) are not expected to be sufficient for an effective
oxidation or reduction of glyoxylate 12 (Ered = −1.16 V versus
SCE; Ered = −1.75 V versus SCE; see Supporting Information
for additional details).14
Based on these combined results, we propose a triplet energy
transfer mechanism to be operative under our optimal reaction
̀
conditions for Paterno−Buchi reactions in which the carbonyl
̈
triplet state (312*) is accessible via energy transfer from an
excited state photocatalyst (Figure 5). The observed
regioselectivity indicates the C−O bond formation occurs
first to give the stabilized biradical, which can then recombine
to form the oxetane product 14.
Figure 3. Evaluation of the substrate scope of visible-light-enabled
̀
Paterno−Buchi reactions. Reactions were performed with glyoxylate
̈
substrate (0.1 mmol), alkene (1.5 equiv), and 15 (1.0 mol %) in
MeCN (0.1 M) under blue LED irradiation (456 nm) at ambient
temperature (fan cooling) for 0.5−1 h; diastereomer ratios (d.r.) and
1
regioisomer ratios (r.r.) were determined by H NMR analysis of the
crude reaction mixture; isolated yields provided.
14 was observed in 25% yield after 0.5 h (entry 1, Figure 4).
We also tried directly irradiating the glyoxylate substrate 12
with visible light; however, at 456 nm, no product formation
Figure 5. Proposed triplet energy transfer mechanism for the
synthesis of oxetane 14.
We herein report the development of a visible-light-
̀
mediated Paterno−Buchi reaction between carbonyls and
̈
alkenes relying on triplet energy transfer. Importantly, the
reaction is greatly accelerated in the presence of a suitable
photocatalyst and demonstrates the capability of visible-light-
absorbing photocatalysts to efficiently transfer energy to
carbonyls. This reaction platform further expands the toolbox
for medicinal chemists interested in modulating drug proper-
ties through the incorporation of functionalized oxetanes, as
this method negates the need for UV light and proceeds
rapidly under the optimized reaction conditions.
Figure 4. Mechanistic control experiments of visible-light-enabled
̀
Paterno−Buchi reactions. Reactions were performed with 12 (0.05
̈
mmol), alkene 13 (10 equiv), and if indicated photocatalyst (2.5 mol
%) in MeCN (0.1 M) under blue LED (465 nm) or UV-A (365 nm)
a
irradiation at ambient temperature (fan cooling) for 0.5−16 h. Yield
determined by quantitative 1H NMR analysis from the crude mixture
using an internal standard.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02316.
■
sı
̀
̀
(7) Paterno−Buchi: (a) Paterno, E.; Chieffi, G. Synthesis in Organic
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Chemistry Using Light. Note II. Compounds of Unsaturated
Hydrocarbons with Aldehydes and Ketones. Gazz. Chim. Ital. 1909,
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39, 341. (b) Buchi, G.; Inman, C. G.; Lipinsky, E. S. Light-Catalyzed
Experimental details and spectroscopic data for all new
reactants and products (PDF)
Organic Reactions. I. The Reaction of Carbonyl Compounds with 2-
methyl-2-butene in the Presence of Ultraviolet Light. J. Am. Chem.
Soc. 1954, 76, 4327. (c) Bach, T. Stereoselective Intermolecular [2 +
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(e) D’Auria, M.; Racioppi, R. Oxetane Synthesis Through the
AUTHOR INFORMATION
Corresponding Author
■
Corinna S. Schindler − Department of Chemistry, Willard
Henry Dow Laboratory, University of Michigan, Ann Arbor,
Michigan 48109, United States; orcid.org/0000-0003-
4968-8013; Email: corinnas@umich.edu
̀
Paterno-Bu
(8) Mateos, J.; Vega-Pen
̈
chi Reaction. Molecules 2013, 18, 11384−11428.
̃
aloza, A.; Franceschi, P.; Rigodanza, F.;
́
Andreetta, P.; Companyo, X.; Pelosi, G.; Bonchio, M.; Dell’Amico, L.
̈
A Visible-Light Paterno-Buchi Dearomatisation Process Towards the
Construction of Oxeto-Indolic Polycycles. Chem. Sci. 2020, 11, 6532−
Author
̀
Katie A. Rykaczewski − Department of Chemistry, Willard
Henry Dow Laboratory, University of Michigan, Ann Arbor,
Michigan 48109, United States
6538.
(9) Li, H. F.; Cao, W.; Ma, X.; Xie, X.; Xia, Y.; Ouyang, Z. Visible-
Light-Driven [2 + 2] Photocycloadditions between Benzophenone
and CC Bonds in Unsaturated Lipids. J. Am. Chem. Soc. 2020, 142,
3499−3505.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02316
(10) (a) Becker, M. R.; Richardson, A. D.; Schindler, C. S.
Notes
̀
Functionalized Azetidines Via Visible Light-Enabled Aza Paterno-
The authors declare no competing financial interest.
Buchi Reactions. Nat. Commun. 2019, 10, 5095. (b) Becker, M. R.;
̈
Wearing, E. R.; Schindler, C. S. Synthesis of Azetidines via Visible
Light-Mediated Intermolecular [2 + 2] Photocycloaddition. ChemRxiv
2020, DOI: 10.26434/chemrxiv.11832993.v1.
ACKNOWLEDGMENTS
■
We thank the University of Michigan Office of Research and
the NIH/National Institute of General Medical Sciences (R01-
GM118644) for financial support. C.S.S. thanks the David and
Lucile Packard Foundation, the Alfred P. Sloan Foundation,
and the Camille and Henry Dreyfus Foundation. K.A.R. thanks
the National Science Foundation for a Graduate Research
Fellowship.
(11) Previously published preprint: Rykaczewski, K. A.; Schindler, C.
̀
S. Visible Light-Enabled Paterno−Buchi Reaction via Triplet Energy
̈
Transfer for the Synthesis of Oxetanes. ChemRxiv. Preprint. 2020,
DOI: 10.26434/chemrxiv.12606377.v2.
(12) Herkstroeter, W. G.; Lamola, A. A.; Hammond, G. S.
Mechanisms of Photochemical Reactions in Solution. XXVIII. Values
of Triplet Excitation Energies of Selected Sensitizers. J. Am. Chem. Soc.
1964, 86, 4537−4540.
(13) (a) Hu, S.; Neckers, D. C. Rapid Regio- and Diastereoselective
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