External-Photocatalyst-Free Visible-Light-Mediated Synthesis of Indolizines

Article abstract of DOI:10.1002/anie.201506868

A visible-light-mediated synthesis of valuable polycyclic indolizine heterocycles from easily accessed brominated pyridine and enol carbamate derivatives has been developed. This process, which operates at room temperature under irradiation from readily available light sources, does not require the addition of an external photocatalyst. Instead, an investigation into the reaction mechanism indicates that the indolizine products themselves may be in some way involved in mediating and accelerating their own formation. Preliminary studies also show that these simple heterocyclic compounds may be capable of facilitating other visible-light-mediated transformations.

Full text of DOI:10.1002/anie.201506868

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201506868
German Edition: DOI: 10.1002/ange.201506868
Photomediated Synthesis
External-Photocatalyst-Free Visible-Light-Mediated Synthesis of
Indolizines
Basudev Sahoo, Matthew N. Hopkinson, and Frank Glorius*
Dedicated to Stephen L. Buchwald on the occasion of his 60th birthday
Abstract: A visible-light-mediated synthesis of valuable poly-
cyclic indolizine heterocycles from easily accessed brominated
pyridine and enol carbamate derivatives has been developed.
This process, which operates at room temperature under
irradiation from readily available light sources, does not
require the addition of an external photocatalyst. Instead, an
investigation into the reaction mechanism indicates that the
indolizine products themselves may be in some way involved in
mediating and accelerating their own formation. Preliminary
studies also show that these simple heterocyclic compounds
may be capable of facilitating other visible-light-mediated
transformations.
T
he harvesting of energy from visible light, the most
abundant part of the solar spectrum, is a sustainable and
cost-effective approach to activate chemical transforma-
tions.[1,2] However, most organic compounds do not them-
selves absorb in the visible region and strategies must be
employed that allow for the efficient and selective transfer of
energy from visible light to the reactants of interest. This can
be achieved through the use of photocatalysts, which are
capable of either passing on energy directly to the visible-
light-inactive reagents or of engaging in single-electron-
transfer (SET) events from their photoexcited states. Fur-
thermore, photocatalysis can also provide access to interest-
ing and often exotic reactivity pathways not commonly
observed in the absence of light. Recent years have seen
a resurgence of interest in photocatalysis with visible light,
particularly SET-based photoredox activation processes.[3]
Inspired by these transformations, we envisaged that
photocatalysis by visible light could open up mild and general
synthetic routes to valuable heterocyclic compounds. In this
regard, we identified the indolizine core as a promising target
for investigation.[4] Indolizines are widely found as structural
motifs in various pharmaceutical compounds,[5] while the
reduced form is the key feature of the extensive indolizidine
natural product family (Scheme 1a).[6] Although many strat-
Scheme 1. a) Selected examples of the indolizine motif in pharmaceut-
icals; b) proposed visible light photoredox-catalyzed synthesis of
indolizines.
egies have been employed to build up the heterocyclic core of
these compounds under thermal conditions,[4,7] to the best of
our knowledge, only one photochemical route to indolizines,
involving irradiation with UV light, has been reported to
date.[8]
A visible-light-mediated synthesis of indolizines 3 starting
from brominated 2-pyridine acetic acid ester derivatives 1 and
enol carbamates 2 was designed, taking advantage of well-
established light-induced SET processes from a photocatalyst
(Scheme 1b). Our envisaged mechanism is shown in
Scheme 2. Initial excitation of a transition-metal/polypyridyl
complex of the type commonly employed in photoredox
catalysis ([PC]) would be followed by single-electron transfer
to the brominated pyridine substrate 1a to afford a radical
anion 1aCÀ and the oxidized photocatalyst [PC]+. Mesolytic
loss of a bromide ion from 1aCÀ would then deliver an alkyl
radical A, which could in turn add to the enol carbamate
derivative 2a. Oxidation of the resulting radical B to cation D
could then occur either as part of a radical-chain process with
another molecule of 1a or by SET with the oxidized photo-
catalyst [PC]+, thereby regenerating the ground-state species
and closing the photoredox catalytic cycle. Subsequent
trapping of the cation in D by the intramolecular pyridine
nitrogen atom followed by a series of proton-transfer steps
and elimination of a carbamic acid derivative would finally
deliver the desired indolizine heterocycle 3aa.
[*] B. Sahoo,[+] Dr. M. N. Hopkinson,[+] Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
[+] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201506868.
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outcome, with 3aa being deliv-
ered in a comparable yield of
52% (GC, Scheme 3). Exten-
sive optimization studies involv-
ing the screening of different
solvents, bases, light sources,
protected enol substrates, and
reagent stoichiometries led to
an improvement in the yield of
3aa to 77% (63% yield of
isolated product) by using
a,a,a-trifluorotoluene as the
solvent and hexamethyldisila-
zane (HMDS) as the base.[9] As
before, a control reaction per-
formed without irradiation by
visible light was unproductive
(1% GC yield), thus verifying
the photomediated nature of
the process.
The results of a study into
the scope and limitations of the
process with a variety of differ-
ent pyridines 1 and enol carba-
mates 2 are shown in Table 1.
While an electron-withdrawing
substituent on the brominated
pyridine substrates was required
to sufficiently activate the com-
pounds towards photoactiva-
tion, a range of different ester
groups could be applied to
Scheme 2. Envisaged mechanism for the visible light photoredox-catalyzed synthesis of indolizines.
Here, we report the successful realization of this concept
in a visible-light-mediated route to unprecedented polycyclic
indolizines, which proceeds under mild conditions upon
irradiation with readily available blue light-emitting diodes
(LEDs). As explained below, however, this process does not
in fact require the use of an external photocatalyst. Instead,
initial experiments point towards an interesting mechanistic
scenario, wherein the polycyclic indolizine products them-
selves play a role in facilitating their own formation.
As an initial test reaction, the simple brominated pyridine
1a was treated with the bicyclic enol carbamate 2a (5 equiv)
in N,N-dimethylformamide (DMF) in the presence of the
inorganic base Na2HPO4 and the organometallic photosensi-
Scheme 3. Preliminary investigations and control experiments.
afford the corresponding indolizines 3aa–3da. The cyano-
substituted substrate 1e was also tolerated, but was signifi-
cantly less effective, with 3ea isolated in only 16% yield. A
range of different functional groups including halogens, aryl,
alkyl, methoxy, and trifluoromethyl groups were tolerated
either on the pyridine ring or on various enol carbamates 2
derived from the 1-tetralone core. Access to indolizines with
substituents on the pyridine ring has been comparatively
rarely reported by alternative synthetic methods. Although
a considerable excess of the olefinic coupling partners 2
(5 equiv) was required to ensure a reasonable yield of the
product 3, in all cases the unincorporated enol carbamate
could be recovered from the reaction mixture and subse-
quently recycled. As with all photomediated processes, the
tizer
[Ir(ppy)2(dtbbpy)](PF6)
(ppy = 2-phenylpyridine,
dtbbpy = 4,4’-di-tert-butyl-2,2’-bipyridine), which has been
widely employed in photoredox catalysis. The desired tetra-
cyclic indolizine product 3aa was generated in 62% yield
(GC) after 12 h at room temperature under irradiation by
blue LEDs (lmax = 465 nm). A control reaction performed in
the dark confirmed the necessity of visible light. A more
interesting observation was made, however, upon conducting
the reaction in the absence of the photocatalyst [Ir(ppy)2-
(dtbbpy)](PF6). Rather than shutting down the reactivity as
expected, carrying out the process under the same conditions
without the iridium complex had little impact on the reaction
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Table 1: Scope and limitations of the visible-light-mediated synthesis of
indolizines 3 with various brominated pyridines 1 and enol carbamates
2.[a]
Scheme 4. Derivatization of indolizine 3aa.
With the scope of the process established, a series of
mechanistic experiments were conducted, with the aim of
understanding how energy from visible light is apparently
harnessed during the reaction in the absence of an external
photocatalyst. Firstly, the reaction between 1a and 2a was
performed in the presence of the radical scavengers TEMPO
and galvinoxyl. In both cases, a complete shutdown of
reactivity was observed, thus indicating the involvement of
radical intermediates. Moreover, an ESI mass spectrum of the
reaction performed in the presence of TEMPO exhibited
signals consistent with adducts formed between this radical
scavenger and the proposed radical intermediates A and B
(Scheme 2).[9] At this stage, we sought to identify the species
present in the reaction mixture that was responsible for
absorbing visible light in lieu of a photocatalyst. Thus,
absorption spectra were recorded for all reaction components
both on their own and in combination. As expected, the
spectra for the substrates 1a and 2a and for the base HMDS
in PhCF3 did not reveal any notable absorption of either
visible or near-UV light (l > 300 nm, Figure 1a).[10] An
absorption spectrum of the indolizine 3aa recorded under
the same conditions, however, exhibited a range of peaks with
a maximum in the near-UV region at 340 nm and shoulders at
328 nm and 372 nm. Irradiating at either wavelength resulted
in a detectable fluorescence emission at 442 nm (excited-state
lifetime, t = 4 ns). A selection of variously substituted indo-
lizines have been previously shown to exhibit fluorescence
properties, with some having found applications in solar cells
and in sensors for analyte detection.[11] The implication that
the reaction products could themselves play a role in
mediating their own formation was also supported by an
analysis of the reaction kinetics. As shown in Figure 1b, a plot
of the yield of 3aa as a function of the reaction time revealed
a slight parabolic curve consistent with the expected accel-
eration of the reaction rate as the product concentration
increases over time. Furthermore, spiking the mixture with
increasing amounts of preformed 3aa led to a small, but
notable, corresponding increase in the initial reaction rate.[9]
A Stern–Volmer luminescence quenching analysis of the
reaction also indicated that a mechanism of the type shown in
Scheme 2 with the indolizine product replacing the external
photocatalyst is plausible. Excitation of 3aa at 372 nm in the
presence of various amounts of 1a revealed quenching of the
fluorescence at 442 nm by the brominated substrate, while
[a] Reactions were conducted on a 0.20 or 0.30 mmol scale. See the
Supporting Information for experimental details. R4 =methyl unless
otherwise stated. [b] R4 =ethyl. [c] Reaction conducted in the presence of
[Ir(ppy)2(dtbbpy)](PF6) (2 mol%). EWG=electron-withdrawing group.
reaction progress could also be easily regulated simply by
switching the light irradiation on and off.[9] In most cases, the
indolizines 3 were isolated in moderate to good yields of up to
75%, although compound 3ag, which does not possess
a tethered aryl group, was generated in a much lower yield
of 28%. Unfortunately, however, the all-alkyl-substituted
indolizine 3ah was not formed either under the standard
conditions or in the presence of [Ir(ppy)2(dtbbpy)](PF6).
The indolizine products from these reactions represent
a novel class of tetracyclic or, in the case of 3mb, pentacyclic,
heteroaromatic scaffold, which could warrant further inves-
tigation in the context of pharmaceutical or materials
chemistry. Moreover, as demonstrated for product 3aa,
subsequent facile oxidation using 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) can give easy access to the
corresponding fully aromatic compounds (4, 71%), while
hydrogenation with Adams catalyst (PtO2) provides the
reduced fused-pyrrole derivatives (5, 96%, Scheme 4).
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indole 7 reported by Stephenson and co-workers.[18] The
successful conversion into the alkylated indole product 8
observed after 18 h at room temperature (45% yield of
isolated product, Scheme 5) suggests that this scaffold could
find applications in photochemical synthesis and could
provide a starting point for further studies.
Scheme 5. Application of indolizine 3aa as a photosensitizer in the
addition of ethyl bromomalonate 6 to 1-methylindole 7.
In conclusion, we have developed a novel visible-light-
mediated synthetic method that gives access to functionally
diverse indolizines under mild conditions. The tetracyclic and
pentacyclic structures obtained by using this route represent
a new class of heterocyclic scaffold, which may be of interest
in pharmaceutical or fluorescent materials research. Control
reactions showed that this process proceeds effectively in the
absence of an external photocatalyst, and mechanistic studies
seem to implicate the indolizine products, or species derived
from them, as playing a role in absorbing energy from visible
light and mediating their own formation. Furthermore, the
successful application of one of these simple polycyclic
heterocycles as a photosensitizer in a different transformation
suggests that these compounds may be of interest for photo-
chemical synthesis.
Figure 1. a) Absorption spectra of substrates 1a, 2a, the base HMDS,
and indolizine 3aa; b) reaction profile of the visible-light-mediated
synthesis of 3aa.
similar experiments with the other reaction components had
no significant effect on the emission intensity.[12]
Chemical transformations where the products serve to
mediate their own formation are of fundamental interest, as
they enable compounds to self-replicate and multiply.[13] An
examination of the absorption spectrum of indolizine 3aa and
the emission maximum of the blue LED light source used,
however, would seem to argue against the direct involvement
of the indolizine in self-replication.[14] No significant absorp-
tion was observed for 3aa above approximately 410 nm, while
Acknowledgements
We thank Dr. C. Daniliuc for X-ray crystallographic analysis,
A. Samanta, J. Wysocki, L. Stegemann, Prof. A. Studer, Prof.
H. J. Schäfer, Prof. B.-J. Ravoo, Dr. C. A. Strassert (all WWU
Münster), and Prof. C. R. J. Stephenson (University of
Michigan) for helpful discussions and technical assistance.
This work was generously supported by the Deutsche
Forschungsgemeinschaft (Leibniz Award), the European
Research Council under the European Community’s Seventh
Framework Program (FP7 2007-2013)/ERC Grant agreement
no. 25936, and the Alexander von Humboldt Foundation
(M.N.H.).
blue LED visible-light sources were used with lmax
=
465 nm.[15] At this stage, we tentatively propose that the
emission tail of the blue LEDs at wavelengths shorter than
the emission maximum could be sufficient to excite the
indolizine and initiate a radical-chain process of the type
outlined in Scheme 2.[16,17] Alternatively, a photoactive spe-
cies derived from the indolizine products with greater
absorption at longer wavelengths may form in low concen-
trations and mediate the reaction. Finally, the implication
from these studies that simple polycyclic indolizine hetero-
cycles can play a role in harvesting energy from visible light
and initiate or otherwise facilitate photochemical reactions
was tested by employing indolizine 3aa as a photosensitizer in
a different transformation. In a proof of principle experiment,
3aa was used in place of [Ru(bpy)3]Cl2 (bpy = 2,2’-bipyridine)
for the radical addition of bromomalonate 6 to 1-methyl-
Keywords: heterocyclic compounds · indolizines ·
photocatalysis · radicals · visible light
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would seem to imply that the visible-light tail of the blue LEDs
at wavelengths below 455 nm (and above 400 nm) is mostly
responsible for the observed reactivity.
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[16] The involvement of EDA complexes formed between the
indolizine products and the other reaction components was
also ruled out by a series of absorption studies (see the
Supporting Information for more details).
[17] The involvement of radical chains in this process is supported by
the success of the reaction using the thermal radical initiator
dibenzoyl peroxide. Conducting the reaction between 1a and 2a
in the presence of this species (0.5 equiv) at 1058C without light
resulted in the formation of 3aa in 26% yield (see the
Supporting Information for more details).
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Revised: September 1, 2015
Published online: November 4, 2015
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