Hypervalent Iodine(III)-Induced Domino Oxidative Cyclization for the Synthesis of Cyclopenta[b]furans

A new strategy for cyclopenta[b]furan synthesis mediated by hypervalent iodine(III) has been described. The approach employs diacetoxyiodobenzene-induced initial dehydrogenation to a putative trienone intermediate and triggered sequential cycloisomerization to form the cyclo-penta[b]furan targets.


Results and Discussions
In the study described below, we have explored a method for the synthesis of cyclopenta [b] furans containing a stereogenic, quaternary, aryl-substituted bridgehead carbon. For the preparation of 2-aryl-1,4-dibromopenta-2,4-dienes 2 we used a literature procedure developed in our group [17]. The β-ketoesters linked with pentadiene tether 3 were prepared by C-alkylation of ethyl acetoacetate enolate with 2; however, the chromatographic purification of compounds 3 is difficult in most cases (Table 1). In fact, only 3h can be isolated in pure form by recrystallization after chromatographic purification. Crude analogues 3a-g as obtained after silica-gel plug treatment were carried directly into the next step, therefore, purity and exact yields of 3a-g are not given in Table 1. In order to evaluate the feasibility of the new strategy for cyclopenta [b]furan synthesis, 3b serves as effective substrate in the reaction with diacetoxyiodobenzene that takes place by a one-pot, initial dehydrogenation to give a putative trienone intermediate and sequential cycloisomerization to form the cyclopenta[b]furan ( Table 2). The results show that the putative trienone produced in these reactions is not isolable using chromatography, and at ambient temperature only the formation of the trienone was observed (

Results and Discussions
In the study described below, we have explored a method for the synthesis of cyclopenta [b] furans containing a stereogenic, quaternary, aryl-substituted bridgehead carbon. For the preparation of 2-aryl-1,4-dibromopenta-2,4-dienes 2 we used a literature procedure developed in our group [17]. The β-ketoesters linked with pentadiene tether 3 were prepared by C-alkylation of ethyl acetoacetate enolate with 2; however, the chromatographic purification of compounds 3 is difficult in most cases (Table 1). In fact, only 3h can be isolated in pure form by recrystallization after chromatographic purification. Crude analogues 3a-g as obtained after silica-gel plug treatment were carried directly into the next step, therefore, purity and exact yields of 3a-g are not given in Table 1. In order to evaluate the feasibility of the new strategy for cyclopenta [b]furan synthesis, 3b serves as effective substrate in the reaction with diacetoxyiodobenzene that takes place by a one-pot, initial dehydrogenation to give a putative trienone intermediate and sequential cycloisomerization to form the cyclopenta[b]furan ( Table 2). The results show that the putative trienone produced in these reactions is not isolable using chromatography, and at ambient temperature only the formation of the trienone was observed ( Table 2, entries 1 and 8). At elevated temperature, the putative trienone underwent cycloisomerization to Scheme 2. Synthetic plans for the synthesis of cyclopenta[b]furan derivatives 1.

Results and Discussions
In the study described below, we have explored a method for the synthesis of cyclopenta[b]furans containing a stereogenic, quaternary, aryl-substituted bridgehead carbon. For the preparation of 2-aryl-1,4-dibromopenta-2,4-dienes 2 we used a literature procedure developed in our group [17]. The β-ketoesters linked with pentadiene tether 3 were prepared by C-alkylation of ethyl acetoacetate enolate with 2; however, the chromatographic purification of compounds 3 is difficult in most cases (Table 1). In fact, only 3h can be isolated in pure form by recrystallization after chromatographic purification. Crude analogues 3a-g as obtained after silica-gel plug treatment were carried directly into the next step, therefore, purity and exact yields of 3a-g are not given in Table 1. In order to evaluate the feasibility of the new strategy for cyclopenta [b]furan synthesis, 3b serves as effective substrate in the reaction with diacetoxyiodobenzene that takes place by a one-pot, initial dehydrogenation to give a putative trienone intermediate and sequential cycloisomerization to form the cyclopenta[b]furan ( Table 2). The results show that the putative trienone produced in these reactions is not isolable using chromatography, and at ambient temperature only the formation of the trienone was observed ( Table 2, entries 1 and 8). At elevated temperature, the putative trienone underwent cycloisomerization to form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol (Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1). form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol (Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).   form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).   form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).  a Reagents and Conditions: 3 (0.3 mmol), PhI(OAc) 2 (0.6 mmol) and Na 2 CO 3 (0.66 mmol) in EtOH (1.2 mL). b PhI(OCOCF 3 ) 2 was employed instead of PhI(OAc) 2 . c 1 (0.5 mmol), Cs 2 CO 3 (1.5 mmol, 3.0 mmol for 4b, 4g), PhB(OH) 2 (0.75 mmol, 1.5 mmol for 4b, 4g), Pd(dppf)Cl 2 (0.05 mmol) in dioxane/water (5/1, 0.5 mL) 100 • C for 2 h. form cyclopenta[b]furans (entry 1 vs. entry 2, entry 7 vs. entry 8), reactions in which inorganic bases gave better yields than organic bases (entry 4 vs. entry 5, entry 8 vs. entry 9). In addition, the oxidation-cycloisomerization process happened smoothly when [bis(trifluoroacetoxy)iodo]benzene was employed. The ideal conditions for this process involve the use of diacetoxyiodobenzene and sodium carbonate in refluxing ethanol ( Table 2, entry 7). Next, a variety of aryl-substituted substrates 3 were examined and Suzuki reactions were pursued in order to confirm the structural determination and the relative stereochemistry at the ring junction of the cyclopenta[b]furans 1 (Table 1).   The stereochemistry of the fused-bicyclic ring system in 4b was shown to be cis using X-ray crystallographic analysis (Figure 1 and Supplementary Material) [18].

Entry
The stereochemistry of the fused-bicyclic ring system in 4b was shown to be cis using X-ray crystallographic analysis (Figure 1 and Supplementary Material) [18]. A proposed plausible mechanism is shown in Scheme 3. First, the formation of putative trienone A through diacetoxyiodobenzene-mediated dehydrogenation reaction gave the newly formed C-C double bond as E/Z-form mixtures or ones where the Z-isomer predominated [15]. However, only the E-isomer possesses the proper steric alignment to form the target cyclopenta[b]furans 1. Therefore, a simple thermal cycloisomerization of the trienone to a cyclopenta[b]furan is not likely in this scenario. In the diacetoxyiodobenzene-mediated dehydrogenation process at elevated temperature, acetic acid produced during the reaction presumably plays an important role in promoting the sequential cycloisomerization from a cationic dienyl structure B to form the cyclopenta[b]furans.

General Information
All commercially available chemicals were used without further purification. TLC analyses were run on a TLC glass plate (silica gel 60 F254, EMD Millipore, Darmstadt, Germany) and were visualized using UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash chromatography was performed using silica gel (70-230 mesh, EMD Millipore). 1 H-NMR spectra were recorded on a 300 MHz spectrometer (Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, Germany). 13   A proposed plausible mechanism is shown in Scheme 3. First, the formation of putative trienone A through diacetoxyiodobenzene-mediated dehydrogenation reaction gave the newly formed C-C double bond as E/Z-form mixtures or ones where the Z-isomer predominated [15]. However, only the E-isomer possesses the proper steric alignment to form the target cyclopenta[b]furans 1. Therefore, a simple thermal cycloisomerization of the trienone to a cyclopenta[b]furan is not likely in this scenario. In the diacetoxyiodobenzene-mediated dehydrogenation process at elevated temperature, acetic acid produced during the reaction presumably plays an important role in promoting the sequential cycloisomerization from a cationic dienyl structure B to form the cyclopenta[b]furans.
Molecules 2016, 21, 1713 4 of 9 The stereochemistry of the fused-bicyclic ring system in 4b was shown to be cis using X-ray crystallographic analysis (Figure 1 and Supplementary Material) [18]. A proposed plausible mechanism is shown in Scheme 3. First, the formation of putative trienone A through diacetoxyiodobenzene-mediated dehydrogenation reaction gave the newly formed C-C double bond as E/Z-form mixtures or ones where the Z-isomer predominated [15]. However, only the E-isomer possesses the proper steric alignment to form the target cyclopenta[b]furans 1. Therefore, a simple thermal cycloisomerization of the trienone to a cyclopenta[b]furan is not likely in this scenario. In the diacetoxyiodobenzene-mediated dehydrogenation process at elevated temperature, acetic acid produced during the reaction presumably plays an important role in promoting the sequential cycloisomerization from a cationic dienyl structure B to form the cyclopenta[b]furans.

General Information
All commercially available chemicals were used without further purification. TLC analyses were run on a TLC glass plate (silica gel 60 F254, EMD Millipore, Darmstadt, Germany) and were visualized using UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash chromatography was performed using silica gel (70-230 mesh, EMD Millipore). 1 H-NMR spectra were recorded on a 300 MHz spectrometer (Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, Germany). 13

General Information
All commercially available chemicals were used without further purification. TLC analyses were run on a TLC glass plate (silica gel 60 F254, EMD Millipore, Darmstadt, Germany) and were visualized using UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-anisaldehyde stain. Flash chromatography was performed using silica gel (70-230 mesh, EMD Millipore). 1 H-NMR spectra were recorded on a 300 MHz spectrometer (Bruker AV-300, Bruker BioSpin GmbH, Karlsruhe, Germany). 13 C-NMR spectra were recorded at 75 MHz on the same instrument with complete proton decoupling (see Supplementary Material). Chemical shifts are reported relative to CHCl 3 [δ H 7.24, δ C (central line) 77.0]. Mass spectra and high-resolution mass spectra were recorded on the Thermo/Finnigan Quest MAT Mass Spectrometer (Thermo Finnigan LLC, San Jose, CA, USA).