Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes

Article abstract of DOI:10.1021/jacs.1c01173

This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn- or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.

Full text of DOI:10.1021/jacs.1c01173

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Article
Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-
Light Triplet Photosensitization: Expedient Access to
Polysubstituted 2‑Oxaspiro[3.3]heptanes
Philip R. D. Murray,§ Willem M. M. Bussink,§ Geraint H. M. Davies, Farid W. van der Mei,
Alyssa H. Antropow, Jacob T. Edwards, Laura Akullian D’Agostino, J. Michael Ellis,
Lawrence G. Hamann, Fedor Romanov-Michailidis,* and Robert R. Knowles*
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ABSTRACT: This paper describes an intermolecular cross-
selective [2 + 2] photocycloaddition reaction of exocyclic arylidene
oxetanes, azetidines, and cyclobutanes with simple electron-
deficient alkenes. The reaction takes place under mild conditions
using a commercially available Ir(III) photosensitizer upon blue
light irradiation. This transformation provides access to a range of
polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane,
and spiro[3.3]heptane motifs, which are of prime interest in
medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A
variety of further transformations of the initial cycloadducts are
demonstrated to highlight the versatility of the products and enable
selective access to either of a syn- or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively.
Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.
by the current rarity of synthetic methods.9 The synthesis of
compounds containing oxaspiro[3.3]heptanes generally stems
from stoichiometric reactions utilizing two building blocks:
INTRODUCTION
■
Oxetanes are proven isosteres for a variety of functional groups
in drug discovery, including gem-dimethyl groups and carbonyl
compounds (Figure 1A).1−3 Gem-dimethyl groups are widely
3,3-bis(bromomethyl)oxetane or 2-oxaspiro[3.3]heptan-6-
one.10 Indeed, all three of the biologically active compounds
used in medicinal chemistry for their ability to increase
in Figure 1B are synthesized using the latter ketone starting
material. This typically limits substitution on oxaspiro[3.3]-
heptanes to the 5- and 6-position, and the substituent is
generally a heteroatom. Thus, rapidly generating oxaspiro[3.3]-
heptanes with carbon substituents at multiple positions
remains a challenge. For example, accessing the TDO2
inhibitor (Figure 1B) requires a four-step synthetic
sequence.8,11 To date, there have been no catalytic methods
described which can synthesize 2-oxaspiro[3.3]heptanes from
simple components.12 Therefore, a general method that could
afford functionalized oxaspiro[3.3]heptanes from readily
available substrates and in a modular fashion is of interest to
the synthetic and pharmaceutical communities.
potency, improve metabolic stability, and introduce conforma-
tional restriction through the Thorpe-Ingold effect.4 However,
due to the lipophilicity of alkyl groups, their incorporation can
often be accompanied by a reduction in aqueous solubility.
The replacement of gem-dimethyl groups with oxetanes
maintains these desirable characteristics while improving the
solubility of the drug molecule (Figure 1A).4 In a similar
fashion, oxetanes have found use as replacements for the
carbonyl groups of amides, esters, and ketones in drug
development. Oxetanes can mimic potential hydrogen-bonding
interactions of carbonyl compounds while not being as
susceptible to the enzymatic activity of hydrolases and
reductases, thus improving the metabolic stability of drug
leads.1
Oxaspiro[3.3]heptanes, where an oxetane is incorporated
into a spirocyclic scaffold, are unique heterocycles which can
impart potential therapeutic agents with a variety of desirable
properties.5 Several groups have successfully leveraged the
potential of these heterocycles for their pharmaceutical
candidates (Figure 1B).6−8 Expansive efforts to incorporate
these spirocycles into candidate molecules however are limited
Received: January 30, 2021
Published: March 5, 2021
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Scheme 1. (A) Historical Survey of Photosensitized [2 + 2]
Cycloaddition Reactions, and (B) This Work
Figure 1. Oxetane and 2-oxaspiro[3.3]heptane motifs in drug-
discovery.
A novel and step-economical disconnection to the
oxaspiro[3.3]heptane skeleton could involve one of several
possible photochemical [2 + 2] cycloaddition reactions,
constructing either the oxetane or cyclobutane ring.13 The
earliest examples of these photochemical processes described
sunlight-mediated [2 + 2] photodimerization reactions, with
the first report published by Liebermann in 1877, concerning
the dimerization of thymoquinone in the solid state.14,15 These
early examples proceed through direct irradiation of the
organic substrate to form the lowest-energy triplet state (T1)
via excitation to the first singlet excited state (S1) and
subsequent intersystem crossing (ISC). Indirect population of
the triplet state of the organic substrate is also possible through
an energy transfer process from another photoexcited
molecule.16 This process of sensitization expands the range
of organic substrates amenable to [2 + 2] photocycloaddition,
and the range of wavelengths of light able to drive the process
(Scheme 1A). An early example of a sensitized reaction was
reported by Schenck and co-workers in 1963, demonstrating
that in the presence of benzophenone under UV irradiation, an
intermolecular, crossed [2 + 2] cycloaddition occurs between
thiophene and 3,4-dimethylfuran-2,5-dione.17
Bu
intermolecular visible light photosensitized aza-Paterno-Bu
̈
chi reactions.26,27 Schindler has also described intra- and
̀
̈
chi
reactions between oxime ethers and alkenes for the synthesis of
azetidines.28−30
The development of cross-selective intermolecular [2 + 2]
cycloaddition reactions remains a challenge, with recent work
largely focused on intramolecular variants. For example, in
1999, the Bach group reported a diastereoselective [2 + 2]
cycloaddition of a chiral vinylglycine-derived N-cinnamyl-N-
allyl carbamate using acetophenone as a sensitizer under UV
irradiation.18,19 The Yoon group made significant improve-
ments to a similar photosensitized cycloaddition in 2012 by
utilizing an Ir(III) dye as a triplet photosensitizer.20 This
enabled the reaction to proceed under visible-light irradiation
rather than the highly ionizing UV radiation utilized in
previous methods. Since then, the Yoon group has developed a
suite of catalytic and enantioselective intermolecular crossed [2
+ 2] cycloadditions of cinnamic acid derivatives with 1,3-
dienes and styrenes.21−23 Oderinde, Dhar, and co-workers have
recently demonstrated sensitized intra- and intermolecular
dearomative [2 + 2] cycloaddition reactions of N-acyl
(aza)indoles to yield bicyclo-fused (aza)indoline products.24,25
Very recently, the Schindler and Yoon groups both reported
visible light photosensitized [2 + 2] cycloaddition reactions of
α-keto esters and alkenes for the synthesis of oxetanes in a
State-of-the-art intermolecular crossed [2 + 2] cyclo-
additions are currently limited to these classes of substrates.
In this paper, we detail the discovery and development of an
intermolecular, cross-selective [2 + 2] cycloaddition reaction
between arylidene oxetanes (1) and simple electron deficient
olefins (2) catalyzed by an Ir(III) complex upon blue light
irradiation (Scheme 1B). Notably, the reaction generates
valuable 5,6-disubstituted 2-oxaspiro[3.3]heptanes (3) from
these readily available starting materials. In addition, we
demonstrate the facile derivatization of these cycloadducts to
accomplish broad structural diversification. We note here that
these and related exocyclic benzylidene substrates have
recently been investigated in the context of copper-catalyzed
olefin hydroboration by Engle, Liu, and McAlpine,31,32 and
electrochemical olefin hydrocarboxylation by Malkov and
Buckley.33
RESULTS AND DISCUSSION
■
Our studies in this area began through investigation of
benzylidene oxetane 1a toward visible-light mediated olefin
hydroamination with secondary alkyl amines, under our
̀
notable extension to traditional UV-light mediated Paterno-
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previously described conditions (Scheme 2).34 In the presence
of [Ir(dF(Me)ppy)2(dtbpy)]PF6 ([Ir-1]PF6, where dF(Me)-
ppy = 2-(2,4-difluorophenyl)-5-methylpyridine and dtbpy =
4,4′-di-tert-butyl-2,2′-bipyridine) photocatalyst and 2,4,6-trii-
sopropylbenzenethiol (TRIP thiol) HAT cocatalyst, these
substrates gave very low yields of the desired tertiary amine
products (e.g., 4, 10% NMR yield). We reasoned that this poor
efficiency may be due to competing triplet sensitization of the
styrene substrate through energy transfer, as opposed to the
intended redox pathway to generate an aminium radical cation
intermediate.35 To probe this hypothesis, we substituted the
amine partner for methyl vinyl ketone (MVK, 2a) and
fortuitously observed formation of the corresponding [2 + 2]
cycloadducts 3a as an equal mixture of diastereoisomers in
27% yield by 1H NMR (Scheme 2). Encouraged by this
surprising result, we began to further explore this visible-light
mediated [2 + 2] photocycloaddition reaction.
Table 1. Reaction Optimization
We examined the [2 + 2] photocycloaddition of 4-
ox
chlorobenzylidene oxetane (1b, Ep/2 = +1.33 V vs Fc+/Fc
in MeCN, ET (calc.) = 56.9 kcal/mol, UB3LYP/6-311++G(d,p)
CPCM = MeCN) with methyl vinyl ketone (2a) as a model
system (Table 1). With 3.0 equiv of acceptor olefin 2a relative
to styrene coupling partner 1b in PhMe solution under blue
light irradiation, [Ir(dF(Me)ppy)2(dtbpy)]PF6 ([Ir-1]PF6, ET
= 60.2 kcal/mol)29 catalyzed the formation of the desired 2-
oxaspiro[3.3]heptane 3b in 25% NMR yield and 1:1 d.r. (entry
1). MeCN proved to be a more suitable solvent for this
process, and the same photocatalyst under otherwise identical
conditions gave 3b in 70% NMR yield in 1.6:1 d.r. (entry 2).
Attempting to improve the reaction efficiency, we studied
photocatalyst selection. We anticipated that a key determinant
in the success of this transformation would be the triplet
energy (ET) of the photocatalyst relative to that of substrate
1b. Other heteroleptic Ir(III) dyes also proved highly efficient.
One of the most commonly employed Ir(III) dyes, [Ir(dF-
(CF3)ppy)2(dtbpy)]PF6 ([Ir-2]PF6, ET = 60.1 kcal/mol,36
where dF(CF3 )ppy
= 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine), gave product 3b in an improved
80% NMR yield and 1.5:1 d.r. (entry 3). [Ir(dF(CF3)-
ppy)2(bpy)]PF6 ([Ir-3]PF6, ET = 60.4 kcal/mol)36 was also
highly efficient at promoting the [2 + 2] photocycloaddition,
giving 85% NMR yield and 1.4:1 d.r. (entry 4). A related
photocatalyst bearing electron-withdrawing − CF3 substituents
on the bipyridine ligand, [Ir(dF(CF3)ppy)2(4,4′-d(CF3)bpy)]-
PF6 ([Ir-4]PF6, ET = 56.2 kcal/mol),37 was less efficient (13%
NMR yield, 1.7:1 d.r., entry 5), which is consistent with its
lower triplet energy. A homoleptic Ir(III) complex, Ir(dFppy)3
([Ir-5], ET = 60.1 kcal/mol,36 where dFppy = 2-(2,4-
difluorophenyl)pyridine), despite having sufficiently high
triplet energy to sensitize styrene 1b, catalyzed the formation
of the desired 2-oxaspiro[3.3]heptane 3b in only 21% NMR
yield and 1.5:1 d.r. (entry 6). On the other hand, the neutral
a
1
Determined by H NMR analysis of crude reaction mixtures using
b
1,2-dibromoethane as internal standard. Inverse diastereoisomer
ratio observed. Carried out at 0.1 M and 2.5 mol % catalyst loading.
c
Ir(III) complex [Ir(dF(CF3)ppy)2(pic)] ([Ir-6], ET = 61.1
kcal/mol,38 where pic = 2-picolinate) displayed high reaction
efficiency (82% NMR yield, 1.5:1 d.r., entry 7). Experiments
using a cationic Ru photocatalyst with lower triplet energy,
[Ru(bpy)3](PF6)2 ([Ru-1](PF6)2, ET = 48.9 kcal/mol,39 where
bpy = 2,2′-bipyridine), led to only trace observable product 3b
(entry 8).
Further improvements were made from an examination of
the reaction solvent (Table 1). For example, when performing
the [2 + 2] cycloaddition with photocatalyst [Ir-2]PF6 in
DMF, a more polar solvent than MeCN, a slight increase from
80% to 87% NMR yield was observed (compare entries 3 and
9). An inversion of the major diastereomer and reduction in
reaction efficiency is seen when moving to the less polar
solvent DCE (entry 11). Best results were obtained when
photocatalyst [Ir-3]PF6 or [Ir-6] were used in t-BuCN solvent
(94% and 92% NMR yields, entries 13 and 14). Furthermore,
Scheme 2. Reaction Discovery
a
1
Determined by H NMR analysis of crude reaction mixture using
dimethyl terephthalate as internal standard.
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a
the reaction works equally well when carried out at a higher
concentration (0.1 M) and with reduced catalyst loading (2.5
mol %). Control experiments revealed the requirement for
both photocatalyst and visible light irradiation (entries 15 and
16). Data from additional optimization experiments are
presented in the Supporting Information (Tables S1, S2).40
Importantly, in its photoexcited state, [Ir-6] dye is less
oxidizing (E1/2 Ir(III)*/Ir(II) = +0.89 V vs Fc+/Fc in
MeCN)41 than cationic [Ir-3]PF6 (E1/2 Ir(III)*/Ir(II) =
+0.94 V vs Fc+/Fc);42 thus, [Ir-6] is expected to be more
chemoselective in general for an energy transfer process and
was chosen for further investigation of substrate scope.
Having established the optimal reaction conditions, we next
examined the scope of this visible-light promoted [2 + 2]
cycloaddition. We were pleased to find that a wide array of
substituted benzylidene oxetanes 1 participated in the reaction
to give 2-oxaspiro[3.3]heptane products 3 in high yields (65−
89%, Scheme 3A). Substituents at the para (3b-3i), meta (3j
and 3k), and ortho (3l) positions on the phenyl ring are well
tolerated. In addition, these substituents can be either electron-
withdrawing, such as −Cl, −F, −CF3, and −CN (3b, 3c, 3f,
and 3h), or electron-donating, such as −Me, −OMe, and
−SiMe3 (3d, 3e, and 3i).
Scheme 3. Arylidene Scope
As shown in Scheme 3B,C, this [2 + 2] protocol is highly
tolerant of a wide range of heteroaromatic substrates. 2-
Oxaspiro[3.3]heptanes appended to thiophene (3n), furan
(3o), imidazole (3p), pyrazole (3q), indole (3r), indazole
(3s), benzoxazole (3t), and isoquinoline (3u) rings can all be
efficiently synthesized (82−88% isolated yields). Given the
prevalence of heteroaromatic rings in pharmaceuticals,43−45 we
are hopeful that this cycloaddition methodology will find utility
in drug discovery efforts.
Furthermore, as shown in Scheme 3D, the [2 + 2] reaction
is not limited to oxetane substrates but also works well with
other exocyclic benzylidene 4-membered ring substrates, such
as N-Boc azetidines (3v and 3w, 90% and 82% yield) and
cyclobutanes (3x and y, 78% and 82% yield). Indeed, the
obtained substituted 2-azaspiro[3.3]heptane and spiro[3.3]-
heptane ring systems are important building blocks for
pharmaceutical development and are otherwise difficult to
synthesize by conventional methods.9,46
With respect to the alkene coupling partner 2, various acrylic
acid derivatives behave well, affording the anticipated 2-
oxaspiro[3.3]heptane cycloadducts in good yields (64−90%,
Scheme 4). Notably, electron-withdrawing groups such as ester
(3zf and 3aa), amide (3ab and 3ac), Weinreb amide (3ad),
nitrile (3ae), unprotected carboxylic acid (3af), sulfone (3ag),
and Bpin (pin = pinacolato) (3ej) are all are tolerated in the [2
+ 2] photocycloaddition process.
Importantly, this protocol also works well with more densely
substituted alkenes (Scheme 4). For example, α-methyl
substituted acrylate and vinyl-Bpin substrates are converted
to 2-oxaspiro[3.3]heptane products with a tetrasubstituted
carbon atom in high yields (90% 3ah, and 88% 3ak).
Additionally, N-methyl maleimide is highly reactive toward
[2 + 2] cycloaddition and affords the intriguing tricyclic
product 3ai in 86% combined yield of both diastereomers. A
more exhaustive list of obtainable 2-oxaspiro[3.3]heptane
products (>60 examples) is compiled in the Supporting
Information (Figure S3).40
a
Conditions: 1 (1.0 equiv), 2 (3.0 equiv), [Ir-6] (2.5 mol %) in t-
BuCN (0.1 M).
column chromatography and isolated in high yields.
Furthermore, diastereomeric ratios can be greatly improved
by subjecting crude cycloadducts to base-catalyzed epimeriza-
tion (Scheme 5A,B). The major diastereomer was assigned as
1
syn by comparison of H NMR spectra of product 3x to those
of a reported compound with known stereochemistry,46 and
this assignment was extended by analogy across the scope of
the transformation.
Across all substrates, diastereoselectivity remains moderate
(up to 2.0:1 d.r.) but, in favorable cases, the two
diastereomeric products can be readily separable by silica gel
Of particular significance is the synthetic versatility of the
substituted 2-oxaspiro[3.3]heptane cycloadducts. Therefore,
we investigated a range of derivatization reactions that convert
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a
a
Scheme 4. Electron Deficient Alkene Scope
Scheme 5. Synthetic Derivatization of Products
a
Conditions: 1 (1.0 equiv), 2 (3.0 equiv), [Ir-6] (2.5 mol %) in t-
BuCN (0.1 M).
these primary products into value-added fragments (Scheme
5). Given that a limitation of the above photocycloaddition is
the low to moderate diastereoselectivity observed, we sought
to investigate the epimerization of the carbonyl substituent.
Products such as 3n that contain a methyl ketone functional
group are readily epimerized postreaction by simply stirring the
crude mixture with catalytic 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) (Scheme 5A). This one-pot procedure gives highly
diastereomerically enriched anti-stereoisomers (>12:1 d.r.) and
is applicable to a broad range of methyl ketone-bearing
products (see the Supporting Information for more exam-
ples).40 Epimerized product anti-3n can be subjected to
subsequent reactions such as the Wittig olefination to yield 5a
without erosion of the anti-stereochemistry (Scheme 5A).
The stronger base t-BuOK is required to epimerize ester-
containing products such as 3k (Scheme 5B). In addition to
“thermodynamic” epimerization that affords the anti-stereo-
isomer, these products are readily converted to the opposite
syn-stereoisomer via “kinetic” epimerization with lithium
diisopropylamide (LDA) at low temperature, followed by
protonation with pivalic acid (PivOH). This ability to
selectively access both diastereomers of product 3k compen-
sates for the low diastereoselectivity in the [2 + 2]
cycloaddition step and showcases the synthetic value of the
method.
In addition, pharmaceutically relevant cyclobutylamines are
easily accessed from [2 + 2] cycloaddition products by Curtius
rearrangement (Scheme 5C). For example, the ester moiety of
2-oxaspiro[3.3]heptane 3z is first hydrolyzed with potassium
trimethylsilanoate (KOTMS) (5b), followed by conversion to
the acyl azide and Curtius rearrangement to the desired N-Cbz
cyclobutylamine 5c in 64% yield over the two steps.
Importantly, the initial ester hydrolysis takes place with
concomitant anti-epimerization, while the subsequent Curtius
rearrangement is stereospecific. The net result is thus a
a
A diastereomeric ratio >12:1 d.r. refers to the limit of detection of
the NMR instrument.
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Table 2. Collected Voltammetric, Computational, and Spectroscopic Results
a
b
Conditions: Styrene (1.0 equiv), 2a (3.0 equiv), [Ir-6] (2.5 mol %) in t-BuCN (0.1 M), blue LED irradiation, 40 °C, 20 h. UB3LYP/6-311+
c
+G(d,p), CPCM MeCN. Nonlinear quenching observed at high sample concentration. Linear fit made at low sample concentration to determine
KSV. See Supporting Information and ref 53.
stereoconvergent process where the starting syn/anti-3z 1.4:1
mixture is converted to highly enriched anti-cyclobutylamine
product 5c.
The furan ring of cycloadduct 3o is oxidatively cleaved in
78% yield under mild conditions using a recent Ru-catalyzed
protocol from Bull and co-workers (Scheme 5D).47 This
affords a versatile diacylated 2-oxaspiro[3.3]heptane building
block (5d) with two orthogonal functional handlesa free
carboxylic acid and a benzyl esterfor subsequent incorpo-
ration into drug candidates.
Being unstable and prone to polymerization, acrolein is not a
competent substrate for this [2 + 2] photocycloaddition.
However, the readily accessible product 3ad is converted to its
corresponding aldehyde in 76% yield by reduction of the
Weinreb amide moiety (Scheme 5E). Moreover, the product
aldehyde is readily epimerized to its pure anti-stereoisomer
with catalytic DBU to afford 5e.
2-Oxaspiro[3.3]heptane products obtained by [2 + 2]
cycloaddition of vinyl-Bpin are versatile synthetic intermedi-
ates. For example, the Bpin group of 3aj is oxidized in 81%
yield to give a valuable cyclobutanol derivative (5f, Scheme
5F). Alternatively, cycloadduct 3aj is smoothly converted to its
corresponding BF3K salt (5g) by treatment with potassium
hydrogen difluoride. This BF3K salt can then be cross-coupled
to a pyridyl bromide under Molander’s Ni/photoredox
conditions48,49 to give a drug-like 2-oxaspiro[3.3]heptane
derivative in 81% yield (5h, Scheme 5G). Importantly, this
process is stereoconvergent,50 affording highly enriched anti-
product (<1:12 d.r.) starting from a 1.9:1 syn/anti BF3K salt
mixture.
A more complex product containing an all-carbon
quaternary center is derived from cycloadduct 3ak by 1,2-
migration of a boronate complex (Scheme 5H).51 Starting
from the purified diastereomer anti-3ak, the Bpin “ate”
complex is first formed in situ by addition of lithiated furan.
Stereospecific 1,2-migration is then induced by electrophilic
bromination with N-bromosuccinimide (NBS) to give desired
product 5i in 79% yield. Additional synthetic product
derivatizations are compiled in the Supporting Information.40
Excited by the synthetic utility of this methodology, we
sought to study its mechanism through electrochemical and
spectroscopic techniques and density-functional theory (DFT)
calculations. These studies were carried out across a series of
seven styrenes (6−10, 1a, 1v), where the nature of the β,β-
substituents and ring size at the styrene terminus were
systematically varied (Table 2). We were particularly interested
to probe the origin of the superior reactivity of this class of
benzylidene-substituted 4-membered ring substrates toward
intermolecular [2 + 2] photocycloaddition in comparison to
other styrenes in this series and in general (Table 2, line 1).
For example, only trace reactivity was observed between parent
styrene (6) and methyl vinyl ketone (2a) under the optimized
reaction conditions for this photochemical [2 + 2] reaction.
With β,β-dimethylstyrene (7), benzylidene cyclohexane (8),
and benzylidene cyclopentane (9), only low levels of reactivity
were observed (≤28% NMR yields). Only with four-
membered ring benzylidene cyclobutane (10), oxetane (1a),
and azetidine (1v) substrates were highly efficient cyclo-
addition reactions realized (≥83% NMR yields). In all cases,
remaining mass balance was recovered starting material.
Cyclic voltammetry was performed on each of these
substrates to study the feasibility of a redox mechanism for
this transformation (Table 2, line 2). The oxidation potentials
ox
Ep/2 of all seven styrene derivatives in this series are
ox
significantly greater than (ΔEp/2 ≥ 240 mV) that of the
photoexcited state of the [Ir-6] catalyst (E1/2 Ir(III)*/Ir(II) =
+0.88 V vs Fc+/Fc in MeCN).41 Triplet energies of the seven
substrates at the planar 1,2-triplet geometry were computed
(Table 2, line 3, UB3LYP/6-311++G(d,p) CPCM = MeCN).
These show little difference across the series and all fall within
the range 56.7−58.4 kcal/mol, slightly below that of the triplet
energy of the optimal [Ir-6] photocatalyst (ET = 61.1 kcal/
mol).38 These combined data, in addition to the observed
trends in reaction efficiency as a function of the photocatalyst
triplet energy (Table 1), strongly suggest that this [2 + 2]
process proceeds via an energy transfer mechanism as opposed
to an electron transfer pathway.52 We can also rule out a
change in mechanism between sensitization and electron
transfer accounting for the differential reactivity observed
across the series.
Steady-state Stern−Volmer luminescence quenching studies
were performed to study the possibility of a selective
quenching mechanism (Table 2, line 4). All styrene substrates
across this series show efficient quenching of the photoexcited
state of [Ir-6].53 Methyl vinyl ketone (2a) showed very
minimal luminescence quenching (KSV = 0.02 M−1) with [Ir-
6]. This observation is consistent with the triplet energy of
acyclic enones being higher than that of this Ir(III) dye
(typically ≥63 kcal/mol).54,55 These data indicate that the
styrene component of the reaction is selectively sensitized
before reaction with the closed-shell electron-deficient olefin.
Compared to the parent styrene (6, KSV = 1619 M−1), β,β-
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dimethylstyrene (7) and benzylidene cyclohexane (8) quench
the photocatalyst less efficiently (KSV = 664 M−1, and 284 M−1
respectively). This can be understood when considering the
torsional strain across the olefin-arene C−C bond (θcalc. = 38°
and 43°, respectively) twisting the olefin out of conjugation
due to a destabilizing steric interaction between the β-
substituent and the arene. This unfavorable interaction is
alleviated through contraction of the ring size on moving to 5-
and 4-membered rings, and thus more efficient quenching is
seen (KSV = 3423 M−1, 3295 M−1, 3130 M−1, and 2650 M−1
for 9, 10, 1a, and 1v, respectively). Though our studies
indicate that the reactive 4-membered ring substrates are
indeed more efficient quenchers than some poorly reactive
examples, the magnitude of this increase is not sufficient to
account for their privileged reactivity. In addition, benzylidene
cyclopentane (9) quenches this photocatalyst most efficiently
across this series, yet still displays poor reactivity in this
protocol (13% NMR yield with 2a). Thus, a selective
quenching mechanism does not account for the superior
efficiency of these 4-membered ring substrates.
To study whether the [2 + 2] cycloaddition is reversible
under the reaction conditions and if isolated yields are in fact a
reflection of varying photostationary states, we carried out a set
of crossover experiments (Scheme 6). A number of reaction
products of the efficient 4-membered ring substrates and
inefficient benzylidene cyclohexane and dimethylstyrene
substrates were subjected to otherwise standard reaction
conditions in the presence of 10.0 equiv of t-Bu acrylate. In
all cases, no t-Bu ester-containing crossover products were
observed, confirming that the reaction is irreversible from the
closed-shell spiro[3.3]heptanes. Mass recovery was essentially
complete in all cases and diastereoisomeric ratios were
unchanged.
Scheme 7. Proposed Mechanism for the Formation of 2-
Oxaspiro[3.3]heptanes
of the ring size at the styrene terminus, with 4-membered rings
exclusively displaying high reactivity. The collected spectro-
scopic, voltammetric and computational observations to date
(Table 2) do not yet explain the superior reactivity toward
intermolecular [2 + 2] cycloaddition of this substrate class
compared to other styrenes. Neither a selective quenching of
the photoexcited state Ir(III) complex across the series, nor a
change in mechanism between energy and electron transfer, for
example, is operative. The reaction is irreversible from the
closed-shell cyclobutane products, so isolated yields are not a
reflection of any photostationary state. This unusual
observation will be the subject of follow-up theoretical studies
which are beyond the scope of this initial synthetic report.
In summary, we have developed an intermolecular cross-
selective [2 + 2] cycloaddition of exocyclic arylidene oxetanes,
azetidines, and cyclobutanes with electron-deficient alkenes
promoted by visible-light triplet photosensitization. The
described methodology is remarkably general in terms of
scope, and its high synthetic value is showcased by the
synthetic versatility of the obtained cycloadducts. The reaction
reported herein provides expedient access to polysubstituted 2-
oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]-
heptane ring systems which are frequently incorporated into
drug candidates as gem-dimethyl and carbonyl bioisosteres.
Taken together, our studies are supportive of the following
mechanistic picture (Scheme 7). Visible light excitation of the
Ir(III) photocatalyst yields an excited state complex which
sensitizes the benzylidene oxetane substrate (1) through
energy transfer. The resultant 1,2-triplet styrene (3[1]) engages
in intermolecular C−C bond formation with a closed-shell
electron deficient olefin partner (2), yielding a 1,4-triplet
diradical. Intersystem crossing (ISC) then forms a 1,4-singlet
diradical, through which subsequent C−C bond formation
yields the [2 + 2] product 3. Success or failure to yield [2 + 2]
product across a series of seven studied styrenes is a function
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01173.
■
sı
Coordinate files (ZIP)
Reaction Procedures, product characterizations, mecha-
nistic and computational details, and NMR spectra
(PDF)
Scheme 6. Crossover Experiments to Rule Out Reaction
Reversibility
a
AUTHOR INFORMATION
Corresponding Authors
■
Robert R. Knowles − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0003-1044-4900; Email: rknowles@
princeton.edu
Fedor Romanov-Michailidis − Bristol Myers Squibb,
Cambridge, Massachusetts 02140, United States;
orcid.org/0000-0002-0997-478X;
Email: fedorromanov87@gmail.com
Authors
Philip R. D. Murray − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0001-7873-5232
Willem M. M. Bussink − Bristol Myers Squibb, Cambridge,
Massachusetts 02140, United States
a
Conditions: 3 (1.0 equiv), t-Bu acrylate (10.0 equiv), [Ir-6] (2.5 mol
%) in t-BuCN (0.1 M).
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0002-5986-0756
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Farid W. van der Mei − Bristol Myers Squibb, Cambridge,
Massachusetts 02140, United States; orcid.org/0000-
0002-9585-0408
Alyssa H. Antropow − Bristol Myers Squibb, Cambridge,
Massachusetts 02140, United States; orcid.org/0000-
0001-7449-0004
Jacob T. Edwards − Bristol Myers Squibb, San Diego,
California 92121, United States; orcid.org/0000-0002-
7585-2844
Laura Akullian D’Agostino − Bristol Myers Squibb,
Cambridge, Massachusetts 02140, United States;
orcid.org/0000-0002-8218-1428
J. Michael Ellis − Bristol Myers Squibb, Cambridge,
Massachusetts 02140, United States; orcid.org/0000-
0003-4303-3972
Lawrence G. Hamann − Bristol Myers Squibb, Cambridge,
Massachusetts 02140, United States; orcid.org/0000-
0002-8997-7912
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01173
Author Contributions
§These authors contributed equally. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
̈
saureanhydrid an Olefine. Chem. Ber. 1963, 96 (2), 498−508.
ACKNOWLEDGMENTS
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Diallyl Amines. Tetrahedron Lett. 1999, 40 (11), 2103−2104.
■
The authors gratefully acknowledge the Princeton Catalysis
Initiative between Bristol Myers Squibb and Princeton
University for funding this work.
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