Synthesis of novel fluorinated 4H-benzo[h]chromen-4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.11.146

New fluorinated 4H-benzo[h]chromen-4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives are obtained in moderate to good yields, through a one-pot aldolization-intramolecular S_NAr process, from the tetrakis(dimethylamino)ethylene (TDAE) mediate

Full text of DOI:10.1016/j.tetlet.2007.11.146

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 589–593
Synthesis of novel fluorinated 4H-benzo[h]chromen-4-one
and 4H-pyrano[3,2-h]quinolin-4-one derivatives
a,
a
b
c
*
´
Maurice Medebielle , Robert Keirouz , Etsuji Okada , Dai Shibata ,
William R. Dolbier, Jr. d
a Universite´ Claude Bernard Lyon 1 (UCBL), Universite´ de Lyon, Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires (ICBMS),
Equipe SERCOF, UMR 5246 CNRS-UCBL-INSA-CPE, 43 bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
b Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
c Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
d Department of Chemistry, University of Florida, Gainesville, FL 32611, USA
Received 15 October 2007; revised 7 November 2007; accepted 23 November 2007
This Letter is dedicated to the memory of Professor Yoshihiro Matsumura
Abstract
New fluorinated 4H-benzo[h]chromen-4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives are obtained in moderate to good yields,
through a one-pot aldolization–intramolecular SNAr process, from the tetrakis(dimethylamino)ethylene (TDAE) mediated reductive
cleavage of two N,N-dimethylamino-bis-chlorodifluoroacetyl substrates in the presence of heteroaryl aldehydes.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Tetrakis(dimethylamino)ethylene; Electron transfer; Fluorine; Flavone; SNAr
Fluorinated substituted aromatics and heterocycles have
found broad applications such as agrochemicals, anti-
cancer and antiviral agents.1 The similarity in size makes
fluorine an obvious candidate to replace hydrogen, often
without significant disturbance of the molecular geometry
and shape.2 Flavonoids form a class of benzo-c-pyrone
derivatives which are common in plants. They possess a
wide spectrum of biological activities. Most notably
flavonoids have been found to possess anticancer
activities.3 Recently, some derivatives have been evaluated
as potential anti-HIV agents for the treatment of AIDS.4
Fluorinated flavones have been rarely described in the
literature. Fuchigami and co-workers described the
electrochemical partial mono-fluorination of a series of
6-substituted flavones to yield the corresponding 3-fluoro-
6-substituted flavones in moderate yields.5 The same group
extended their studies to the electrolytic partial fluorination
of (E)-3-benzylidene-2,3-dihydrochroman-4-ones.6 Laurent
and co-workers also reported the anodic fluorination of
2-phenylthiochromen-4-one to give the corresponding
mono-fluorinated product in 46% yield.7 More recently
some B-Ring fluorinated flavonoids have been screened
as potential telomerase inhibitors;3a one compound showed
a very promising activity (IC50 = 0.6 lM), comparable to
the analog lacking the fluorine atom. In addition B-Ring
trifluoromethylated flavonoids have been prepared and
tested in vitro against cancer cell lines (Fig. 1).8 For some
years we have been interested in the aromatic nucleophilic
substitution reactions of N,N-dimethyl-2,4-bis(trifluoro-
acetyl)-1-naphthylamine,9 N,N-dimethyl-2-trifluoroacetyl-
4-halo-1-naphthyl-amines,10 N,N-dimethyl-5,7-bis(trifluo-
roacetyl)-8-quinolylamine,11 with amines, thiols and
alcohols and we have shown that the corresponding
exchanged products could be easily converted to various
*
Corresponding author. Tel.: +33 (4) 72 43 19 89; fax: +33 (4) 72 43
13 23.
´
E-mail address: medebiel@univ-lyon1.fr (M. Medebielle).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.146

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M. Me´debielle et al. / Tetrahedron Letters 49 (2008) 589–593
of chlorodifluoroacetic anhydride (CDFAA) and pyridine
in anhydrous CH2Cl2 at room temperature for 18 h. Sub-
strate 2 was similarly prepared in a 72% isolated yield,
using N,N-dimethyl-8-quinolylamine13e as starting mate-
rial, in ClCH2CH2Cl as solvent, at 45 °C for 18 h (Scheme
2).
Careful examination, by cyclic voltammetry of the
reduction potential of starting materials 1 and 2 (in
DMF + 0.1 M NBu4PF6), indicated that these substrates
were reduced at relatively low potentials (E1 ꢀ À1.1 V vs
SCE), suggesting that they were good-electron acceptors
and that they may be effectively reduced by TDAE. Usually
the reduction potential corresponding to the reductive
cleavage of the two C–Cl bonds is very close (ꢀ100 mV)
with the one from the chlorodifluoroacetyl moiety at the
para position of the –NMe2 group being the more positive.
When 2.2 equiv of TDAE (to generate the bis-enolate)
was added dropwise to 1 equiv of ketone 1 and 4 equiv of
PhCHO in anhydrous DMF at À20 °C, the familiar dark
red colour of the charge transfer complex appeared. When
the addition of TDAE was completed, the mixture was
then stirred at À20 °C for 1 h and slowly warmed to room
temperature over 1 h. TLC analysis of the reaction mixture
(orange-brown with some insoluble solid) revealed that
some starting material was still present in addition with
several products. Fluorine NMR analysis revealed besides
the presence of unreacted ketone 1, the formation of
N,N-dimethyl-2,4-bis(difluoroacetyl)-1-naphthylamine as
the major component, as well as the presence of two other
products characterized by two doublets of doublets. In
addition two singlets were observed at dF close to
À57 ppm/CFCl3 and À159.60 ppm/CFCl3. These rather
disappointing results indicated that the reduction and pro-
tonation of the bis-enolate was the major pathway. Optimi-
zation of the reaction conditions showed that a large excess
of the aldehyde (8 equiv) was necessary, as well as a longer
reaction time (2 h at À20 °C followed by 3 h at room tem-
perature) for complete consumption of starting material,
cleaner reaction and higher yield of cyclized products.
Using 8 equiv of PhCHO, 1 equiv of ketone 1 and 2.2 equiv
of TDAE, and after warming-up the solution to room tem-
perature over 3 h, the solution was quenched with brine
and the resulting copious precipitate was extracted with
EtOAc. Evaporation of the organic extracts and trituration
of the oily residue with cyclohexane (to remove unreacted
benzaldehyde) left an orange solid. Fluorine NMR analysis
Fig. 1. Biologically active fluorinated and trifluoromethylated flavonoids.
fluorinated fused-heterocycles of potential biological
importance. Recently, these aromatic nucleophilic substitu-
tion reactions were extended to N,N-dimethyl-2-trifluoro-
acetyl-1-naphthylamine.12
As part of our ongoing efforts in search of synthetic
approaches for the synthesis of novel fluorinated hetero-
cycles with potential biological applications, we envisaged
to prepare novel fluorinated fused flavone-type derivatives
3–8, utilizing the tetrakis(dimethylamino)ethylene (TDAE)13
reagent and N,N-dimethyl-2,4-bis(chlorodifluoroacetyl)-
1-naphthylamine 1 and N,N-dimethyl-5,7-bis(chlorodi-
fluoroacetyl)-8-quinolylamine 2 as model substrates, in
the presence of aromatic and heteroaldehydes (Scheme 1).
In addition, and relevant to the work presented in this
Letter, we also described an approach to the synthesis of
novel difluorinated 5-aminodihydropyrano[2,3-b]quinolin-
4-ones through a one-pot zinc mediated aldolization–intra-
molecular SNAr process.14 Our targets can be regarded as
analogs of a-naphthoflavone and derivatives, known for
their anticancer activities,15 as potential cystic fibrosis
transmembrane conductance regulators,16 adenosine recep-
tor antagonists,17 and potent antiplatelet.18 We wish to
present herein our preliminary results.
Substrate 1 was conveniently prepared in a 75% isolated
yield, by bis-chlorodifluoroacetylation of the commercially
available N,N-dimethyl-1-naphthylamine, using 2.5 equiv
Scheme 1. Proposed strategy.
Scheme 2. Starting materials synthesis.

M. Me´debielle et al. / Tetrahedron Letters 49 (2008) 589–593
591
of this solid clearly showed two doublets of doublets
centred at dF À106.7 and À118.7 ppm/CFCl3 with
3
2JF–F = 272 Hz and JH–F = 6.3 and 17.7 Hz and two
doublets centred at dF À122.4 and À122.7 ppm/CFCl3 with
2JH–F ꢀ 55 Hz [corresponding to the N,N-dimethyl-2,4-
bis(difluoroacetyl)-1-naphthylamine], in the ratio of 8 to
2. Also two singlets were observed at dF À158.51 and
À158.81 ppm/CFCl3 in the ratio of 3 to 1. TLC analysis
and proton NMR also indicated that still some PhCHO
remained. Further trituration with hot cyclohexane,
filtration over silica gel gave the pure 4H-benzo[h]-
chromen-4-one derivative 3 in a 65% isolated yield.19 The
fluorine NMR spectrum of 3 confirmed the presence of
two doublets of doublets centred at dF À106.04 and
2
3
À117.14 ppm/CFCl3 with JF–F = 272 Hz and JH–F
=
6.27 and 17.70 Hz and a singlet at dF À159.61 ppm/
CFCl3.
The reaction was found to be quite general when
extended to other aldehydes and to substrate 2. A series
of new benzo[h]chromen-4-one derivatives 3–6 and 4H-pyr-
ano[3,2-h]quinolin-4-one derivatives 7,8 were thus obtained
in moderate to good yields (Scheme 3), with the exception
of compound 6, bearing a 3,4-dimethoxyphenyl moiety,
obtained in a relatively low yield (18%). With this
aldehyde, the major product was found to be the
N,N-dimethyl-2,4-bis(difluoroacetyl)-1-naphthyl-amine in
addition to other fluorinated impurities. Usually all the
reactions needed less than 4 h for completion as checked
by TLC and fluorine NMR. Target compounds 3–8 were
obtained by simple trituration of the crude extract with
cyclohexane and filtration over silica gel.
All the compounds have quite poor solubility in organic
solvents such as CHCl3, CH2Cl2, acetone, acetonitrile and
hexane. They are relatively soluble in EtOAc, DMSO and
MeOH.
A tentative mechanism for this reaction is depicted in
Scheme 4. TDAE is able to promote the reduction of the
two C–Cl bonds thus generating a bis-enolate, that can
be trapped with the aldehyde (in excess) to yield the corre-
sponding bis-alcoholate A; it subsequently undergoes an
Scheme 4. Proposed mechanism.
addition–elimination reaction yielding the difluoromethyl-
ene derivative B and the corresponding NMe2 anion
(N–O exchange reaction), which could act as a strong base
and induces an H–F elimination, giving finally the fused
derivatives 3–8. Also an internal proton-transfer from the
enolate may also occur.
The efficient synthesis of these new 4H-benzo[h]chro-
men-4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives
using substrates 1 and 2, is in sharp contrast to the TDAE
mediated reduction of the N,N-dimethyl-2-chlorodifluoro-
acetyl-4-bromo-1-naphthylamine 9 in the presence of
heteroaryl aldehydes, where the corresponding carbinol
adducts were obtained in moderate to good yields, without
any formation of the cyclized products (Scheme 5).13e
Therefore the presence of two activating –COCF2Cl
moieties seem to be essential for the intramolecular SNAr
cyclization.
We are currently trying to optimize some of the yields,
and to extend the approach to other ortho-chlorodifluoro-
acetyl substrates, and there are preliminary results showing
Scheme 5. Previous TDAE mediated reductive addition of N,N-dimethyl-
2-chlorodifluoroacetyl-4-bromo-1-naphthyl-amine 9 in the presence of
aldehydes.
Scheme 3. TDAE mediated synthesis of fluorinated 4H-benzo[h]chromen-
4-one and 4H-pyrano[3,2-h]quinolin-4-one derivatives 3–8.

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M. Me´debielle et al. / Tetrahedron Letters 49 (2008) 589–593
3. (a) Menichincheri, M.; Ballinari, D.; Bargiotti, A.; Bonommini, L.;
Ceccarelli, W.; D’Alessio, R.; Fretta, A.; Moll, J.; Polucci, P.; Soncini,
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(b) Hojo, M.; Masuda, R.; Okada, E. Tetrahedron Lett. 1987, 28,
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Scheme 6. Extension of the methodology to new substrates 14 and 15.
that the reaction can be extended to substrates 14–15,
which undergo reaction with benzaldehyde under similar
conditions previously described for 1 and 2 (Scheme 6).
The corresponding benzo[h]chromen-4-one derivatives 16
and 17 were thus obtained in 58% and 45% yields. The full
results for this system will be reported in due course. Exten-
sion of this useful approach to more complex fused-deriv-
atives as well to other electrophiles is one of our next goals.
The products described in this Letter will be screened as
potential anticancer and antiviral agents.
10. Okada, E.; Tsukushi, N.; Otsuki, Y.; Nishiyama, S.; Fukuda, T.
Synlett 1999, 126.
11. (a) Okada, E.; Tsukushi, N.; Shimomura, N. Synthesis 2000, 237; (b)
Okada, E.; Tsukushi, N. Synlett 1999, 210.
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12. Okada, E.; Otsuki, Y.; Shinohara, M.; Medebielle, M.; Shimizu, Y.;
Takeuchi, H. Tetrahedron Lett. 2003, 44, 741.
13. We have already demonstrated the broad scope of nucleophilic di-
and trifluoromethylation reactions from the reduction of a series of
halogenodifluoromethyl substrates and CF3I by TDAE: (a) Pooput,
´
C., Jr.; Dolbier, W. R.; Medebielle, M. J. Org. Chem. 2006, 71, 3564;
´
(b) Medebielle, M.; Kato, K.; Dolbier, W. R., Jr. Tetrahedron Lett.
´
2003, 44, 7871; (c) Takechi, N.; Ait-Mohand, S.; Medebielle, M.;
In conclusion, we have demonstrated that TDAE is an
effective reducing agent that promotes, under mild condi-
tions, the synthesis of novel fluorinated fused-heterocyclic
derivatives. Although the reaction mechanism is not fully
understood, a mechanistic pathway involving an SET tan-
dem aldol/SNAr process has been proposed.
´
Dolbier, W. R., Jr. Org. Lett. 2002, 4, 4671; (d) Medebielle, M.; Kato,
´
K., ; Dolbier, W. R., Jr. Synlett 2002, 1541; (e) Medebielle, M.;
Keirouz, R.; Okada, E.; Ashida, T. Synlett 2001, 821; (f) Billard, T.;
Langlois, B. R.; Medebielle, M. Tetrahedron Lett. 2001, 42, 3463; (g)
Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. R., Jr.
Org. Lett. 2001, 3, 4271; (h) Burkholder, C.; Dolbier, W. R., Jr.;
Medebielle, M.; Ndedi, A. Tetrahedron Lett. 1998, 39, 8853; (i)
´
´
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Burkholder, C.; Dolbier, W. R., Jr.; Me´debielle, M. J. Org. Chem.
1998, 63, 5385. We have also demonstrated that the TDAE reagent
can be used with non-fluorinated substrates for the synthesis of
potential anticancer agents: (a) Giuglio-Tonolo, G.; Terme, T.;
Acknowledgements
We would like to thank the Centre National de la
Recherche Scientifique (CNRS) for support of this
research, the Direction des Relations Internationales
(DRI) of the CNRS for travel funds (M.M.) and the Japan
Society for the Promotion of Science (JSPS) for a research
fellowship (M.M.).
´
Medebielle, M.; Vanelle, P. Tetrahedron Lett. 2003, 44, 6433; (b)
´
Giuglio-Tonolo, G.; Terme, T.; Medebielle, M.; Vanelle, P. Tetra-
hedron Lett. 2004, 45, 5121.
´
14. Medebielle, M.; Hohn, S.; Okada, E.; Myoken, H.; Shibata, D.
Tetrahedron Lett. 2005, 46, 7817.
15. Cardenas, M.; Marder, M.; Blank, V. C.; Roguin, L. P. Bioorg. Med.
Chem. 2006, 14, 2966.
16. Springsteel, M. F.; Galietta, L. J. V.; Ma, T.; By, K.; Berger, G. O.;
Yang, H.; Dicus, C. W.; Choung, W.; Quan, C.; Shelat, A. A.; Guy,
R. K.; Verkman, A. S.; Kurth, M. J.; Nantz, M. H. Bioorg. Med.
Chem. 2003, 11, 4113.
References and notes
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39, 2293.
18. Hsiao, G.; Chang, C.-Y.; Shen, M.-Y.; Chou, D.-S.; Tzeng, S.-W.;
Chen, T.-F.; Sheu, J.-R. J. Agric. Food. Chem. 2005, 53, 5179.
19. A typical procedure for the reaction between 1, TDAE and
benzaldehyde is as follows: Into a two-necked flask were added,
under nitrogen at À20 °C, a 5 ml anhydrous DMF solution of 1
1. (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applica-
tions; Springer: Berlin, 2000; (b) Burger, K.; Wucherpfennig, U.;
Brunner, E. Adv. Heterocycl. Chem. 1994, 60, 1; (c) Bergstrom, D. E.;
Swartling, D. J. Fluorine Substituted Analogues of Nucleic Acid
Components. In Liebman, J. F., Greenberg, A., Dolbier, W. R., Jr.,
Eds.; Fluorine-Containing Molecules, Structure, Reactivity, Synthesis
and Applications; VCH: New York, 1988; pp 259–308.
2. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim,
2004.

M. Me´debielle et al. / Tetrahedron Letters 49 (2008) 589–593
593
(0.50 g, 1.26 mmol) and benzaldehyde (1.07 g, 10.08 mmol, 1.02 ml).
The solution was stirred and maintained at this temperature for
30 min and then was added dropwise (via a syringe) the TDAE
(0.51 g, 2.53 mmol, 0.59 ml). A red colour immediately developed
with the formation of a white fine precipitate. The solution was
vigorously stirred at À20 °C for 2 h and then warmed up to room
temperature for 3 h. After this time TLC analysis (petroleum ether/
EtOAc, 80:20) showed that ketone 1 was totally consumed. The
brown-orange turbid solution was filtered (to remove the octameth-
yloxamidinium dichloride) and hydrolyzed with 50 ml of brine. A
copious precipitate was formed which was extracted with EtOAc
(3 Â 50 ml), the combined organic extracts washed with brine
(3 Â 50 ml), H2O (3 Â 50 ml) and dried over Na2SO4. Evaporation
of the solvent left an orange viscous liquid as crude product.
Trituration with hot cyclohexane (to remove unreacted aldehyde) left
an orange solid (0.42 g). TLC analysis (petroleum ether/EtOAc,
70:30) revealed that this solid contain one major product with some
aldehyde. The solid was further triturated with hot cyclohexane,
purified by filtration over silica gel (elution with petroleum ether/
EtOAc, 90/10) to yield 0.31 g (0.65 mmol, 65%) of pure 3 as a yellow
solid. 6-(2,2-Difluoro-3-hydroxy-3-phenylpropanoyl)-3-fluoro-2-phenyl-
4H-benzo[h]-chromen-4-one. 1H NMR (DMSO-d6/300 MHz): dH
5.36 (1H, dt, J = 20.5, 5.46 Hz, –CHOH), 6.91 (1H, dd, J = 6.60,
1.32 Hz), 7.39–7.54 (5H, m), 7.71–7.73 (3H, m), 7.91–8.00 (2H, m),
8.16–8.24 (3H, m), 8.65 (1H, d, J = 2.07 Hz), 8.75–8.79 (1H, m). 19F
NMR (DMSO-d6/280 MHz): dF À106.04 (1F, dd, J = 272.0,
6.27 Hz), À117.14 (1F, dd, J = 272.0, 17.70 Hz), À159.61 (1F, s).
MS (CI/CH4): 475 (MH+), 369 (MH+ÀPhCHOH), 107 (PhCHO).
HRMS (ESI): calcd for C28H17F3O4 474.1079, found 474.1157. Anal.
Calcd for C28H17F3O4: C, 70.89; H, 3.61. Found 71.20; H, 3.82.