Synthesis of furan-substituted dihydrofuran compounds by radical-cyclization reactions mediated by manganese(III) acetate

In this study, novel furan substituted dihydrofuran compounds were synthesized by the radical addition of 1,3-dicarbonyl compounds to 1,1-and 1,2-disubstituted alkenes using manganese(III) acetate in HOAc. It is observed that 1,1-disubstituted alkenes gave better yields whereas 1,2-disubstituted alkenes gave moderate yields. Besides, 1,2-disubstituted alkenes gave us cis - isomers whereas trifluoromethylated 1,3-dicarbonyl compounds with 1,2-disubstituted alkenes gave us trans -isomers of dihydrofuran determined by NOSY spectra


Introduction
During the past decades manganese(III) acetate is used as one-electron oxidant for the formation of C-C bonds in free-radical chemistry. 1Radical precursors such as carboxylic acids, malonates, ketones, 1,3-diketones, and β-keto esters treated with manganese(III) acetate undergo inter-and intramolecular cyclization for the formation of furans, 2 dihydrofurans, 3 lactones, 4 and lactams. 5n addition, manganese(III) acetate-promoted addition reactions have been applied to the synthesis of natural products, such as pheromones. 6reviously, we have reported the formation of furan 7 and dihydrofuran [8][9][10] derivatives resulting in the radical additions with alkenes and alkynes.4-Hydrocoumarins, 2-hydroxy-1,4naphtoquinones 11 and 3-oxopropanenitriles 12 have been used as enolizable compounds.Also, 3cyanodihydrofurans synthesized by our group has shown anti-bacterial and anti-fungal activities. 13n this study, aiming the synthesis of the 2-furyl substituted dihydrofuran compounds (3a-e, 4a-d, 5a-d) was used as 1,1-and 1,2-disubstituted alkenes with 1,3-dicarbonyl compounds mediated by manganese(III) acetate in HOAc at 60 ºC.As a result of the radical addition reactions, we obtained the 2-furyl substituted 4,5-dihydrofuran compounds with modest to high yields.Besides, an investigation of the configuration determination was studied in the resulting dihydrofurans.

Results and Discussion
In our previous studies, we published radical addition reactions of 1,1-and 1,2-disubstituted alkenes with various 1,3-dicarbonyl compounds.It is observed that a single carbocation center is formed with 1,1-disubstituted alkenes while two possible carbocation centers are formed with 1,2-disubstituted alkenes. 14,15 Reaction mechanism for the formation of 2-furyl substituted 4,5-dihydrofurans.
Reaction mechanism proposed for radical addition reactions was depicted in Scheme 1.According to the mechanism, interaction of Mn(OAc)3 with 1,3-dicarbonyl compounds result in a manganese(III)-enolato complex A. An -carbon radical B is formed while Mn 3+ is reduced to Mn 2+ .Addition of B to the alkene 2c may be achieved in two pathways (i and ii).If the reaction follows pathway i, radical intermediate F is generated and final product G is obtained.On the other hand, if the pathway ii occurs, radical intermediate C is generated, which then oxidizes to carbocation D with an equivalent manganese(III) acetate.Thereafter the intramolecular ring closure dihydrofuran E is obtained.Moreover, there are two possible carbocations can be formed depending on the addition to alkene.This resulted in the formation of products E and G.However, only 4,5-dihydrofuran product E was isolated.The other cyclization product has not been observed.Differentiation of products E and G was clarified by 1 H-NMR and HMBC as described in literature. 16-Furyl moeity in the dihydrofuran (4b) resulting from the reaction of 1,3-dicarbonyl compound 1c with 1,2-disubstituted alkene 2b may be substituted on dihydrofuran's 2or 3position.The determination of the product formed was detected by using HMBC.Accordingly, due to C-3 carbon atom correlates with the ortho-H atoms of the phenyl group, this indicates that phenyl group is attached to C-3 and thus the 2-furyl group is attached to the C-5 atom of the dihydrofuran.
Within this study, 1,1-disubstituted alkene 2a was used in the radical addition reactions with various 1,3-dicarbonyl compounds.It is determined that the product yields are higher than the ones of 2b.3c was yielded in 80% with the radical cyclization reaction of 1c with 2a.However, the radical cyclization with another cyclic 1,3-dicarbonyl compound 1d yielded 3d in 57%.The 1 H-NMR spectra of the products showed that the H-4 protons in 3a-b and H-3 protons in 3c-e were diastereotopic with the chemical shifts of δ = 3.2 -3.8 ppm.Also, an AB system with 2 JAB = 14.4 -14.8 Hz was found for H-4 protons in 3a and 3b.The AB system was further split into a quartet by a coupling of 5 J = 1.5 -2.0 Hz with the protons of methyl group substituted to C-2 carbon.Similarly, H-3 protons split into a dublet by a 5 J = 2.0 Hz with the H-7 in 3c-e.
Treatment of 1b with 2c gave us a mixture of cis-and trans-isomers.These isomers were identified by 1 H-NMR spectrum, namely H-4 proton of 4a resonates with H-5 proton with 3 Jtrans = 5.5 Hz, whereas other isomer resonated with 3 Jcis = 6.5 Hz.The amount of the isomers were 1:1 which was calculated from 1 H-NMR spectrum.However, interestingly, the cyclization reaction of 1c with 2b gave us 4b as a sole isomer which is in cis-configuration due to vicinal constant coupling 3 Jcis = 6.4 Hz between H-2 and H-3 protons.Similarly, the cyclization reaction of 1d and 1e gave use 4c and 4d in cis-configuration in 42% and 60% yields, respectively.Thus, this result is considered from the hindered structure of the cyclohexenone.As a result of the rotational barrier, cis-isomer is obtained.The configuration of the compounds 4b-d and were identified by using 1 H-NMR and NOSY.Thus, discussions about the configuration of 2-furyl and phenyl moeities directed us to understand the configuration of the compounds.In the NOSY spectum of 4b, it is definitely clear that the phenyl and 2-furyl moeities are in cis-configuration, because of the fact that strong correlation of H-2 and H-3 is clearly seen in the spectrum.Also, coupling constants of H-2 and H-3 were found in 3 J = 6.4 Hz which is in cis-configuration belonging to 4b-d.Furthermore, H-3 protons gave a dublet by a 5 J = 1.6 Hz with the H-7 (Scheme 2).In addition, H-2 protons of 4b-d were observed at lower field than that of H-3 protons, due to H-2 protons are next to the ether oxygen.
Additionally, acetylation of alkene was observed as a side product in the cyclization reactions of 2b.The cyclization reactions of alkene 2b gave us acetoxy substituted alkene 6 as well as 1,2-acetoxy substituted alkenes in both syn-and anti-products as a mixture in 1:5 ratio (7 and 8) (Scheme 3).
Finally, a comparison of 1,1-disubstituted alkene 2a with 1,2-disubstituted 2b with the reaction of 1c in terms of the yields, better yields were observed with 1,1-disubstituted alkene 2a because of the intermediate carbocation stability.
On the other hand, these results led us to deal with configuration change.Thus, trifluoromethyl substituted 1,3-dicarbonyl compounds 1f and 1g with 1,2-disubstituted alkenes 2c-d were employed in the radical cyclization reactions in the presence of manganese(III) acetate (Table 2).It has been reported by Antonioletti et.al.that the vicinal coupling constants of methine protons appear Jcis = 6 -12 Hz in cis-configuration of dihydrofurans, whereas Jtrans = 3-6 Hz in trans-configuration. [17][18][19] Surprisingly, we observed that the H-4 and H-5 protons are in trans-configuration in terms of the coupling constants of the compounds 5a-d.We observed lower coupling constants ranging from 2.4 Hz to 5.2 Hz which are less than that of the cisisomers of 4a-d.A part of NMR spectrum belonging to H-4 and H-5 protons of 5b was shown in Scheme 2. Thus, the lower coupling constants indicate us that the compounds 5a-d are in transconfiguration.

Conclusions
Consequently, radical addition reactions of 1,3-dicarbonyl compounds with 1,1-and 1,2disubstituted alkenes were investigated in this study in the presence of manganese(III) acetate, it is observed that the highest yields were observed with 1,1-disubstituted alkene 2a.However, synand anti-products mixture and acetoxy substituted alkene products obtained from the reaction of 2b with ethylacetoacetate (1b).Thus, due to the strained structure of the cyclic 1,3-carbonyl compounds 1c-e, only one cis-isomers of the products was obtained in the radical cyclization reaction of 2b.On the other hand, on the contrary to the results with the reactions of alkene 2b, trans-isomers were obtained in the reaction of trifluoromethylated-1,3-dicarbonyl compounds with various 1,2-disubstituted alkenes (2c and 2d).
General procedure for the synthesis of dihydrofurans.Manganese(III) acetate dihydrate (0.83 g, 3 mmol) in 20 mL of glacial HOAc was heated under nitrogen atmosphere to 80 ºC until it dissolved.Thereafter the solution was cooled to 60 ºC, a solution of 1,3-dicarbonyl compound (2 mmol) and alkene (1 mmol) in 5 mL HOAc was added to this mixture.The reaction was completed when the initial dark brown color of the solution had changed to red.H2O (20 mL) was added and the mixture extracted with CHCl3 (3x20 mL).The combined organic phases were neutralized with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and then evaporated.Crude products were purified by column chromatography on silica gel or preparative TLC using n-hexane/EtOAc as eluent.