Chemoselective fluorination of 2-hydroxy-3,4,7,8-tetrahydro-2H-chromen- 5(6H)-ones using DAST

Article abstract of DOI:10.1016/j.tetlet.2011.04.070

In this study, diethylaminosulfur trifluoride (DAST) was successfully applied in monofluorination reactions of some trifluoromethyl substituted 2-hydroxy-2H-chromenones, employing a general, mild, and efficient methodology. The fluorinated compounds (2-fl

Full text of DOI:10.1016/j.tetlet.2011.04.070

Tetrahedron Letters 52 (2011) 3333–3335
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Chemoselective fluorination of 2-hydroxy-3,4,7,8-tetrahydro-2H-chromen-
5(6H)-ones using DAST
⇑
Helio G. Bonacorso , Liliane M. F. Porte, Jussara Navarini, Gisele R. Paim, Fábio M. Luz, Lenon M. Oliveira,
Carson W. Whietan, Marcos A. P. Martins, Nilo Zanatta
Núcleo de Química de Heterociclos—NUQUIMHE, Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, diethylaminosulfur trifluoride (DAST) was successfully applied in monofluorination reac-
tions of some trifluoromethyl substituted 2-hydroxy-2H-chromenones, employing a general, mild, and
efficient methodology. The fluorinated compounds (2-fluoro-2H-chromenones) were synthesized as
unique products by a chemoselective reaction in 63–81% yield despite the presence of different reactive
sites subjected to reactions with DAST.
Received 15 February 2011
Revised 11 April 2011
Accepted 18 April 2011
Available online 24 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Multi-component reactions (MCRs), by virtue of their conver-
gence, productivity, facile execution, and generally high yields of
products, have attracted much attention from the vantage point
of combinatorial chemistry.
Recently obtained also by MCR’s, functionalized chromenes and
benzopyranes are an important class of compounds, which have
received considerable attention in recent years due to their wide
range of biological activities. They display not only spasmolytic,
diuretic, clotting, antiviral, anti-tumoral and anti-anaphylactic
activities, but can also be used as pigments, photo active materials,
and biodegradable agrochemicals.1
On the other hand, fluorine substitution can alter the chemical
properties, disposition, and biological activity of drugs.2 Many
fluorinated compounds are currently widely used in the treatment
of diseases. These include antidepressants, antiinflammatory
agents, antimalarial drugs, antipsychotics, antiviral agents, ste-
roids, and general anesthetics.3 The chemistry and medicinal
chemistry of fluoro-organic compounds and drugs have been re-
viewed.2,4–6 The development of new fluorinating agents has vastly
increased the potential for synthesis of novel fluorinated drugs. In
addition, the development of sophisticated noninvasive analytical
techniques based on fluorine nuclear magnetic resonance (NMR)
and positron emission topography has transformed the study of
fluorinated drugs in man and animals.7
The inclusion of a fluorine atom in a drug molecule can influ-
ence both the disposition of the drug and the interaction of the
drug with its pharmacological target. For example, the effects of
fluorine substitution on the inter- and intramolecular forces that
affect the binding of ligands, and thus introduce the receptor sub-
type selectivity, at cholinergic and adrenergic receptors are now
well understood.8
Fluorine substitution can also have a profound effect on drug
disposition, in terms of distribution, drug clearance, route(s), and
extent of drug metabolism.9 Such changes can be used construc-
tively by medicinal chemists to improve both the safety and the
efficacy of a drug.
Thus, considering the importance described and based on the
works previously published by us,10,11 the aim of this work is to re-
port a facile, efficient, and chemoselective fluorination of 2-hydro-
xy-2H-chromenones 1 using DAST.
Commercially available diethylaminosulfur trifluoride (DAST)
reacts with aldehydes and ketones under mild conditions to give
geminal difluorides,11 while organic acids react with DAST to give
acid fluorides.12 Reaction of mono alcohols with DAST replaces
the hydroxy group13 with fluorine while reaction with diols allows
isolation of difluorides, sulfite esters, or cyclic ethers.14 In addition,
reactions of propargylic ketones and acetophenone in the presence
of 2 equiv of DAST furnished gem-difluoro derivatives.15
a,b-Unsat-
urated ketones, such as 2(1H)-naphthalenones were converted also
to gem-difluoro-naphathalenes by dehydroxy-fluorination using
DAST.16 Recently, a ring enlargement and contraction17 as well as
cyclization reactions of
were described.
a
-acylaminoketones18 promoted by DAST
Thus, considering the wide reactivity of DAST, we initially exam-
ined several possibilities of reaction in 2-hydroxy-2H-chromenones
(1a–e), previously synthesized by us,19 since there are different
reactive sites present in these compounds (one hydroxyl and two
carbonyl groups), offering the possibility to obtain different prod-
ucts, such as di- or monofluorinated, dehydrated products among
others. Moreover, because of the two enolization possibilities
(Fig. 1) of the ketone function at the C-5, and at the aroyl substituent
attached to the C-3, the alternative dehydroxy-fluorinations cannot
be ruled out.15,16
In an attempt to evaluate the behavior of 2-hydroxy-2H-
chromenones (1a–e) in the presence of DAST, we initially carried
⇑
Corresponding author. Tel.: +55 55 3220 8867; fax: +55 55 3220 8031.
E-mail address: heliogb@base.ufsm.br (H.G. Bonacorso).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.070

3334
H. G. Bonacorso et al. / Tetrahedron Letters 52 (2011) 3333–3335
OH
Ar
O
OH
O
Ar
O
OH
Ar
O
OH
R
R
R
OH
OH
OH
CF3
O
CF3
CF3
Figure 1. Tautomeric forms of chromenones 1.
.
O
Ar
O
O
O
Ar
O
DAST, CH2Cl2,
0 - 25 ºC, 24 h
R
R
OH
F
63-81 %
CF3
O
CF3
2a-e
1a-e
a
b
c
d
e
1,2
Ar Ph
Ph
Ph
Ph
Ph
4-ClPh
2-furyl
2-thienyl 2-thienyl
R
4-FPh
Scheme 1.
out reactions employing DAST in a 1:2 molar ratio (excess of the
DAST), in dichloromethane as a solvent, for 24 h at room tempera-
ture (Scheme 1).20 These reactions demonstrated that only a mono-
fluorination reaction in the 2 position occurred (2a–e) with 100%
chemoselectivity and no other product was obtained. The products
2a–e were easily isolated as solids by filtration and purified by sim-
ple washing with cold ethanol, in good yields.21
With the goal of also promoting the difluorination reaction on
the carbonyl functions present, we carried out reactions employing
DAST in different molar ratios (1:3, 1:4 and 1:5), in dichlorometh-
ane as solvent, for 24, 36, and 48 h, at room temperature. However,
under any condition, again only the fluorination reaction in the 2
position was observed (2a–e) and the presence of the difluorinated
or dehydrated compounds was not observed.
Compounds 2 are constituted by a 3,4,7,8-tetrahydro- 2H-chro-
men-5(6H)-one ring which is the core of the structure and it has
four main substituents attached: a fluorine and a trifluoromethyl
group at the C2-position and an acyl and an aryl substituent at
the C3- and C4-positions, respectively. The structures of com-
pounds 2 were fully confirmed by 1H NMR, 13C NMR, 19F NMR,
MS with chemical ionization, in the positive mode (CI+), and ele-
mental analysis.21
Thus, for example, compound 2b, obtained as a yellow solid,
showed a [M+1] ion peak at m/z 437 in the mass spectrum, according
to the molecular formulaC23H17F5O3. 1H NMR spectra showed the H-
3 at d 4.5 ppm as a doublet (J = 6 Hz), characterizing the coupling
with fluorine atom. The H-4 of the chromenone appeared at d 4.0
ppm as one singlet peak. Due to the presence of the fluorine and a
Figure 2. A perspective view of 2-fluoro-3-(4-fluorobenzoyl)-4-phenyl-2-(trifluoromethyl)- 3,4,7,8-tetra-hydro-2H-chromen-5(6H)-one (2b) with atoms labeled (CCDC
794627).22 Displacement ellipsoids are drawn at 50% probability level.

H. G. Bonacorso et al. / Tetrahedron Letters 52 (2011) 3333–3335
3335
CF3 group in the C-2 position, compounds 2 presented characteristic
References and notes
13C chemical shifts. The C-2 exhibited signals at d 103.7 ppm, as a
characteristic doublet of quartet, with 1JCF = 236 Hz, 2JCÀCF = 36 Hz,
due to the attachment to a fluorine and a CF3 group. The CF3 group
showed a signal at d 118.6 ppm, as a quartet of doublet, with
1. Rueping, M.; Sugiono, E.; Merino, E. Chem. Eur. J. 2008, 14, 6329.
2. Kirk, K. L.; Filler, R. Recent Advances in the Biomedicinal Chemistry of Fluorine-
containing Compounds In Biomedical Frontiers of Fluorine Chemistry, Symp. Ser.;
Washington: USA, 1996; 639, pp 1–24.
3. Dollery, C. Therapeutic Drugs; Edinburgh: Churchill Livingstone, UK, 1999.
4. O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 7, 645.
5. Resnati, G. Farmaco 1990, 45, 1137.
6. Resnati, G. Farmaco 1990, 45, 1043.
7. Scarfe, G. B.; Wright, B.; Clayton, E.; Taylor, S.; Wilson, I. D. Xenobiotica 1999,
29, 77.
8. Lu, S. F.; Herbert, B.; Haufe, G.; Laue, K. W.; Padgett, W. L.; Daly, W.; Kirk, K. J.
Med. Chem. 2000, 43, 1611.
9. Park, B. K.; Kitteringham, N. R. Drug Metab. Rev. 1994, 26, 605.
10. Bonacorso, H. G.; Porte, L. M. F.; Cechinel, C. A.; Paim, G. R.; Deon, E. D.; Zanatta,
N.; Martins, M. A. P. Tetrahedron Lett. 2009, 50, 1392.
11. Bonacorso, H. G.; Porte, L. M. F.; Paim, G. R.; Luz, F. M.; Martins, M. A. P.;
Zanatta, N. Tetrahedron Lett. 2010, 51, 3759.
12. Rye, C.; Baell, J.; Strett, I. Tetrahedron 2007, 63, 3306.
13. Kermarrec, C.; Madiot, V.; Grée, D.; Meyer, A.; Grée, R. Tetrahedron Lett. 1996,
32, 5691.
2
1JCF = 286 Hz; JCÀCF = 36 Hz. Unexpectedly and with the exception
for 2a (Ar = R), the 19F NMR spectra for 2b–e (Ar – R) showed two
singlets for the fluorine atom attached to the C-2 and one singlet
for the CF3 group bonded to the same carbon (C-2). Complementa-
rily, the X-ray diffraction measurement was carried out for com-
pound 2b (Fig. 2)22 proving that the fluorine atom replaced the
hydroxyl group in the 2 position. In addition, this paper confirmed
what had been suggested by Arbilla et al.23 The author proposed that
the mechanism by which the reaction occurred with DAST should be
an SN2 type. This fact was confirmed by us as we watched the inver-
sion of configuration at C-2 in comparison to the spectroscopy and
X-ray diffraction data for the precursors 1.19
In the present Letter, we have demonstrated that using a
mild and an efficient protocol for the chemoselective fluorina-
tion reaction of the 2-hydroxy-tetrahydro-2H-chromenones by
DAST in CH2Cl2 at 0–25 °C for 24 h, 2-fluoro-2H-chromenones
can be easily obtained in good yields (63–81%) and as a unique
product, because no side reaction products were observed or
isolated.
Unless otherwise indicated all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. All melting points were determined on a Reichert
Thermovar apparatus. 1H, 13C and 19F NMR spectra were acquired
on a Bruker DPX 200 spectrometer (1H at 200.13 MHz) and Bruker
DPX 400 (13C at 100.32 MHz and 19F at 376.3 MHz) spectrometer,
5 mm sample tubes, 298 K, digital resolution 0.01 ppm, in CDCl3,
using TMS as internal reference (1H and 13C) or fluorobenzene as
external reference (19F). The CHN elemental analyses were per-
formed on a Perkin Elmer 2400 CHN elemental analyzer (São Pau-
lo University–USP/Brazil). Mass spectra were registered in a HP
5973 MSD connected to a HP 6890 GC and interfaced by a
Pentium PC. The GC was equipped with a split-splitless injector,
autosampler, cross-linked HP-5 capillary column (30 m,
0.32 mm of internal diameter), and He was used as the carrier
gas.
14. Shellhamer, D. F.; Anstine, D. T.; Gallego, K. M.; Ganesh, B. R. J. Chem. Soc. Perkin
Trans. 2 1995, 861.
15. Matsumoto, T.; Kusomoto, A. Jpn. Kokai Tokkyo Koho, 2005170900, 30 Jun 2005.
16. Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Tetrahedron Lett. 2007, 48, 5305.
17. Cossy, J.; Hijfte, L. V.; Pardo, D. G.; Ferret, H. ARKIVOC 2010, viii, 126.
18. Loiseleur, O.; Wagner, T.; Pandya, C.; Blythe, J.; Bigot, A. Org. Lett. 2010, 13, 192.
19. Bonacorso, H. G.; Navarini, J.; Wiethan, C. W.; Bortolotto, G. P.; Paim, G. R.;
Cavinatto, S.; Martins, M. A. P.; Zanatta, N.; Caro, M. S. B. J. Fluorine Chem.
2011, 132, 160.
20. Synthesis of 2-fluoro-2H-chromenones (2a–e). General Procedure: To a stirred
solution of 1a–e (1 mmol) in dichloromethane (10 mL) was added dropwise
DAST (2 mmol) in dichloromethane (5 mL) at 0 °C. After addition, the reaction
mixture was stirred at 25 °C for 24 h, and then the reaction was quenched by
the slow addition of aqueous NaHCO3 solution until effervescence was
completed. The dichloromethane layer was separated, dried over anhydrous
Na2CO3, and filtered. The solvent was evaporated under reduced pressure,
obtaining the corresponding compounds 2a–e, which were isolated as solids by
filtration and purified by simple washing with cold ethanol.
21. Compounds 2 were obtained as solids and were characterized by 1H, 13C and
19F NMR and GC–MS. Data of 2-fluoro-3-(4-fluorobenzoyl)-4-phenyl-2-
(trifluoromethyl)- 3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (2b): Yield 74%,
mp 70–72 °C. 1H NMR (400 MHz, CDCl3): d = 8.0–8.04 (m, 2H, Ph), 7.1–7.3 (m,
7H, Ph), 4.5 (d, 1H, J = 6, H-3), 4.0 (d, 1H, H-4), 2.7–2.8 (m, 2H, H-6), 2.4–2.5 (m,
2H, H-8), 2.1–2.2 (m, 2H, H-7). 13C NMR (CDCl3): d = 196.2 (C@O), 191.0 (C-5),
165.6 (d, JCÀF = 253), 165.1 (C-8a), 140.4, 131.2, 128.6, 127.2, 121.2, 120.8,
1
2
111.8 (Ph), 118.6 (qd, CF3, JCF = 286, JCF = 36), 106.4 (C-4a), 103.7 (dq, C-2,
1JCF = 236, 2JCF = 36), 46.2 (d, C-3, J = 21), 36.8 (C-6), 31.6 (C-4), 27.6 (C-8), 20.3
(C-7). 19F NMR = d (376 MHz, CDCl3) À67.2 and À108.7 (CF); À81.8 (CF3). GC–
MS (CI+): m/z (%) 437 (M+1, 100), 313 (17), 217 (14), 123 (10). Anal. Calcd: C,
63.31; H, 3.93. Found: C, 63.57; H, 4.22%. Melting points and yields of new
compounds 2: Compd. [mp (°C), yield (%)]: 2a [60–62, 63]; 2c [88–90, 65]; 2d
[54–56, 78]; 2e [74–76, 81];
22. Crystallographic data for the structure of 2b, reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre and allocated the
deposition number CCDC 794627. Copies of the data can be obtained free of
charge, on application to CCDC 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44 1223 336033 or e-mail: deposit@ccdc.com.ac.uk).
Acknowledgments
The authors thank the financial support from Conselho Nacional
de Desenvolvimento Científico e Tecnológico –CNPq. Fellowships
from CAPES and CNPq are also acknowledged.
23. Arbilla, G.; Baptista, L.; Bauerfeldt, G. F.; Silva, E. C. J. Mol. Struct. 2006, 761, 73.