Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic Strategies and Photophysical Studies

Article abstract of DOI:10.1021/acs.orglett.5b02680

A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λ_max of excitation for DBNs with varying electronic character.

Full text of DOI:10.1021/acs.orglett.5b02680

Letter
pubs.acs.org/OrgLett
Dibenzonaphthyridinones: Heterocycle-to-Heterocycle Synthetic
Strategies and Photophysical Studies
Teresa A. Palazzo,† Digambara Patra,‡,§ Joung S. Yang,†,∥ Elsy El Khoury,‡,∥ Mackenzie G. Appleton,†,∥
Makhluf J. Haddadin,‡,§ Dean J. Tantillo,*,† and Mark J. Kurth*,†
†Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
‡Department of Chemistry, American University of Beirut, Beirut, Lebanon
S
* Supporting Information
ABSTRACT: A heterocycle-to-heterocycle strategy is pre-
sented for the preparation of highly fluorescent and
solvatochromic dibenzonaphthyridinones (DBNs) via method-
ology that leads to the formation of a tertiary, spiro-fused
carbon center. A linear correlation between the results of
photophysical experiments and time dependent density
functional theory calculations was observed for the λmax of
excitation for DBNs with varying electronic character.
Scheme 1. Previous (a) and Current (b) Reductive 3,5-Bis-o-
nitrophenyl Substituted Isoxazole Methodology
he importance of late-stage skeletal diversification of small
1
Tmoleculelibrariesiswellestablished, andpreviousworkhas
demonstrated the utility of heterocycle-to-heterocycle trans-
formations as valuable toolsfor implementingthis strategy.2 Most
recently, we have shown that an isoxazole core (such as in
isoxazole 3a; Scheme 1) can be selectively converted into 4-
aminoquinolines, 3-acylindoles (not depicted here), and 4-
quinolinones based on the location of a 2-nitrophenyl substituent
(e.g., at the C3, C4, or C5 position, respectively) on the isoxazole,
which is then subjected to reductive conditions.3 Of particular
relevance to the work reported here, 3,5-bis-o-nitrophenyl
substituted isoxazoles (e.g., 3a) were shown to undergo reductive
transformationselectivelyyieldinga4-quinolinone, andnotthe4-
aminoquinoline (Scheme 1a).3 In an extension of this initial
finding, we now show that 3,5-bis-o-nitrophenyl substituted
isoxazolereduction inthe presenceof anaddedketone candeliver
dibenzonaphthyridinones (DBNs, Scheme 1b). Furthermore,
while others have studied the optical properties of DBNs (and
related structures),4 we present new synthetic methodology for
constructing these highly fluorescent and solvatochromic
materials as well as experimental and theoretical exploration of
their optical properties.
quinolinone based antibacterials.8 Arylpiperazinyl naphthyridi-
nones have been reported by Johnson et al. to have utility in the
treatments of bipolar disorder and schizophrenia.9 Thus, DBNs
are ripe targets for synthetic strategies that promote rapid
structural and functional diversification to facilitate further
activity studies. While isoxazole-based reductive quinolinone
synthetic methods have been reported by us and others,2a,b,3
previous synthetic methodologies to DBNs rely on commercially
available substituted quinolinone starting materials and acid
mediated condensations with aminobenzoic acids to afford the
targeted molecular frameworks.2b,10 The methodology reported
here uses a fundamentally different approach to producing DBNs
that starts with aryl iodides and readily synthesized aryl oximes.
The key 3,5-bis(o-nitrophenyl)-isoxazole intermediates 3a−d
were synthesized starting from the appropriately substituted 1-
Solvatochromism is defined in the IUPAC Gold Book as “the
pronounced change in position and sometimes intensity of an
electronicabsorptionoremissionbandaccompanyingachangein
the polarity of the medium.”5 It has been demonstrated that
solvatochromic materials make intruiging biomarkers, which
allow for tracking of a material in vitro, and also provide
information about the polarity of the region where the tracked
molecule resides.6
In addition to their photophysical properties, DBNs have also
been studied for their biological activities. For example, DBNs
have been shown by Miolo et al. to be DNA intercalators,7 and
Checcheti et al. have studied their application as modified
Received: September 15, 2015
© XXXX American Chemical Society
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Table 1. Substituents and Yields for Alkyne/Nitrile Oxide 1,3-
Dipolar Cycloadditions Yielding Isoxazoles 3a−d
compound
R1
R2
yield (%)
3a
3b
3c
3d
H
H
H
76
40
43
20
Figure 1. Thermal ellipsoid plot (30% probability) of 5a with a final R
value of 3.35% (monoclinic space group P21).
4-Cl
H
4-OMe
4-OMe
Scheme 3. Reduction of Isoxazole 3a Followed by Addition of
Various Electrophiles To Yield 6, 7, and 8
5-Cl
iodo-2-nitrobenzene and 2-nitrobenzaldehyde precursors (Table
1; see the Supporting Information for full details).3,11
Isoxazoles 3a−dwerethen reduced usingFe0 inneatacetic acid
at 90 °C to ultimately give 5a−d, but in low yields.12 It was
determined that the reduction to 4a−d and subsequent
condensation can be carried out in a one-pot “domino” fashion,
wherein acetone is added at the start of the reduction reaction.
However, under these conditions the yield remained low.
Fortunately, neat acetone dissolution of crude 4a−d from the
worked up reduction reaction followed by heating to 90 °C (8 h,
sealed tube) delivered 5a−d in moderate to excellent yields
(Scheme 2 and Table 2). The combination of electron-rich and
Scheme 2. Reduction of Isoxazoles 3a−d to Quinolinones 4a−
dFollowedbyCondensation withAcetoneDeliversDBNs5a−
d
added electrophiles in the reaction with 4, the products were, in
each case, observable in the crude reaction mixture via LCMS but
not isolable in pure form. For example, after workup and column
chromatography, the product from the acetophenone reaction
was obtained in ∼10% yield and was still impure as judged by 1H
NMR analysis. Table 3 provides representative examples of
electrophiles that do not react effectively with intermediate 4.
Table 3. Electrophile Limitations in Reactions of Intermediate
4
electrophile
concluding result
Table 2. Substituents and Yields for DBNs 5a−d
acetophenone
2-pentanone
trace product via LCMS; intractable
compound
R1
R2
yield (%)
5a
5b
5c
5d
H
H
H
89
80
92
33
4-Cl
H
benzaldehyde
propionaldehyde
formaldehyde
mixture of products; intractable
(see footnote 13)
4-OMe
4-OMe
5-Cl
CH2I2
trace product via LCMS; intractable
-poor substituents in 3d likely contributes to the low yield of 5d
(push−pull delocalization would be expected to decrease the
reactivity of 4d). The structure of compound 5a was
unambiguously assigned by X-ray diffraction (Figure 1).
A thorough workup of the 3 → 4 reaction prior to
heterocyclization with non-acetone ketones (→ 5a) is critical,
as any carryover iron species and acetic acid lead to in situ
formation of acetone,12 which then competes with the added
ketone. Indeed, following removal of all iron species/acetic acid,
both cyclohexanone and N-boc-piperidinone successfully con-
densed with intermediate 4a leading to DBNs 6 and 7 (Scheme
3).
acetyl chloride
amide from reaction with 4; determined via LCMS
Lastly, the quinolinone → DBN heterocyclization reaction was
alsoconducted with1,4-cyclohexanedioneinanattempttoisolate
the bis-heterocyclization product. While the reaction afforded
desiredproduct8inlowyield(16%, Scheme3), itwasintriguingly
obtained as a single diastereomer. The remainder of the crude
reaction mixture was composed of 4-quinolinone intermediate
4a, and the condensation product, of 1,4-cyclohexanedione with
only 1 equiv of 4a (as determined by LCMS).
While several additional ketones (most notably acetophe-
The structure of 8 was unambiguously verified by X-ray
crystallography (Figure 2). Interestingly, the N,N-trans diaster-
none), aldehydes,13 and 1,1-dihaloalkanes were examined as
B
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Letter
in lifetime are attributed to explicit solvent interactions that
selectively stabilize the excited state.15 The longest lifetime
observed was 12.05 ns for 5a in DMSO.
Therelativefluorescenceefficiencywas alsosensitivetosolvent
environment and was highest in THF and lowest in water.
Lippert−MatagaplotsweregeneratedtocorrelatetheStokesshift
to the orientation polarizability of the various solvents (for a
summary of all photophysical properties in all solvents, see the
emission
Supporting Information). The λmax
of 5a shifts a striking
3623 cm−1 in CCl4 (460 nm) versus water (552 nm). The largest
Stokes shift observed was 8062 cm−1 (552 nm) for compound 5a
in water. Lastly, these experimental results were compared to
calculations performed using time dependent-density functional
theory (TD-DFT), which is effective at predicting and replicating
the photophysical properties of cyclic azacyanines and other
cyclic conjugated heterocyclic systems.16 The UV−vis spectra of
5a−d were computed for structures optimized with Gaussian0917
using B3LYP/6-31+G(d,p)18 and the SMD implicit solvent
model.19 Excluding water, which is difficult to model due to
explicitsolute−solventinteractions,16 linearcorrelationsbetween
computed and experimental data were developed [5a R2 = 0.69
(see Figure 4); 5b R2 = 0.68; 5c R2 = 0.64; 5d R2 = 0.43 (see
Figure 2. Thermal ellipsoid plot (30% probability) of 8 with a final R
value of 5.99% (monoclinic space group P21/c).
eomerobtained inthis bis-heterocyclization reactionpossesses an
intramolecular hydrogen bond in the solid state (Figure 2), which
is precluded in the N,N-cis diastereomer. This difference perhaps
partially explains the observed diastereoselectivity as this
hydrogen bond may stabilize the transition state structure leading
to 8. In a thermodynamic sense, the N,N-trans diastereomer is
12.4 kcal/mol lower in energy than the N,N-cis counterpart as
determined by density functional theory (DFT) calculations,14
indicating that the N,N-trans species is also the thermodynamic
product.
Having observed fluorescence and solvatochromism with these
DBNs during the course of this investigation (Figure 3), we also
Figure 4. Correlation of experimental and computed λmaxexcitation for 5a.
The R2 value shown was determined without inclusion of the data point
for water.
Figure3. Compound5ainfivedifferent solvents(ranging fromrelatively
nonpolar DCM to highly polar H2O) under long wavelength UV light
(365 nm) displaying intense solvatochromism (photo taken with 3
megapixel camera; color unaltered).
Supporting Information)].20 Although these correlations are not
strong, they do indicate a reproduceable trend in the data: a red
shift in the λmaxexcitation observed when nonpolar to polar solvents
are considered.
explored their photophysical properties. Four compounds (5a−
d) were chosen as candidates for experimental and theoretical
study, as they collectively represent electronically neutral (5a),
skewed (5b/5c), and push−pull (5d) systems. By employing
these four systems, this study spanned a range of electronic
combinations and thus allowed determination of the relative
significance of electronic effects on this system’s photophysical
properties. The λmaxexcitation, λmaxemission, Stokes shift, fluorescence
efficiency, and fluorescence lifetime for each of these four DBNs
in various solvents can be found in the Supporting Information.
An n → π* transition in the visible region (e.g., 5a: 382−416 nm
experimental; 406−417 nm calculated) is proposed as the
λmaxexcitation responsible for the variable λmaxemission observed. The
λmaxexcitation and λmaxemission are dependent upon their environment,
In summary, a new route to dibenzonaphthyridinones (DBNs)
has been developed, and the photophysical properties of these
compounds were evaluated both experimentally and computa-
tionally. The reported DBNs are highly solvatochromic with
λmaxemission varying by as much as 3623 cm−1 in CCl4 versus water.
The lifetime of fluorescence of these DBNs is also highly solvent
dependent, varyingoverarangeof10nsbasedonsolventpolarity,
with shorter lifetimes in nonpolar solvents. Lastly, we have shown
excitation
that TD-DFT provides reasonable predictions of the λmax
for these heterocycles. DBNs that have the potential to both bind
biological targets and express useful optical properties, which may
find application as tools for probing and visualizing the polarity of
various biological environs.
as evidenced by the observed solvatochromism of these DBNs
excitation
(Figure 3). It is noteworthy that a red shift in λmax
is
observed for each compound 5a−d as the polarity of the solvent
increases. Moreover, when considering the 5a−d compound
series in a given solvent, push−pull compound 5d always
displayed the largest red shift in λmaxexcitation relative to the neutral
species 5a (note: the magnitude of the λmaxexcitation shift increases
as solvent polarity increases). The fluorescence lifetimes for these
DBNsarealsoincreasedinmorepolarsolvents,mostsoinDMSO
(2.02 ns in CCl4 vs 12.05 ns in DMSO). These observed increases
ASSOCIATED CONTENT
* Supporting Information
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.5b02680.
■
S
Experimental and computational details (PDF)
Crystallographic data for 5a (CIF)
Crystallographic data for 8 (CIF)
C
DOI: 10.1021/acs.orglett.5b02680
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Letter
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: mjkurth@ucdavis.edu.
*E-mail: djtantillo@ucdavis.edu.
Author Contributions
§D.P. and M.J.H. contributed equally.
Author Contributions
∥J.S.Y., M.G.A., and E.E.K. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors dedicate this work in memory of Esther M. Kurth
(Baum Harmon Mercy Hospital, Primghar, IA), a wonderful and
gracious mentor. Financial support was provided by the NIH
(DK072517 and GM089153), the NSF (XSEDE program), and
the Tara K. Telford Fund (fellowship to T.A.P.). We thank Dr.
Chris S. Hamann of Albright College as well as University of
California, Davis scientists Dr. Kelli M. Farber and Dr. Keith C.
Coffman for insightful discussions and Dr. Marilyn M. Olmstead
and Mr. Jeremy D. Erickson for their assistance in preparing the
crystallographic data for publication.
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presented in kcal/mol. For additional details, references to computa-
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