Photoassisted Synthesis of Complex Molecular Architectures: Dearomatization of Benzenoid Arenes with Aza-o-xylylenes via an Unprecedented [2+4] Reaction Topology

Article abstract of DOI:10.1002/anie.201602288

A new method was developed for the photoinduced dearomatization of arenes through an intramolecular cycloaddition with aza-o-xylylenes generated by excited-state intramolecular proton transfer (ESIPT) in the readily available photoprecursors. The [2+4] topology of this cycloaddition is unprecedented for photo-dearomatizations of benzenoid aromatic carbocycles. It provides rapid access to novel heterocycles, cyclohexadieno-oxazolidino-quinolinols, as valuable synthons for a broad range of post-photochemical transformations. I'm so excited: Photoinduced dearomatization of arenes was achieved through intramolecular cycloaddition with aza-o-xylylenes generated by excited-state intramolecular proton transfer in the readily available photoprecursors. The [2+4] topology of this cycloaddition is unprecedented for photo-dearomatizations of benzenoid aromatic carbocycles and produces the novel heterocycles cyclohexadieno-oxazolidino-quinolinols.

Full text of DOI:10.1002/anie.201602288

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201602288
German Edition: DOI: 10.1002/ange.201602288
Photochemistry
Photoassisted Synthesis of Complex Molecular Architectures:
Dearomatization of Benzenoid Arenes with Aza-o-xylylenes via an
Unprecedented [2+4] Reaction Topology
Dmitry M. Kuznetsov, Olga A. Mukhina, and Andrei G. Kutateladze*
Abstract: A new method was developed for the photoinduced
dearomatization of arenes through an intramolecular cyclo-
addition with aza-o-xylylenes generated by excited-state intra-
molecular proton transfer (ESIPT) in the readily available
photoprecursors. The [2+4] topology of this cycloaddition is
unprecedented for photo-dearomatizations of benzenoid aro-
matic carbocycles. It provides rapid access to novel hetero-
cycles, cyclohexadieno-oxazolidino-quinolinols, as valuable
synthons for a broad range of post-photochemical trans-
formations.
We now report a new photo-dearomatization of arenes via
the missing [2+4] topology, resulting in the formation of
unique cyclohexadiene-fused heterocycles as primary photo-
products, which are amenable to further growth of framework
complexity through straightforward post-photochemical
transformations.
As we have recently shown, cycloadditions of excited-
state intramolecular proton transfer (ESIPT)-generated aza-
xylylenes involve triplet species.[6d] The reaction is initiated by
the electrophilic N-centered radical, with the overall process
resembling a formal inverse-electron-demand Diels–Alder
reaction. We hypothesized that a similar initial step should
occur with donor-substituted benzenoid arenes. This indeed
was the case: a readily available anilide of phenoxyacetic acid
(1a) proved cycloaddition-competent, furnishing cyclohexa-
dieno-quinolinol syn-4a upon irradiation with 365 nm LEDs
(Scheme 2).
D
earomatization of aryls provides an appealing preparative
shortcut from ubiquitous aromatic hydrocarbons to complex
sp3-rich molecular topologies (see the excellent review by
Porco),[1] offering access to vast areas of underexplored
chemical space.[2] Dearomatization of electron-rich hetero-
cycles such as indoles,[3] furans,[4] and pyrroles[5] have been
reported, including our own recent contributions.[6,7]
By contrast, the options for the ground-state dearomati-
zation of carbocyclic benzenoid arenes are limited,[8] with
a predominance of phenolic oxidation[9] and transition metal-
assisted dearomatization.[10] Photocycloadditions to arenes
nicely complement these methods to give diverse product
topologies (Scheme 1).[11] Among these, [3+2] reactions[12] are
often used as key steps in the synthesis of natural products,[13]
while the [2+2],[14] [4+2],[15] and [4+4][16] cycloadditions of
arenes remain somewhat underutilized. Furthermore, [2+4]
photocycloadditions, with an arene acting as a 2p “dieno-
phile”, are unknown.[17] Instructively, such [2+4] reactions in
the ground state are very rare.[18]
Scheme 2. A typical [2+4] cycloaddition of 1a.
The scope of this cycloaddition was assessed with a matrix
of amides comprised of three photoactive cores, o-amino-
benzaldehyde 1, aminoacetophenone 2, and aminotetralone
3, and twelve aromatic pendants: derivatives of phenoxy-
acetic- (a–h) and phenylpropanoic- (i–k) acids, and biphenyl
l (Figure 1).
Optimization of the reaction conditions and solvent led to
DMSO as the solvent of choice. The products resulting from
irradiations of 1a–1c, 1h, 1j, 2d, 3d, 3e, and 3j are
summarized in Figure 2. For aldehyde-based precursors 1a–
1c, the syn-diastereomer was observed as the sole product,
where “syn” refers to the relative position of the benzylic OH
and the newly formed cyclohexadiene ring. The stereochem-
ical assignment was based on analysis of proton spin–spin
coupling constants (SSCC) and their comparison with values
calculated with our relativistic force field (rff) DU8c
method[19] (Table S1 in the Supporting Information).
Phenylpropanoic derivatives, such as 1j, gave two
regioisomers, syn-4j and syn-4j’, in a ratio approximately 2:1.
The reaction scope is not limited to photoprecursors
derived from benzaldehyde. Compounds 2d, 3d, 3e, and 3j,
Scheme 1. Molecular topologies accessible through photochemical
dearomatization of benzenoid arenes.
[*] D. M. Kuznetsov, Dr. O. A. Mukhina, Prof. Dr. A. G. Kutateladze
Department of Chemistry and Biochemistry, University of Denver
2190 E. Iliff Ave., Denver, CO 80208 (USA)
E-mail: akutatel@du.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602288.
6988
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Scheme 3. Spontaneous hydrolysis of primary photoproducts. Yields of
isolated product were calculated over two steps.
Figure 1. Substrate matrix.
Scheme 4. Ketal formation from the syn-photoproducts.
Figure 2. Primary photoproducts from anilides 1a–1c, 1h, 1j, 2d, 3d,
3e, and 3j. Yields of isolated products after chromatographic separa-
tion of diastereomers are given. [a] 7% of anti-4j’ was additionally
isolated.
Figure 3. Formation of cyclic ketals. Conditions for ketal formation:
[a] spontaneous; [b] HCl in ether, [c] p-TsOH·H2O.
In this context, reaction of the aldehyde-based photo-
precursor 1d is instructive (Scheme 5). The initially formed
syn- and anti-4d are unstable on the column. Upon the
addition of tosic acid, anti-4d hydrolyzes to enone anti-10d.
Product syn-4d initially undergoes cyclic ketalization to form
9d, but its hydrolysis could be driven further to enone syn-
10d, with subsequent acid-catalyzed nucleophilic capture of
the benzylic hydroxy group by the a,b-unsaturated ketone to
produce stable ether 11d. The structure of ether 11d was
initially assigned based on NMR analysis, with the rff-
calculated SSCCs matching the experimental data with high
accuracy (rmsd = 0.09 Hz), and this was later confirmed by X-
ray analysis.
which contain acetophenone and tetralone-based photoactive
cores, also underwent cycloaddition. The stereo- and regio-
chemistry of the cycloaddition for compounds anti-6d,e,j and
j’, as well as syn- and anti-5d, was unambiguously confirmed
by X-ray analysis.
In several cases, the methoxycyclohexadiene moiety in the
primary photoproducts underwent hydrolysis into cyclohex-
enone. This reaction can be spontaneous as in the case of syn-
4g, or can happen during the chromatography as in the case of
anti-6d (Scheme 3).
A special case of interrupted post-photochemical hydro-
lysis is represented by syn-products 4 (YR = OMe or NHAc,
Scheme 4 and Figure 3). After protonation of the vinyl ether
moiety, the methoxyallyl cation is trapped by the benzylic
hydroxy group to yield cyclic ketal 9.
Synthetically appealing post-photochemical modifications
to diversify and grow the complexity of the resulting core
scaffolds are not limited to ketalization. The primary photo-
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can be ring-opened with urea or bases, thereby offering rapid
access to complex pentasubstituted cyclohexenes fused to
oxazolidino-quinolinol cores, for example ketal 16, triol 17,
and enone 18 (Scheme 7).
In conclusion, we have developed a new method for the
dearomatization of benzenoid arenes, with the arene reacting
as the 2p component—an unprecedented topology for
a photochemical reaction of benzenoid aromatics. The
primary photoproducts are cyclohexadieno-quinolinol fused
heterocycles, which can be subjected to experimentally simple
post-photochemical transformations to further grow scaffold
diversity and complexity.
Acknowledgements
Scheme 5. Acid-catalyzed post-photochemical transformations.
Ts =4-toluenesulfonyl, THF=tetrahydrofuran.
This work was supported by grant GM093930 from the NIH.
Keywords: [2+4] reactions · aza-o-xylylenes · dearomatization ·
photochemistry · polyheterocycles
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6988–6991
Angew. Chem. 2016, 128, 7102–7105
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Received: March 5, 2016
Published online: April 21, 2016
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