Efficient synthesis and fluorescence properties of highly functionalized 2-aryl-quinazolin-4(3H)-ones

Article abstract of DOI:10.1016/j.tetlet.2009.03.139

Three different methodologies for the preparation of highly substituted 2-aryl-quinazolin-4(3H)-ones including short and high-yielding reaction sequences are described. The 2-aryl-substituent of most of the target compounds bears three functional groups.

Full text of DOI:10.1016/j.tetlet.2009.03.139

Tetrahedron Letters 50 (2009) 2767–2769
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis and fluorescence properties of highly functionalized
2-aryl-quinazolin-4(3H)-ones
*
Michael Waibel, Jens Hasserodt
Laboratoire de Chimie, UMR CNRS 5182, Université de Lyon—ENS, 46 allée d’Italie, 69364 Lyon, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Three different methodologies for the preparation of highly substituted 2-aryl-quinazolin-4(3H)-ones
including short and high-yielding reaction sequences are described. The 2-aryl-substituent of most of
the target compounds bears three functional groups. The fluorescence properties of these compounds
are presented and potential correlations between structure and optical properties are discussed.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 January 2009
Revised 16 March 2009
Accepted 18 March 2009
Available online 25 March 2009
Keywords:
Quinazolin-4(3H)-one
Heterocycle
HPQ
Fluorophore
Quinazolin-4(3H)-ones, especially their 2-alkyl and 2-aryl
derivatives, are a class of nitrogen-containing heterocycles of con-
siderable interest, owing to the remarkable diversity of their bio-
logical activities.1 Anticancer,2 anticonvulsant,3 antiinflamatory,4
antidiabetic,5 and antimalarial6 effects are only some of their re-
ported characteristics. Additionally, 2-(20-hydroxyphenyl)-quinaz-
olin-4(3H)-one HPQ (1) and some of its derivatives have been
reported to be highly fluorescent in the solid state.7,8 Their fluores-
cence properties arise from excited state intramolecular proton
transfer (ESIPT) from the phenol hydroxyl to the imine function
(Fig. 1). Such compounds can serve different useful applications,
for example, in chemical sensing systems or in fluorogenic probes
for biological assays.7,9
The construction of the quinazolin-4(3H)-one ring system has
been achieved via condensation of anthranilic acid derivatives with
acid chlorides or other benzoic acid derivatives,10,11 by the conden-
sation of imidates with anthranilic acid,12–14 or aza-Wittig reac-
Figure 1. Basic mechanism for excited state intramolecular proton transfer (ESIPT)
in HPQ 1. (S0: ground state, S0* excited state, S00 and S*: vibrationally excited forms of
tions of
a
-azido-substituted aromatic imides.15 Although some of
*
S0 and S0 , respectively).
these methods provide useful strategies for the synthesis of these
bicyclic compounds, they often suffer from major drawbacks, such
as low yields, too many synthetic steps, and lack of general appli-
cability.10 Moreover, only few methods have been described for the
synthesis of 2-aryl-quinazolin-4(3H)-ones with rather reactive
functional groups at the 2-aryl ring, such as hydroxyl or amino
groups.7,16,17 In particular, the literature lacks methods for the syn-
thesis of quinazolin-4(3H)-ones that tolerate multiple functional
groups on the 2-aryl substituent.
Therefore, there is certainly a need for improved concepts that
allow further derivatization of the quinazolin-4(3H)-one system
at the 2-aryl substituent in order to create novel fluorophores or
compounds of pharmaceutical potential.
We herein report three rapid and efficient routes to quinazolin-
4(3H)-ones with a phenol or aniline ring as the 2-substituent, some
of which are highly substituted. The fluorescence properties of the
synthesized compounds were evaluated, and relationships be-
tween the observed fluorescence and the substitution pattern on
the 2-aryl ring were deduced.
* Corresponding author. Tel.: +33 472 72 8394; fax: +33 472 72 8860.
E-mail address: jens.hasserodt@ens-lyon.fr (J. Hasserodt).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.139

2768
M. Waibel, J. Hasserodt / Tetrahedron Letters 50 (2009) 2767–2769
Initially, we synthesized an HPQ derivative with a dimethyl
amino group in para position to the phenol and another compound
with an additional ortho-methoxy substituent. Aldehydes 3a,b
were prepared from commercial compounds under reductive ami-
nation conditions18, transforming the nitro function of 2a,b into a
dimethylamino group in a single one-pot reaction in good yield.
This comprises the reduction of the nitro group, and two subse-
quent reductive amination steps. Subsequently, aldehydes 3a,b
were condensed with anthranilamide 4,7 followed by in situ oxida-
tion to establish the imine function, furnishing target compounds
5a,b in high yield (Scheme 1).
Scheme 2 illustrates the preparation of HPQ derived nitroani-
lines. The synthesis of aniline 10a bearing two nitro groups started
with acid 7 that was transformed into aldehyde 8a by reduction
and subsequent oxidation of the crude alcohol intermediate.19 This
highly electrophilic species was efficiently converted to 9a via an
SNAr type reaction.20 Subsequent condensation of highly substi-
tuted aldehyde 9a with 4, followed by in situ oxidation gave target
compound 10a in excellent yield. In order to obtain mono-nitro
aniline 10b, commercial fluoroaldehyde 8b was treated in a similar
way than 8a, quantitatively furnishing aldehyde 9b.21 Reaction
with 4 yielded target compound 10b.
Scheme 3 illustrates the synthesis of anilines bearing either an
unsubstituted amino group, or an electron-rich (methylation) or an
electron-poor (Cbz substitution) one. Aminoalcohols 11a and 11b
were Cbz-protected22, followed by oxidation of benzylic alcohols
23
12 using MnO2 furnishing aldehydes 13. Reaction with anthra-
Scheme 2. Synthesis of quinazolin-4(3H)-ones with nitroanilines at the 2-position.
nilamide 4, followed by in situ oxidation with DDQ gave N-Cbz ani-
line 14. The protecting group was removed using 5% Pd-C to
quantitatively produce free HPQ-derived aniline 15b and its meth-
ylated congener 15a. It should be noted that use of 10% Pd-C was
found to cause partial reduction in the imine function. As in the
preparation of 5 and 10, the preparation of the target compounds
was achieved in short syntheses with good to excellent yields.
Table 1 summarizes the fluorescence properties of the synthe-
sized compounds in the solid state. This table also includes data
of HPQ 1 which was used as reference, and of its analog 16 (MeO-
Scheme 3. Synthesis of quinazolin-4(3H)-ones with N-substituted anilines at the 2-
position.
HPQ)7 bearing a methoxy group para to the phenolic hydroxyl. As
is the case for the parent fluorophore HPQ, these compounds are
fluorescent only in the solid state, but not in solution. It is generally
assumed that solvation of the phenol or aniline function precludes
an intramolecular hydrogen bond and thus ESIPT. Among the new
molecules, aniline 14b was found to be highly fluorescent, being in
the same range as HPQ 1, and that of its methoxy derivative 16. But
Scheme 1. Synthesis of phenolic quinazolin-4(3H)-ones.

M. Waibel, J. Hasserodt / Tetrahedron Letters 50 (2009) 2767–2769
2769
Table 1
the access to new derivatives of the quinazolin-4(3H)-one core that
are of interest in pharmaceutical research.
Fluorescence properties of HPQ and the synthesized analogs
Entry
Compound
kex,max (nm)
kem,max (nm)
Relative fluorescence
intensity a.u.
Acknowledgments
1
2
3
4
5
6
7
1
16
365
365
280
280
365
Sa
495
550
460
460
525
Sa
1.00 0.06
0.96 0.05
0.08 0.004
0.09 0.005
0.89 0.06
<0.0001
This work was supported by the French Research Ministry and
the CNRS. Michael Waibel acknowledges a European Doctoral Fel-
lowship from the Research Ministry.
15b
15a
14b
5a,b
10a,b
Sa
Sa
<0.0001
Supplementary data
a
S = screening of all possible wavelengths between k = 250 and k = 850 nm.
Experimental details for the synthesis and the characterization
data for all compounds are provided. Supplementary data associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.03.139.
also anilines 15a and 15b showed good fluorescence intensities
that were still four orders of magnitude higher than the one of
compounds 5 and 10. In addition, fluorophores 14b, 15a, and 15b
exhibit large Stokes shifts (P160 nm), which are useful for the de-
sign of fluorescence-based sensing systems of high sensitivity. For
example, a large Stokes shift can circumvent the problem of tissue
background fluorescence in in vivo tests.9
In attempting to correlate the structure with the fluorescence
properties, one finds among the phenols that lack of substitution
or introduction of an ortho-methoxy group is favorable, while a
para-amino group appears to be detrimental to fluorescence (1 vs
16 vs 5a,b).
References and notes
1. For a review see: Eguchi, S. Top. Heterocycl. Chem. 2006, 6, 113–156.
2. Bavetsias, V.; Skelton, L. A.; Yafai, F.; Mitchell, F.; Wilson, S. C.; Allan, B.;
Jackman, A. L. J. Med. Chem. 2002, 45, 3692–3702.
3. Wolfe, J. F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J. A.; Greenwood, T. D. J. Med.
Chem. 1990, 33, 161–166.
4. Ozaki, K.-I.; Yamada, Y.; Oine, T.; Ishizuka, T.; Iwasawa, Y. J. Med. Chem. 1985,
28, 568–576.
5. DeRuiter, J.; Brubaker, A. N.; Millen, J.; Riley, T. N. J. Med. Chem. 1986, 29, 627–
629.
6. Dempcy, R. O.; Skibo, E. B. Biochemistry 1991, 30, 8480–8487.
7. Zhang, X. B.; Cheng, G.; Zhang, W. J.; Shen, G. L.; Yu, R. Q. Talanta 2007, 71, 171–
177.
8. Williams, D. L.; Heller, A. J. Phys. Chem. 1970, 74, 4473–4480.
9. Waibel, M.; Zhang, X. B.; Hasserodt, J. Synthesis 2009, 315–324. and references
cited therein.
10. For a review see: Connoly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153–10202.
11. Kikelj, D.. In Science of Synthesis; Thieme: Germany, 2004; Vol. 16, pp 573–749.
12. Ried, W.; Sinharay, A. Chem. Ber. 1963, 96, 3306–3311.
13. Hennequin, L. F.; Boyle, F. T.; Wardleworth, J. M.; Marsham, P. R.; Kimbell, R.;
Jackman, A. L. J. Med. Chem. 1996, 39, 695–704.
14. Connolly, D. J.; Guiry, P. J. Synlett 2001, 11, 1707–1710.
15. Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375–6386.
16. Petridou-Fischer, J.; Papadopoulos, E. P. J. Heterocycl. Chem. 1983, 20, 1159–
1167.
17. Luo, H.-Y.; Zhang, X.-B.; He, C.-L.; Shen, G.-L.; Yu, R.-Q. Spectrochim. Acta, Part A
2008, 70, 337–342.
18. Ando, M.; Emoto, S. Bull. Chem. Soc. Jpn. 1978, 51, 2433–2434.
19. Rosenström, U.; Sköld, C.; Plouffe, B.; Beaudry, H.; Lindeberg, G.; Botros, M.;
Nyberg, F.; Wolf, G.; Karlen, A.; Gallo-Payet, N.; Hallberg, A. J. Med. Chem. 2005,
48, 4009–4224.
20. Yang, Y.; Babiak, P.; Reymond, J.-L. Org. Biomol. Chem. 2006, 4, 1746–1754.
21. Wilshire, J. F. K. Aust. J. Chem. 1982, 35, 2497–2504.
22. Dei, S.; Bellucci, C.; Buccioni, M.; Ferraroni, M.; Gualtieri, F.; Guandalini, L.;
Manetti, D.; Matucci, R.; Romanelli, M. N.; Scapecchi, S.; Teodori, E. Bioorg. Med.
Chem. 2003, 11, 3153–3164.
In case of the anilines, molecules with electron-withdrawing ni-
tro groups in ortho or para position of the aryl ring displayed neg-
ligible fluorescence (10a,b). On the other hand, simple anilines
showed an increase in fluorescence intensity by four orders of
magnitude (15a,b vs 10a,b). Alkyl substitution of the aniline nitro-
gen appeared to have no significant impact (15a vs 15b). On the
other hand, introduction of an electron-withdrawing Cbz substitu-
ent into the amino group further increases the fluorescence inten-
sity by one order of magnitude (14b vs 15a, 15b). Similar
observations were reported in related compounds where the ani-
line nitrogen was part of an amide or sulfonamide unit.24
In conclusion, we have established efficient routes to novel phe-
nol and aniline derivatives of the quinazolin-4(3H)-one system.
The condensation of aldehydes with anthranilamide proved to be
tolerant to multiple substitution patterns, furnishing target com-
pounds that are highly functionalized on the 2-aryl ring. In partic-
ular, three of the synthesized compounds showed good to high
fluorescence intensities and large Stokes shifts and might thus find
applications in chemical sensor systems or enzyme assays. More-
over, the correlations between the substitution pattern on the 2-
aryl ring and the fluorescence properties made in this study will
help to direct our future work in the development of novel fluoro-
phores based on this system. Beyond these advantages, the syn-
thetic procedures established in this study may prove useful in
23. Le Sann, C.; Baron, A.; Mann, J.; van den Berg, H.; Gunaratnam, M.; Neidle, S.
Org. Biomol. Chem. 2006, 4, 1305–1312.
24. Haugland, R. P.; Steinberg, T. H.; Patton, W. P.; Diwu, Z. Patent US20020137068,
2002.