Highly chromic, proton-responsive phenyl pyrimidones

Article abstract of DOI:10.1021/ol2014945

Aryl pyrimidones are pharmacologically relevant compounds whose optical properties have only been partially explored. We report the synthesis and optical characterization of a series of aryl- and diaryl-2(1H)-pyrimidones. The electronic transitions of the

Full text of DOI:10.1021/ol2014945

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4188–4191
Highly Chromic, Proton-Responsive
Phenyl Pyrimidones
Jyothi Dhuguru, Chirag Gheewala, N. S. Saleesh Kumar, and James N. Wilson*
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables,
Florida 33124, United States
jnwilson@miami.edu
Received June 3, 2011
ABSTRACT
Aryl pyrimidones are pharmacologically relevant compounds whose optical properties have only been partially explored. We report the synthesis
and optical characterization of a series of aryl- and diaryl-2(1H)-pyrimidones. The electronic transitions of these chromophores are modulated by
the extent of conjugation between the pendant phenyl ring and the pyrimidone core as well as the presence of electron-donating auxochromes.
Monoprotonation of the pyrimidone ring results in large hyperchromic and bathochromic shifts as well as switching of fluorescence making these
phenyl pyrimidones of interest as sensory materials.
The pyrimidone moiety is one of the most prevalent,
biologically relevant heterocycles; it is featured promi-
nently in nucleic acid chemistry1 and in many pharmaco-
logically active compounds.2 In the latter context, aryl-
substituted pyrimidones have been examined as kinase
inhibitors, antimicrobials, and analgesics.3 The hydrogen
bonding pyrimidone core coupled to a hydrophobic aryl
substituent promotes several modes of interaction in bind-
ing to a biomacromolecular target. This structural motif
also makes arylpyrimidones of interest as optically active
materials, particularly for the 4-aryl and 4,6-diarylpyrimi-
dones.
Only a few reports have investigated their photophysical
properties.4,5 Wu et al.4 examined a series of asymmetric
4,6-diarylpyrimidones and identified a Zn2þ responsive
ligand; coordination of the metal ion via the pyrimidone
core resulted in an increase in fluorescence. This behavior
may be extended to the arylpyrimidones with biological
activity provided interactions with the pyrimidone moiety,
such as protonation or hydrogen bonding, induce a similar
optical response. For example, Shafer et al.3a recently
reported a family of 4, 6-diarylpyrimidone-based inhibi-
tors of CDC7 serine/threonine kinase with nanomolar
affinities. These extended aromatic frameworks suggest
the possibility of self-reporting ligands, provided a distinct
optical response is generated upon binding.
To gain insights into the optical properties of arylpyr-
imidone constructs and their response to protonation,
we have synthesized a family of “double armed” 1-ethyl-
4,6-diphenyl-2(1H) pyrimidones (1c, 2c, and 3c, Figure 1)
and their “single-arm” derivatives, 1-ethyl-4-phenyl-2(1H)
pyrimidones and 1-methyl-6-phenyl-2(1H) pyrimidones
(1a, 1b, 2a, 2b, 3a and 3b). The absorption and emission
wavelengths are modulated through substitution to the aryl
(1) (a) Wang, G.; Tam, R. C.; Gunic, E.; Du, J.; Bard, J.; Pai, B. J.
Med. Chem. 2000, 43, 2566–2574. (b) Winkley, M. W.; Robins, R. K. J.
Org. Chem. 1969, 34, 431–434. (c) Chun, B. K.; Song, G. Y.; Chu, C. K.
J. Org. Chem. 2001, 66, 4852–4858.
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Struthers, R. S.; Xie, Q.; Tucci, F. C.; Reinhart, G. J.; Wu, D.; Saunders,
J.; Chen J. Med. Chem. 2003, 46, 1769–1772. (b) Zhang, Z.; Wallace,
M. B.; Feng, J.; Stafford, J. A.; Skene, R. J.; Shi, L.; Lee, B.; Aertgeerts,
K.; Jennings, A.; Xu, R.; Kassel, D. B.; Kaldor, S. W.; Navre, M.; Webb,
D. R.; Gwaltney, S. L. J. Med. Chem. 2010, 54, 510–524.
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Yabannavar, A.; Jia, W.; Lin, S.; Walter, A. Bioorg. Med. Chem. Lett.
2008, 18, 4482–4485. (b) Prasad, Y. R.; Rajasekhar, K. K.; ShankarananthV.;
Maulaali, S. C.; Kumar, G. S. S. P.; Reddy, K. N. J. Pharm. Res. 2010, 3,
2291–2292. (c) Keri, R. S.; Hosamani, K. M.; Shingalapur, R. V.; Hugar,
M. H. Eur. J. Med. Chem. 2010, 45, 2597–2605.
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r
10.1021/ol2014945
Published on Web 07/26/2011
2011 American Chemical Society

Figure 1. Structures of phenylpyrimidones 1aꢀ3c and represen-
tative synthesis of 1c.
Figure 2. Structural assignment of 4-phenyl- and 6-phenyl-
2(1H)-pyrimidone isomers based on optimized geometries (DF
6-31G*) and 1H NMR spectra.
arms, and the diaryl compounds in particular show a
strong chromic and emission response upon protonation.
1aꢀ3c were synthesized via acid-catalyzed condensation
of ethylurea with the appropriate diketone (Figure 1).6,7
The single arm 4-phenyl-pyrimidone and 6-phenyl-pyrimi-
done isomers were isolated from the same reaction and
separated by column chromatography. Use of an alkyl
urea allows evaluation of the unique isomers, avoiding
tautomeric equilibria. Yields were moderate, ranging from
36% (both isomers) in the case of 1a and 1b (25% and
11%, respectively) to 19% in the case of 2c. The crystalline
solids appeared colorless (1aꢀc) to bright yellow (3aꢀc)
demonstrating the effect of the electron-donating methoxy
and dimethylamino auxochromes on the arylpyrimidone
core.
for 1a the protons Ha are shifted downfield by 0.13 ppm
relative to 1b. The electron-withdrawing nature of the
pyrimidone core exerts an additional effect in the planar
aromatic system of 1a, leading to increased deshielding of
Hb protons that are shifted even further downfield by 0.50
ppm relative to 1b. 1D-NOE spectra confirm the assign-
ment of the two isomers: irradiation of the R-carbon
protons of the N-ethyl substituent reveals an NOE on
the adjacent 6-methyl group for 1a; for 1b, the effect is
observed on the phenyl protons, Hb (see Supporting Infor-
mation).
Identification and structural assignment of the isomers
were made on the basis of 1H NMR and 1D-NOE spectra.
Density functional calculations at the 6-31G* level (M06
basis set)8 reveal that the pendant phenyl substituent is
twisted in the caseofthe 6-phenyl-pyrimidones (1b, 2b, 3b),
while, in the case of the 4-phenyl-pyrimidones (1a, 2a, 3a),
the aromatic framework is essentially planar. Thus, the
chemical shifts of the aromatic protons, Ha and Hb (shown
for 1a and 1b, Figure 2), are expected to vary as a function
of aromatic ring current.9 Inspection of the aromatic
We investigated 1aꢀ3c by UVꢀvis and fluorescence
spectroscopy to determine how conjugation between the
pendant aryl arms and the pyrimidone core may influence
the optical properties of the chromophores. We also
obtained spectra in the presence of TFA to examine the
effects of monoprotonation atN310 on the opticalresponse
of these aromatic molecules. The steric interference be-
tween the 6-phenyl and N-ethyl substituents of 1b, 2b, and
3b results in a twisted geometry modulating the interaction
of the two aromatic rings, while, in the case of 1a, 2a, and
3a, the π-systems of pyrimidone and phenyl rings should
exhibit greater overlap; these effects may be reflected in the
optical spectra with changes in λmax, abs or ε. Also of
interest was the relative contribution or interaction of the
two arms in the diphenyl derivatives, 1c, 2c, and 3c.
1
region of the H NMR spectra of 1a and 1b reveals that
(6) George, S.; Nangia, A.; Bagieu-Beucher, M.; Masse, R.; Nicoud,
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(9) Mitchell, R. H.; Iyer, V. S.; Khalifa, N.; Mahadevan, R.;
Venugopalan, S.; Weerawarna, S. A.; Zhou, P. J. Am. Chem. Soc.
1995, 117, 1514–1532.
(10) (a) Kasende, O.; Zeegers-Huyskens, T. J. Mol. Struct. 1981, 75,
201–207. (b) Shoffner, J. P.; Bauer, L.; Bell, C. L. J. Heterocycl. Chem.
1970, 7, 479–485.
Org. Lett., Vol. 13, No. 16, 2011
4189

The spectra for 1aꢀ3c are depicted in Figure 3 with
Table 1 summarizing the key spectral parameters (λmax, abs, ε,
λmax, em, Φem). Several trends are apparent that reflect
the effects of the auxochromes as well as the molecular
topology (i.e., 4,6-diphenyl vs 4-phenyl vs 6-phenyl de-
rivatives); the 4,6-diphenylpyrimidones are presented first
with the relative contributions of the two “arms” discussed
below. The most pronounced spectral features are the
bathochromic shift of λmax, abs and hyperchromicity ob-
served upon introduction of TFA. For example, 3c ap-
pears colorless in CH2Cl2 and transforms to deep red when
exposed to TFA (Figure 3D). The bathochromic shift was
largest for 3c(126 nm), witha moderate shift for 2c(77 nm)
and only a slight shift for 1c (17 nm) correlating well with
the presence and relative strength of the electron-donating
substituents. Conversely, 1c exhibits the largest enhance-
ment of ε (nearly 3-fold), while 2c and 3c exhibit 2- and 1.5-
fold increases, respectively. Marked changes in fluores-
cencewerealsoobserved uponintroduction ofTFA. While
1c and 2c were weakly or nonemissive in CH2Cl2 solutions,
addition of TFA resulted in a significant enhancement of
fluorescence; for 2c a 30-fold increase inΦem was observed.
Conversely, 3c displays a Φem of 0.49 in CH2Cl2 with
exposure to TFA quenching the emission. The absorption
spectra of the 4-phenyl and 6-phenylderivatives (Figure3B
and 3C) reveal that the electronic transitions of the diphe-
nyl derivatives more closely resemble those found for the
4-phenyl than for the 6-phenyl derivatives based on the
position of λmax, abs as well as the magnitude of the bath-
ochromic and hyperchromic shifts (Table 1).
The molecular basis for the observed spectral behavior is
not immediately apparent. While the bathochromic shifts
are most likely the result of a decrease in the HOMOꢀLU-
MO gap, the physical basis for the hyperchromicity is not
clear. Protonation may serve to enhance the electron-
withdrawing nature of the pyrimidone core lowering the
LUMO and producing an intramolecular charge transfer-
like absorption. However, polarization of the HOMO and
LUMO is associated with low ε,11 which is not observed in
the present case. By considering the molecular orbital
picture for 1aꢀ3c in the neutral and protonated forms,
we gain some insights into the electronic transitions of
these chromophores. The equilibrium geometry of 1aꢀ3c
in the neutral and protonated forms were calculated using
DFT (M06) at the 6-31G* level.9 The energy of the
calculated HOMOfLUMO transitions correlates well
with the experimental values of λmax, abs. Figure 4 depicts
the LUMO and three HOMOs for 1aꢀc in the neutral and
protonated forms; similar MO levels and topologies were
found for 2aꢀc and 3aꢀc. Each of the occupied MOs is
within 1 eV and therefore likely to contribute to the optical
transitions observed in the UVꢀvis spectrum between 250
and 375 nm. Protonation leads to a redistribution of the
atomic orbital contributions to each MO. The HOMO and
HOMOꢀ1 for neutral forms of 1a and 1c effectively
Figure 3. UVꢀvis and fluorescence spectra of 1aꢀ3c in CH2Cl2.
The absorption and emission are modulated by protonation
with TFA. In all cases, modest to large hyperchromic and
bathochromic shifts are observed with TFA addition. For
phenyl (1aꢀ1c) and methoxyphenyl (2aꢀ2c) derivatives, emis-
sion is enhanced by the addition of TFA; in the case of dime-
thylamino-substituted compounds 3aꢀ3c, emission is quenched
by addition of TFA.
combine into the HOMO for the protonated forms. Thus,
the nearly 3-fold enhancement of ε for the lowest energy
transition can be rationalized, in part, on the basis of greater
spatial overlap of the HOMO and LUMO for the proto-
nated species. An additional contribution to the increase in
ε upon protonation may arise from the HOMOꢀ2 to
LUMO transition, which for 1a and 1c is calculated to
be within 0.8 and 0.3 eV, respectively. For the unproto-
nated species, HOMOꢀ2 is largely σ in character and is
orthogonal to the π-system resulting in poor overlap with
the LUMO. Onthe otherhand, inthe protonatedform, the
HOMOꢀ2 is π in nature and possesses good overlap with
the LUMO and may contribute to the high observed ε. In
the case of 1b, the lowest energy optical transition was not
significantly enhanced upon TFA addition. Inspection of
(11) (a) Schulman, S. G.; Underberg, W. J. M. Anal. Chim. Acta 1979,
108, 249–254. (b) Wilson, J. N.; Bunz, U. H. F. J. Am. Chem. Soc. 2005,
127, 4124–4125.
4190
Org. Lett., Vol. 13, No. 16, 2011

Table 1. Photophysical Characteristics of 1aꢀ3c
a
c
d
c,e
a
λmax, abs
,
ε,a,b
Ecalc
,
λmax, abs
,
ε,b,d
ꢀ1, cmꢀ1
Ecalc
,
λmax, em,
ꢀ1, cmꢀ1
eV
nm
M
eV
nm
Φem
λmax, em
Φem
a,b
d
b,d
compd
nm
M
1a
1b
1c
2a
2b
2c
3a
3b
3c
335
329
344
335
321
337
376
348
378
7200
5.0
5.3
4.3
5.0
5.4
4.8
4.4
4.8
4.4
348
331
361
387
358
414
473
474
504
21 000
12 000
28 000
25 000
33 000
34 000
37 000
37 000
47 000
4.5
4.5
4.3
4.0
3.8
3.7
3.5
3.2
3.1
384
ꢀ
0.009
ꢀ
389
390
408
486
424
488
ꢀ
0.14
0.007
0.05
0.40
0.28
0.62
ꢀ
10 000
9900
374
375
420
375
426
448
464
0.01
0.01
0.006
0.02
0.57
0.24
0.49
16 000
23 000
17 000
23 000
22 000
34 000
ꢀ
ꢀ
ꢀ
ꢀ
a CH2Cl2. b (5%. c Energy of the HOMOꢀLUMO transition, DF MO6 6-31G*, ref 8. d CH2Cl2 with 1% TFA. e For the N3 protonated species.
Figure 4. Molecular orbital representations for 1aꢀc. Protonation results in a reorganization of atomic orbital contributions to the
HOMO, HOMOꢀ1, and HOMOꢀ2 which may be correlated to the observed hyperchromic and bathochromic shifts on the basis of
improved orbital overlap and lower energy gaps. ΔELUMOꢀHOMO are given in Table 1.
the HOMO through HOMOꢀ2 for 1b in the protonated and
unprotonated forms shows that the occupied MOs remain
largely localized to either the phenyl arm or the pyrimidone
core. The small increase observed for εlikely results from the
diminished nfπ* and increased πfπ* contribution to the
absorption band centered near 330 nm. The 6-phenylpyr-
imidone derivatives, 1b, 2b, and 3b, display the lowest
quantum yields in their respective series. This may also be
due to the disjoint FMOs; the excited state likely exhibits
of HOMO and LUMO. Additionally, examples of both
“turn-on” and “turn-off” fluorescence were observed; high
overall brightness (ε ꢁ Φem) coupled with large on/off
ratios makes these simple, compact fluorophores of po-
tential interest as sensory materials. Applications of aryl-
pyrimidone derivatives as self-reporting ligands are en-
visaged given the continued interest of this motif as a
broadly active pharmacophore.
more CT character that may contribute to the lower Φem
.
Acknowledgment. This research was supported by an
American Cancer Society Institutional Research Grant.
In summary, we have synthesized and evaluated the
optoelectronic properties of a series of highly chromic,
proton responsive phenyl- and diphenylpyrimidones. The
large hyperchromic and bathochromic shifts observedmay
be rationalized on the basis of the improved spatial overlap
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
4191