Transformation of 3-(Furan-2-yl)-1,3-di(het)arylpropan-1-ones to Prop-2-en-1-ones via Oxidative Furan Dearomatization/2-Ene-1,4,7-triones Cyclization

The approach to 3-(furan-2-yl)-1,3-di(het)arylprop-2-en-1-ones based on the oxidative dearomatization of 3-(furan-2-yl)-1,3-di(het)arylpropan-1-ones followed by an unusual cyclization of the formed di(het)aryl-substituted 2-ene-1,4,7-triones has been developed. The cyclization step is related to the Paal–Knorr synthesis, but the furan ring formation is accompanied in this case by a formal shift of the double bond through the formation of a fully conjugated 4,7-hydroxy-2,4,6-trien-1-one system or its surrogate.


Introduction
Substituted furans play an important role in modern organic and medicinal chemistry. At first, the furan core is an integral part of diverse plant metabolites and, accordingly, a lot of them were isolated from various natural sources; some of them exhibit multifaceted biological activities. Thus, furopelargone B was isolated from several species of the Alpinia genus ( Figure 1) [1][2][3]. The furan fatty acids are important natural compounds due to their health benefits and impact on inflammatory and cardiovascular diseases [4,5]. Brasilamide E, isolated from the plant endophytic fungus Paraconiothynium brasiliense, selectively inhibited the proliferation of the breast and gastric cancer cell lines [6]. Fraxinellone, a partially degraded limonoid isolated from several plants [7][8][9], exhibits antifertility, vascular relaxing, anti-inflammatory, insecticidal activities [10][11][12]. Secondly, there are approved drugs containing the furan ring. For example, ranitidine is a commonly used histamine H 2 -receptor antagonist, which helps to prevent and treat gastric acid-related conditions, including ulcers [13]. Furosemide is a potent loop diuretic that is used for edema secondary to congestive heart failure exacerbation, liver and kidney failure, and high blood pressure [14,15]. Moreover, due to their versatile reactivity, furans are intensively used in organic synthesis as universal building blocks for the preparation of various useful products, including natural compounds [16][17][18][19][20].
The development of methodologies for the synthesis of substituted furans is the focus of many research groups [21][22][23][24]. In 2013, Yin et al. described an original approach for the synthesis of substituted 4-(furan-2-yl)but-3-en-2-ones C based on the oxidative rearrangement of 4-(furan-2-yl)butan-2-ones A (Scheme 1) [25]. The process proceeds through the formation of a key spiro-intermediate B, the hydrolysis of which results in the formation of functionalized furans in moderate to good yields. The formation of intermediate B is driven by the presence of electron-withdrawing group (EWG) at the the formation of a key spiro-intermediate B, the hydrolysis of which results in the formation of functionalized furans in moderate to good yields. The formation of intermediate B is driven by the presence of electron-withdrawing group (EWG) at the α-position to the ketone moiety, that facilitates its enolization and subsequent nucleophilic attack onto the activated furan nucleus. Based on our experience on the use of furans dearomatization in the synthesis of various heterocycles [26][27][28][29][30][31], we assumed that the removal of EWG may lead to a switch of reactivity pattern via the crucial decrease of the enol A' form contribution. As a result, the oxidation of oxoalkyl furans, which lack α-EWG-functionality, may lead to different products. To test this hypothesis, we studied the oxidation of 2-(2-furyl)-2-phenylethyl ketones 1 as convenient model substrates. With this goal, we synthesized a series of these starting compounds using Michael addition of 2-substituted furans to α,β-unsaturated carbonyl compounds [32]. Indeed, we found that the oxidation of substrates 1 followed by treatment with trifluoroacetic acid (TFA) led to unsaturated ketones 3 through the intermediate formation of unsaturated 1,4,7-triketones 2. Herein, we report the results of our investigation.  Based on our experience on the use of furans dearomatization in the synthesis of various heterocycles [26][27][28][29][30][31], we assumed that the removal of EWG may lead to a switch of reactivity pattern via the crucial decrease of the enol A form contribution. As a result, the oxidation of oxoalkyl furans, which lack α-EWG-functionality, may lead to different products. To test this hypothesis, we studied the oxidation of 2-(2-furyl)-2-phenylethyl ketones 1 as convenient model substrates. With this goal, we synthesized a series of these starting compounds using Michael addition of 2-substituted furans to α,β-unsaturated carbonyl compounds [32]. Indeed, we found that the oxidation of substrates 1 followed by treatment with trifluoroacetic acid (TFA) led to unsaturated ketones 3 through the intermediate formation of unsaturated 1,4,7-triketones 2. Herein, we report the results of our investigation.  Based on our experience on the use of furans dearomatization in the synthesis of various heterocycles [26][27][28][29][30][31], we assumed that the removal of EWG may lead to a switch of reactivity pattern via the crucial decrease of the enol A' form contribution. As a result, the oxidation of oxoalkyl furans, which lack α-EWG-functionality, may lead to different products. To test this hypothesis, we studied the oxidation of 2-(2-furyl)-2-phenylethyl ketones 1 as convenient model substrates. With this goal, we synthesized a series of these starting compounds using Michael addition of 2-substituted furans to α,β-unsaturated carbonyl compounds [32]. Indeed, we found that the oxidation of substrates 1 followed by treatment with trifluoroacetic acid (TFA) led to unsaturated ketones 3 through the intermediate formation of unsaturated 1,4,7-triketones 2. Herein, we report the results of our investigation. Scheme 1. Previous approach and concept of this work. Scheme 1. Previous approach and concept of this work.

Results and Discussions
We started this study by searching for optimal reaction conditions for oxidation of model furan 1a. Initially we screened a series of oxidants, commonly applied for performing related processes, and found that the use of N-bromosuccinimide (NBS)/pyridine system in aq. THF leads to the formation of (E)-2a with 77% yield while application of m-chloroperbenzoic acid (m-CPBA) afforded (Z)-2a [33] as the exclusive product in 87% yield (Scheme 2) [34,35]. Other oxidants (ceric ammonium nitrate, pyridinium chlorochromate, 2,3-dichloro-5,6-dicyanobenzoquinone, Oxone, NaClO 2 , MnO 2 , and Pb(OAc) 4 ) led to similar results, but with a lower conversion of the starting compound 1a or in low yield and poor Z,E-ratio of triketone 2a.
It is noteworthy that enetriketones 2, containing several electrophilic and nucleophilic sites with different reactivity, are attractive objects for designing various transformations, including condensations, which could afford diverse alicyclic or heterocyclic products. We attempted to study the chemical behavior of triketone 2a under various conditions. Basic conditions were screened first. We found that the treatment of the starting (Z)-2a with pyridine in aq. THF leads to a quantitative isomerization to (E)-2a. On the other hand, we did not observe any conversion of formed (E)-2a. Similar results were achieved when we used PPh 3 in toluene or 4-(dimethylamino)pyridine in DMF.
On the other hand, it is well known that aldol condensation, Paal-Knorr reaction and many other processes could be initiated by various Brønsted acids; therefore, we studied acid-catalyzed transformations of 2a. We found that the treatment of (Z)-2a with TFA in CH 2 Cl 2 at room temperature unexpectedly leads to the rapid formation of furan 3a. Oppositely, (E)-2a transforms into furan 3a only in trace amounts under the same conditions. We believe that the geometry of the C=C bond and the mutual arrangement of carbonyl groups alter the reactivity dramatically. A wide range of tested Brønsted acids led to a similar result, but after the prolonged reaction time and with lower yield of the desired product 3a. Under the optimal reaction conditions, the product was obtained as a mixture of (Z)-and (E)-isomers in a ratio of ca 89:11 based on NMR analysis.

Results and Discussions
We started this study by searching for optimal reaction conditions for oxidation of model furan 1a. Initially we screened a series of oxidants, commonly applied for performing related processes, and found that the use of N-bromosuccinimide (NBS)/pyridine system in aq. THF leads to the formation of (E)-2a with 77% yield while application of mchloroperbenzoic acid (m-CPBA) afforded (Z)-2a [33] as the exclusive product in 87% yield (Scheme 2) [34,35]. Other oxidants (ceric ammonium nitrate, pyridinium chlorochromate, 2,3-dichloro-5,6-dicyanobenzoquinone, Oxone, NaClO2, MnO2, and Pb(OAc)4) led to similar results, but with a lower conversion of the starting compound 1a or in low yield and poor Z,E-ratio of triketone 2a.
It is noteworthy that enetriketones 2, containing several electrophilic and nucleophilic sites with different reactivity, are attractive objects for designing various transformations, including condensations, which could afford diverse alicyclic or heterocyclic products. We attempted to study the chemical behavior of triketone 2a under various conditions. Basic conditions were screened first. We found that the treatment of the starting (Z)-2a with pyridine in aq. THF leads to a quantitative isomerization to (E)-2a. On the other hand, we did not observe any conversion of formed (E)-2a. Similar results were achieved when we used PPh3 in toluene or 4-(dimethylamino)pyridine in DMF.
On the other hand, it is well known that aldol condensation, Paal-Knorr reaction and many other processes could be initiated by various Brønsted acids; therefore, we studied acid-catalyzed transformations of 2a. We found that the treatment of (Z)-2a with TFA in CH2Cl2 at room temperature unexpectedly leads to the rapid formation of furan 3a. Oppositely, (E)-2a transforms into furan 3a only in trace amounts under the same conditions. We believe that the geometry of the C=C bond and the mutual arrangement of carbonyl groups alter the reactivity dramatically. A wide range of tested Brønsted acids led to a similar result, but after the prolonged reaction time and with lower yield of the desired product 3a. Under the optimal reaction conditions, the product was obtained as a mixture of (Z)-and (E)-isomers in a ratio of ca 89:11 based on NMR analysis. The plausible mechanism of this unusual transformation is presented in Scheme 3. We assumed that hydroxy group of enol D, which is presumably formed in an acidic media, attacks a suitably located carbonyl carbon with the formation of an intermediate 2,5dihydrofuran-2-ol E, which then is converted into the desired product 3a via dehydration. The disclosed cyclodehydration is similar to the Paal-Knorr furan synthesis, wherein, however, saturated 1,4-dicarbonyl compounds are used as starting compounds. In our case the formation of the furan product proceeds through the cyclodehydration of unsaturated 1,4-diketone. Further water elimination leads to the product of the formal side chain oxidation, i.e., α,β-unsaturated ketone 3a [36,37]. The plausible mechanism of this unusual transformation is presented in Scheme 3. We assumed that hydroxy group of enol D, which is presumably formed in an acidic media, attacks a suitably located carbonyl carbon with the formation of an intermediate 2,5dihydrofuran-2-ol E, which then is converted into the desired product 3a via dehydration. The disclosed cyclodehydration is similar to the Paal-Knorr furan synthesis, wherein, however, saturated 1,4-dicarbonyl compounds are used as starting compounds. In our case the formation of the furan product proceeds through the cyclodehydration of unsaturated 1,4-diketone. Further water elimination leads to the product of the formal side chain oxidation, i.e., α,β-unsaturated ketone 3a [36,37].
Since we optimized both stages separately, we decided to realize a one-pot process. First, we treated the Michael adduct 1a with m-CPBA at 0 • C in CH 2 Cl 2 , then we added TFA to the reaction mixture at ambient temperature that led to the formation of the desired product with 90% yield (Scheme 4). Encouraged by this result, we studied the scope of this synthetic protocol. We found that the wide range of triketones, formed through the oxidation of the corresponding Michael adducts 1a-p, could be involved into the discussed cyclization. Such substituents at aromatic rings as alkyl, methoxy, halogen, nitro had no significant influence on the reaction efficiency, and the desired products 3a-e,h-k,n-p were isolated in good to high yields. Moreover, we showed that the heterocyclic and naphthyl-containing Michael adducts 1f,g,l could also be converted into the corresponding products. Unfortunately, we failed to separate (Z)-and (E)-isomers of the resulting mixture using column chromatography, and in addition, we were unable to improve the ratio of isomers using the known methods of isomerization of alkenes.
Molecules 2021, 26, x FOR PEER REVIEW 4 of 13 Scheme 3. The plausible mechanism of cyclodehydration of (Z)-2a with formation of 3a.
Since we optimized both stages separately, we decided to realize a one-pot process. First, we treated the Michael adduct 1a with m-CPBA at 0 °C in CH2Cl2, then we added TFA to the reaction mixture at ambient temperature that led to the formation of the desired product with 90% yield (Scheme 4). Encouraged by this result, we studied the scope of this synthetic protocol. We found that the wide range of triketones, formed through the oxidation of the corresponding Michael adducts 1a-p, could be involved into the discussed cyclization. Such substituents at aromatic rings as alkyl, methoxy, halogen, nitro had no significant influence on the reaction efficiency, and the desired products 3a-e,hk,n-p were isolated in good to high yields. Moreover, we showed that the heterocyclic and naphthyl-containing Michael adducts 1f,g,l could also be converted into the corresponding products. Unfortunately, we failed to separate (Z)-and (E)-isomers of the resulting mixture using column chromatography, and in addition, we were unable to improve the ratio of isomers using the known methods of isomerization of alkenes.
Since we optimized both stages separately, we decided to realize a one-pot process. First, we treated the Michael adduct 1a with m-CPBA at 0 °C in CH2Cl2, then we added TFA to the reaction mixture at ambient temperature that led to the formation of the desired product with 90% yield (Scheme 4). Encouraged by this result, we studied the scope of this synthetic protocol. We found that the wide range of triketones, formed through the oxidation of the corresponding Michael adducts 1a-p, could be involved into the discussed cyclization. Such substituents at aromatic rings as alkyl, methoxy, halogen, nitro had no significant influence on the reaction efficiency, and the desired products 3a-e,hk,n-p were isolated in good to high yields. Moreover, we showed that the heterocyclic and naphthyl-containing Michael adducts 1f,g,l could also be converted into the corresponding products. Unfortunately, we failed to separate (Z)-and (E)-isomers of the resulting mixture using column chromatography, and in addition, we were unable to improve the ratio of isomers using the known methods of isomerization of alkenes.