Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by Visible Light

Article abstract of DOI:10.1021/acs.orglett.0c02193

Enallenes can be readily converted into two families of 3.2.0 (hetero)bicycles with high diastereoselectivities through the combination of visible light with a suitable Ir(III) complex (1 mol percent). Two complementary pathways, namely, a photocycloaddit

Full text of DOI:10.1021/acs.orglett.0c02193

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Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by
Visible Light
̀
Andrea Serafino, Davide Balestri, Luciano Marchio, Max Malacria, Etienne Derat, and Giovanni Maestri*
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ABSTRACT: Enallenes can be readily converted into two families of
3.2.0 (hetero)bicycles with high diastereoselectivities through the
combination of visible light with a suitable Ir(III) complex (1 mol %).
Two complementary pathways, namely, a photocycloaddition versus a
radical chain, can then take place. Both manifolds grant complete
regiocontrol of the allene difunctionalization. This is accompanied by an
original 1,3-group shift using sulfonyl allenamides that deliver a congested
tetrasubstituted headbridging carbon in the corresponding product.
Scheme 2. Regiocontrol in [2 + 2] Cycloadditions of
Enallenes
he 3.2.0 bicyclic unit is found in a myriad of natural
1
Tproducts and functional bioactive molecules. Several of
these examples feature an alkene motif that suggests sealing the
four-membered ring via an intramolecular [2 + 2] cyclo-
addition from an enallene.2 However, the allene functionaliza-
tion presents regiochemical challenges (Scheme 1). This issue
is shown in the synthesis of Bielschowskysin, in which a
mixture of isomers was observed in the key annulation
promoted by UV-C light.3
Scheme 1. 3.2.0 Unit in Functional Molecules and
Regiochemical Issues in [2 + 2] Photocycloaddition of
Enallenes
Complete regiochemical control has been achieved in a few
cases (Scheme 2). The thermal activation of 1,7-enallenes leads
to the corresponding 4.2.0 bicycles with an endocyclic C−C
double bond.4 However, this approach requires heating to 150
°C. Cationic gold(I) complexes can smoothly activate
analogous substrates at room temperature, leading to 3.2.0
products instead. However, a selective reaction requires that
Received: July 2, 2020
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the gold catalyst could discriminate between the two
cumulated double bonds, limiting the method to trisubstituted
allenes.5
We report here the first general visible-light-promoted
cyclization method using enallenes. This approach uses an
Ir(III) photoactive complex to activate the alkene arm,6
pivoting on the seminal work of Yoon on the activation of
styryl fragments, regardless of their electronic demands,2e via
energy transfer (eT)6a,b to trigger intramolecular [2 + 2]
cycloadditions with a tethered alkene partner. This strategy is
complementary to thermal and organometallic strategies for
the cyclization of enallenes. The present process allows us to
control the functionalization of either the proximal or the distal
position of the allenyl fragment.
The reaction of 1,7-enallenes 1 delivers 3.2.0 bicycles 2,
which have three contiguous stereocenters, with high regio-
and diastereocontrol. A different tether between the two
unsaturated partners reverts the outcome under otherwise
identical conditions. Indeed, the use of 1,6-enallenes 3 leads to
products 4. Furthermore, a formal 1,3-sigmatropic rearrange-
ment of sulfonyl groups occurs,7 creating a sterically congested
quaternary carbon at the headbridge position and an imine
function. This synthetically challenging architecture likely
forms through the propagation of a radical chain, in striking
contrast with the catalytic photocycloaddition that gives
product 2.
We turned our attention to the reactivity of 1,7-enallene 1a
as part of an ongoing interest in the cyclization sequences of
polyunsaturated substrates that allow complete atom econo-
my.8 We found that 1a could smoothly deliver 2a in 82%
isolated yield in the presence of 1 mol % of Ir(III) complex A
(Figure 1) upon a preliminary screening of the reaction
conditions. Reactions were carried out on 0.2 mmol scale
under N2 in degassed dimethylformamide (DMF). The
mixtures were placed in nuclear magnetic resonance (NMR)
tubes, kept at 25 °C without stirring, and irradiated for 16 h
with an light-emitting diode (LED) strip.9 The structure of 2a
was confirmed by X-ray analysis, which confirmed the relative
configuration of the three stereocenters initially assigned by
correlation NMR experiments.
Figure 1. Synthesis of vinylidencyclobutanes 2.
Encouraged by this result, we prepared a library of 1,7-
enallenes through homologation of the corresponding 1,6-
enynes.10 The styryl arm could be decorated by electron-
withdrawing groups, including halides and cyano and
trifluoromethyl groups, and the corresponding products were
retrieved in moderate to good yields (2b−e, 53−67%).
Similarly, the presence of donating substituents was well
tolerated (2f,g, 63 and 80%, respectively), although the
diastereocontrol was lower using reagent 1g (dr = 6:1).
Heteroaromatics could be employed, as witnessed by 2h,
which had a 3-pyridyl group (59%). The presence of an
ethereal tether led to 2j (49%, dr = 9:1). Complete control of
the functionalization of the allene proximal double bond was
observed using a trisubstituted allene (2k, 66%). A
disubstituted one followed suit (2i, 71%), although the
product was retrieved as mixture of E/Z isomers (5:1). The
substrate 1l, which had a styryl arm and a phenylallene arm,
afforded two products. Together with 2l (39%, 1:1 E/Z
mixture), we isolated 2′-l in 35% yield and clarified its
structure by X-ray analysis. It had a 4.2.0 bicyclic unit with
three contiguous stereocenters, and its two phenyl rings were
anti with respect to each other. The structure of 2′-l showed
that difunctionalization of the distal double bond of the allene
might have been possible under the present conditions.
We thus thought to elicit a distal-selective variant of the
reaction by preparing 1,6-enallenes, reasoning that the
formation of a 3.2.0 product 4′ would have been favored
over that of the corresponding 2.2.0 product (4′′, Figure 2).
Substrates were synthesized by isomerization of the corre-
sponding 1,6-enynes. Gratifyingly, the reaction of 3a indeed
gave a 3.2.0 bicycle. However, crystallization and subsequent
X-ray analysis revealed that its structure was different from the
expected one, namely, 4′. Surprisingly, sulfonamide activation
and formal 1,3-sigmatropic rearrangement of the sulfonyl
group took place,7 eventually delivering bicyclic imine 4a
(59%) as a single diastereoisomer. To the best of our
knowledge, this reactivity has not been previously reported
in sequences promoted by visible light.11 We therefore tested
its generality.
The method could be extended to different styryl partners,
delivering the corresponding products 4b−e in moderate to
good yields. Electron-rich aromatics, both ortho- and para-
B
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Scheme 3. Double Tagging Experiment
Figure 2. Synthesis of 3.2.0 heterobicycles 4.
substituted (4b,c, 53−58%), performed better than those with
withdrawing groups (4d,e, 31−38%). The tosyl group could be
replaced by a mesyl group (4f,g, 49−55%). Similarly, various
arylsulfonyl groups were employed (4h−l), including bulky
mesitylene and naphthalene units. The variation was well
tolerated by the reaction (46−68%), with the partial exception
of the nosyl derivative, which gave the corresponding product
in 27% yield. A longer tether enabled us to access a
tetrahydropyridine unit, albeit with a moderate yield (4m,
26%).
We then tried to prove whether the sulfonyl fragmentation/
recombination occurred through either a uni- or a multi-
molecular pathway. A 1:1 mixture of enallenes 3b and 3f was
thus reacted under optimized conditions. We analyzed the
crude product by NMR and isolated nearly equimolar amounts
of four products, in which aryls and sulfonyl groups were
evenly scrambled (Scheme 3). This result shows that the
rearrangement is a multimolecular process.
On the basis of literature studies and experimental/
computational studies, we propose the rationale presented in
Figure 3 to account for the present complementary cyclization
of enallenes.
Figure 3. Proposed reaction mechanism.
Monosubstituted allenes have triplet energies that do not
match that of the iridium complex. Their redox potentials are
beyond those accessible using the present catalyst and visible
light.6 The oxidation of styryl fragments, especially those with
electron-withdrawing substituents, follows suit.6a,8a On the
contrary, the triplet state of the iridium catalyst could activate
the vinylarene arm of substrates through an energy transfer
(eT) process.12 This correlates with the absence of reactivity
C
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observed by replacing the photocatalyst with species that have
exoergonic and, moreover, progressively more so. This should
further increase the easiness of the propagation.
Starting from V, the highest energy TS of this manifold is
triplet energies unable to activate β-styryl units, such as the
2
2+
3
popular Ru(bpy)3 complex. Upon eT, intermediate 1 can
then evolve through two different pathways, forming either a
just 0.5 kcal/mol lower in energy than that of the joint radical/
photochemical mechanism, suggesting that the competition
might be too close to call. The chain generating VI has a less
favorable ΔG (−7.3 kcal/mol) than that directly affording 4
(−23.6 kcal/mol). This gap, coupled to the requirement of a
six- or a five-membered ring (3II′ and II, respectively). The
3
latter cyclization prevails, enabling the formation of vinyl-
idenecyclobutane 2 upon intersystem crossing (ISC). Accord-
ing to density functional theory (DFT) modeling, this stems
from both an easier transition state (TS) and the least stable
exoergonic intermediate (ΔΔG of −6.9 and +24.3 kcal/mol,
respectively, at the M06/def2-TZVP level using DMF as an
implicit solvent).
8a,16
3
second excited Ir species to afford the product,
favor the odds of an entirely free-radical pathway.
seems to
In sharp contrast with the β-fragmentation of the C−S bond
that is a routine tool in radical sequences, it is worth noting
that that of α-sulfonamidoyl radicals has very few precedents.17
These are limited at the present to processes promoted by tin
hydrides, which, furthermore, do not allow reincorporation of
the sulfonyl fragment in the final product.
In conclusion, we reported the synthesis of two comple-
mentary families of 3.2.0 bicycles from enallenes. Both
reactions show remarkable regio- and diastereocontrol,
affording complex scaffolds under mild conditions. Mechanistic
studies point out two orthogonal pathways that took place
under identical conditions, namely, a [2 + 2] photo-
cycloaddition versus a radical chain indirectly initiated by a
photoexcited iridium complex. Although catalytic pathways
and innate chains often compete in visible-light-promoted
processes,18 we are unaware of synthetic methods in which
they are similarly interconnected.
3
Analogous activation of the 1,6-enallene gives triplet 3, for
which steric factors disfavor the 4-exo cyclization that would
have led to a 2.2.0 bicycle. The alternative formation of a five-
membered ring delivers 3III. The cyclization can smoothly take
place through a low barrier (ΔG of +6.8 kcal/mol) and thus
3
parallels the results observed with 1,7-allenenes. In III the
spin density on the allyl group is evenly spread, with a slight
preference for the internal carbon atom. The two mono-
3
occupied molecular orbitals are nearly perpendicular in III.
This likely explains its reduced prowess toward the formation
of the expected unobserved [2 + 2] cycloaddition product 4′.
3
However, the N−S bond of III is slightly longer than that of
33 (by +0.008 and +0.0005 Å using def2-SVP and def2-TZVP
basis sets, respectively). This makes possible a relatively easy β-
3
fragmentation, which provides IV by homolytic N−S bond
cleavage. A significant basis set effect on calculated energies
was observed for this TS (ΔG of +14.3 and +19.7 kcal/mol
using def2-SVP and def2-TZVP, respectively; see the SI for a
comparison of the basis sets and the Hartree−Fock
contribution to functionals for this step).13 Nonetheless,
even the least favorable calculated barrier is still viable for a
homolytic bond cleavage.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02193.
Experimental procedures, synthesis of reagents, charac-
terization of products, modeling data, X-ray crystallog-
raphy data, and copies of NMR spectra (PDF)
3
The fate of the two radical fragments of IV posed several
hurdles (see the SI for additional, less favorable pathways),
until we considered a chain reaction.14 Substrate activation,
cyclization, and fragmentation comprise the overall initiation of
the process. The propagation involves the selective addition of
a sulfonyl radical on the C(sp) carbon of a substrate
Accession Codes
CCDC 2009276−2009278 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
molecule,15 affording allyl radical V (ΔG = −12.2 kcal/mol)
2
through a low-lying TS (barrier of +11.9 kcal/mol in ΔG). The
2
β-fragmentation of V occurs through a barrier of +21.4 kcal/
mol in ΔG, and it gives intermediate VI, regenerating the
sulfonyl radical. The former could then undergo a second eT,
AUTHOR INFORMATION
3
■
providing triplet VI, by analogy to the activation of 1 and 3
that is nearly isoenergetic. Triplet 3VI can smoothly evolve into
3VII via 5-exo-trig cyclization (barrier of +8.5 kcal/mol in
ΔG). Product 4 eventually forms by intersystem crossing
(ISC).
Corresponding Author
Giovanni Maestri − Department of Chemistry, Life Sciences and
Environmental Sustainability, Universita di Parma, 43124
Parma, Italy; orcid.org/0000-0002-0244-8605;
Email: giovanni.maestri@unipr.it
̀
An alternative scenario involves a propagation leading
2
directly to bicycle 4. In this case, allyl radical V undergoes a
7-endo-trig cyclization that provides 2VIII upon a relative
barrier of +17.6 kcal/mol in ΔG. The subsequent 4-exo-trig/5-
endo-trig cyclization is the most energy-demanding step of the
pathway (barrier of +24.9 kcal/mol in ΔG), and it gives
bicyclic radical 2IX. The latter could then undergo β-
fragmentation to provide product 4 and regenerate the sulfonyl
radical. This step has a lower barrier compared with the
Authors
Andrea Serafino − Department of Chemistry, Life Sciences and
Environmental Sustainability, Universita di Parma, 43124
Parma, Italy
Davide Balestri − Department of Chemistry, Life Sciences and
Environmental Sustainability, Universita di Parma, 43124
Parma, Italy; orcid.org/0000-0003-3493-9115
̀
̀
3
analogous N−S bond cleavage taking place on III (ΔΔG =
̀
Luciano Marchio − Department of Chemistry, Life Sciences and
̀
−3.4 kcal/mol). Overall, the propagation of this chain reaction
has a largely negative ΔG (−23.6 kcal/mol). All of its steps are
Environmental Sustainability, Universita di Parma, 43124
Parma, Italy
D
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+ 2] Reaction of N-Allenylsulfonamides with Vinylarenes: Enantio-
selective Gold(I)-Catalyzed Synthesis of Cyclobutane Derivatives.
Angew. Chem., Int. Ed. 2012, 51, 11552.
Max Malacria − Faculty of Science and Engineering, CNRS,
́
Institut Parisien de Chimie Moleculaire (UMR CNRS 8232),
Paris 75252 Cedex 05, France; orcid.org/0000-0002-
3563-3508
(6) For selected examples of related non-redox activation, see:
(a) Lu, Z.; Yoon, T. P. Visible Light Photocatalysis of [2 + 2] Styrene
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Melchiorre, P. Visible-light Excitation of Iminium Ions Enables the
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Etienne Derat − Faculty of Science and Engineering, CNRS,
́
Institut Parisien de Chimie Moleculaire (UMR CNRS 8232),
Paris 75252 Cedex 05, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02193
868. (d) Munster, N.; Parker, N.; van Dijk, L.; Paton, R. S.; Smith, M.
̈
Notes
D. Visible Light Photocatalysis of 6π Heterocyclization. Angew. Chem.,
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Zhang, L.; Ullah, Z.; Xie, X.; Harms, K.; Baik, M.-H.; Meggers, E.
Catalytic Asymmetric Dearomatization by Visible-Light-Activated [2
+ 2] Photocycloaddition. Angew. Chem., Int. Ed. 2018, 57, 6242.
(f) Ha, S.; Lee, Y.; Kwak, Y.; Mishra, A.; Yu, E.; Ryou, B.; Park, C.-M.
Ryou B.; Park, C.-M. Alkyne−Alkene [2 + 2] cycloaddition based on
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has benefited from the equipment and framework of
the COMP-HUB Initiative, funded by the “Departments of
Excellence” program of the Italian Ministry for Education,
University and Research (MIUR, 2018-2022). We also
acknowledge the support from UniPR, UPMC, and CNRS.
Use of modeling facilities was provided by ICSN-CNRS, Gif s/
Yvette, France.
(7) Photochemical 1,3-sigmatropic rearrangements involving sec-
ond-row and heavier main-group elements are extremely rare; for a
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Christensen, M. L.; Chen, Y.; Naharro, D.; Liu, F.; Jorgensen, K.
A.; Houk, K. N. An Experimental Stereoselective Photochemical
[1s,3s]-Sigmatropic Silyl Shift and the Existence of Silyl/Allyl Conical
Intersections For computational studies, see. J. Am. Chem. Soc. 2020,
142, 6030. (b) Bernardi, F.; Olivucci, M.; Robb, M. A.; Tonachini, G.
Can a Photochemical Reaction Be Concerted? A Theoretical Study of
the Photochemical Sigmatropic Rearrangement of But-1-ene. J. Am.
Chem. Soc. 1992, 114, 5805. (c) Wilsey, S.; Houk, K. N. H/Allyl and
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(d) Takahashi, M. The Mechanism of Photochemical 1,3-Silyl
Migration of Allylsilane. J. Phys. Chem. A 2005, 109, 11902.
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(16) Multiphoton processes are statistically challenging; see
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