Chromone derivatives have a wide range of applications in medicinal chemistry.[1 ] Their biological activities include tyrosine and protein kinase inhibitory,[2 ]
[3 ] antiinflammatory,[4 ] antiviral,[5 ] antioxidant, and antihypertensive activities,[6 ] as well as activities toward benzodiazepine receptors,[7 ] lipoxygenases, and cyclooxygenases.[8 ] Chromone derivatives have been used as anticancer agents[9 ] and in the treatment of cystic fibrosis, as they activate the cystic fibrosis transmembrane
conductance regulator.[10 ] The vast range of biological effects associated with chromones has led to the chromone
ring system being considered a privileged structure.[11 ] Examples of bioactive molecules derived from chroman-4-ones that have a range of
applications in medicinal chemistry are shown in Figure [1 ].[12 ]
Figure 1 Biologically active chroman-4-one derivatives
Organic compounds in which hydrogen atoms are replaced by fluorine atoms have unique
physical, chemical, and biological properties. Such fluorocarbon compounds play a
central role in drug development due to their greater probability of transformation
into drug candidates.[13 ]
[14 ] Moreover, fluorine-18 is used in radiolabeling of biomolecules for positron emission
tomography.[15 ] For the these reasons, synthetic methods for the efficient installation of fluorine
onto organic compounds have attracted considerable attention. In particular, the Kirk
group has shown that many fluorine-containing compounds have significant biological
activities,[16 ] and they have been actively pursuing research on organofluorine chemistry over recent
decades.[17 ]
The preparation of chromone derivatives has also generated great interest.[18 ] Generally, 3-substituted chromones are synthesized by two different methods.[19 ] The first approach involves addition of a substituent to a preformed chromone moiety.
The second method commences with a o -hydroxyacetophenone, with subsequent cyclization to form the pyranone ring. Nevertheless,
there is still a need for novel synthetic methods for the manipulation of the core
structure of chromones.
Scheme 1 Synthetic approach of 3-fluorochromones
Due its ease of introduction and its biological effects, the CF3 group is widely used in medicinal chemistry;[20 ] moreover, it can be regarded as a bioisostere for a chloro or a methyl group. Fluorine
has a high electronegativity, a relatively small size, and very low polarizability.[13b ] Installation of one or more fluorine atoms into an organic molecule usually improves
its binding, absorption, and transportation properties in biological situations.[21 ]
There are several indirect methods for preparing 3-fluorinated chromones (Scheme [1 ]).[22 ]
[23 ] A general approach involves condensing an o -hydroxyacetophenone derivative[10,11 ] with an aldehyde and an aniline containing a difluorochloro moiety.[24 ] Fuchigami and co-workers adopted a different approach of electrochemically fluorinating
flavones with Et3 N·3HF or Et4 NF·4HF;[25 ] however, yields were relatively low and the synthetic route was not universally
applicable. Rozen and co-workers demonstrated that one should not be intimidated by
diluted F2 ,[26 ] and they reported the preparation of 3-fluorochromone by using elemental fluorine
in a two-step synthetic sequence.[27 ] The difluoro derivatives obtained in the first step were dehydrofluorinated in the
second step to form the corresponding 3-fluorochromones. An expedient and mild strategy
for the synthesis of 3,3-difluorochroman-4-ones using Selectfluor has recently been
reported.[28 ]
Table 1 Screening of the Optimal Conditionsa
Entry
Reaction conditions
Yielda (%)
1
DCE, r.t., 24 h
–
2
Selectfluor (1.0 equiv), DCE, r.t., 24 h
46
3
Selectfluor (1.0 equiv), DCE, r.t., 48 h
48
4
Selectfluor (1.0 equiv), DCE, 70 °C, 24 h
39
5
Selectfluor (2.0 equiv), DCE, r.t., 24 h
82
6
Selectfluor (3.0 equiv), DCE, 70 °C, 24 h
36
7
Selectfluor (2.0 equiv), DCE, 100 °C, 24 h
30
8
Selectfluor (2.0 equiv), DMF, 70 °C, 24 h
61
9
Selectfluor (2.0 equiv), 1,4-dioxane, 70 °C, 24 h
37
10
Selectfluor (2.0 equiv), MeCN, 70 °C, 24 h
32
11
Selectfluor (2.0 equiv), MeCN, r.t., 24 h
62
12
Selectfluor (2.0 equiv), MeCN, r.t., 48 h
77
13
Selectfluor (2.0 equiv), H2 O, 70 °C, 24 h
62b
14
Selectfluor (2.0 equiv), CH2 Cl2 , r.t., 24 h
25
15
Selectfluor (2.0 equiv), CH2 Cl2 , r.t., 24 h
31
a Yield of the isolated product.
b The nonfluorinated chromone 4a was obtained (see below).
In our work on hybrid molecules,[29 ] we needed to synthesize a number of chromone derivatives. Inspired by the work of
Song and co-workers.[28 ] we surmised that Selectfluor {1,4-bis(chloromethyl)-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate)}[30 ] might be used for both the cyclization and fluorination of enamino ketones to give
3-fluorochromones, taking advantage of a suitably positioned hydroxy group on the
aromatic ring. Here, we report the synthesis of chromone analogues by using Selectfluor
(Scheme [2 ]). This is the first example of the use of Selectfluor in the synthesis of 3-fluorochromones
from enaminones.
Scheme 2 Preparation of 3-fluorochromones by using Selectfluor
Initially, we prepared the enamino ketone 2a by treating o -hydroxyacetophenone (1a ) with N ,N -dimethyl formamide dimethyl acetal (DMF-DMA) in toluene under reflux. Compound 2a was fully characterized by 1 H NMR and LC-MS analysis. In particular, a resonance at δ = 8.2 ppm in the 1 H NMR spectrum corresponded to the olefinic proton. The conversion of enamino ketone
2a into 3-fluoro-4H -chromen-4-one (3a ) in the presence of Selectfluor was chosen as a model reaction for the purpose of
optimizing the conditions (Table [1 ]). When enaminone 2a (1 mmol) was treated with Selectfluor (1 equiv) in dichloroethane at room temperature
for 24 hours, we were pleased to find that Selectfluor did indeed mediate the desired
fluorocyclization (Table [1 ], entry 2). Under these conditions, the reaction provided a 46% conversion of 2a into the desired chromone product 3a after 24 hours. Compound 3a was fully characterized by standard spectroscopic techniques (IR and 1 H and 13 C NMR). Because no other byproducts were formed, as evidenced by LC-MS analysis, the
reaction was allowed to continue at room temperature; however, even after 48 hours,
there was little increase in the yield of the product (48%; entry 3). Encouraged by
these result, we attempted to optimize the reaction condition by changing the amount
of Selectfluor, the reaction temperature, the solvent, and the duration of reaction
(Table [1 ]). A 77% yield of product 3a was obtained by using two equivalents of Selectfluor in MeCN as the solvent at room
temperature for 48 hours.
Scheme 3 Control experiments
Finally, to demonstrate that the reaction proceeds via the enaminone, we conducted
a control experiment (Scheme [3 ]). As expected, treating the chromone 4a with Selectfluor in DCE did not give any 3a . Interestingly, however, chromone 4a was obtained when enaminone 2a was treated with Selectfluor in water as the solvent (see also Table [1 ], entry 13).
To establish the generality of this method, the reactions of various substituted aryl
and hetaryl ketones were examined, and the results are summarized in Table [2 ]. High yields were obtained for substrates having alkyl (3b , 3f , 3p , 3q ) or halo groups (3c , 3d , 3o ) in the 6-position. More importantly, the previously inaccessible naphthalene analogue
3e and the substituted pyrazole analogue 3r were synthesized in yields of 62 and 52%, respectively. The pyridochromone derivative
3n was also synthesized in 42% yield. Among these 3-fluorochromone derivatives, three
molecules[27 ] (3a , 3c , and 3d ) are known molecules; all the others are new.
Table 2 3-Fluorochromones Synthesized
a Reaction conditions: enaminone 2 (1.0 equiv), Selectfluor (2 equiv), DCE, r.t., 24 h.
Scheme 4 Preparation of 7-fluoro-2,2-dimethyl-3,4-dihydro-2H ,6H -pyrano[3,2-g ]chromen-6-one (3v )
To demonstrate the versatility of the fluorocyclization reaction, we next explored
the possibility of employing our method to synthesize a chroman–chromone hybrid, starting
with resorcinol (5 ) (Scheme [4 ]). The reaction of 5 with 2-methylbut-3-en-2-ol (6 ) in HCO2 H gave the chromanol 7 , which was treated with acetyl chloride at –10 °C to afford the 6-acetylchromanol
8 in 70% yield.[31 ] Treatment of 8 with DMF-DMA at 100 °C under microwave conditions gave enaminone 9 , which underwent fluorocyclization with Selectfluor in DCE to give the novel chroman–chromone
hybrid 3v in 51% yield. The product was characterized by 1 H NMR, 13 C NMR, and LC-MS analyses.
In summary, we have developed a novel, efficient, and reproducible Selectfluor-mediated
reaction for the synthesis of 3-fluorochromones from readily available o -hydroxyacetophenones.[32 ] This approach offers an alternative to the use of elemental fluorine, which had
previously been used for the fluorination of chromones. The reaction conditions are
sufficiently mild to tolerate a range of functional groups, providing the potential
for further functionalization of the chromone products.
