Palladium Catalyzed Ring-Opening of Diazabicylic Oleﬁns with 4-Halo-1,3-Dicarbonyl Compounds: Accessing 3(2 H )-Furanone-Appended Cyclopentenes

: We have realized a Pd-catalyzed ring-opening of diazabicyclic oleﬁns with 4-halo-1,3-dicarbonyl compounds. This reaction resulted in the formation of 3(2 H )-furanone-appended hy-drazino cyclopentenes. The reaction proceeds via the formation of a π -allylpalladium intermediate which is attacked by the active methylene species, and an intramolecular nucleophilic substitution in the 4-halo-1,3-dicarbonyl moiety furnishes the 3(2 H )-furanone-substituted cyclopentene. We could extend this methodology to cyclopropane-appended spirotricyclic oleﬁn for synthesizing 3(2 H )-furanone-substituted spiro[2.4]hept-5-ene.


Results and Discussion
We planned to assess our hypothesis by taking diazabicyclic olefin 1a and ethyl-4chloro acetoacetate 2a as substrates. The initial reaction was set up with 1.0 equivalent of 1a and 1.5 equivalents of 2a in the presence of Pd(OAc)2 as the catalyst, dppf as ligand and

Results and Discussion
We planned to assess our hypothesis by taking diazabicyclic olefin 1a and ethyl-4chloro acetoacetate 2a as substrates. The initial reaction was set up with 1.0 equivalent of 1a and 1.5 equivalents of 2a in the presence of Pd(OAc) 2 as the catalyst, dppf as ligand and K 2 CO 3 as base in THF at 60 • C. After 12 h, we could isolate the expected 3(2H)-furanoneappended hydrazino cyclopentene 3a in 10% yield from the reaction mixture ( Figure 3). The structure of 3a was assigned based on 1 H NMR, 13 C NMR, high resolution mass spectral analyses and on comparison with literature reports [43][44][45].

Results and Discussion
We planned to assess our hypothesis by taking diazabicyclic olefin 1 chloro acetoacetate 2a as substrates. The initial reaction was set up with 1.0 1a and 1.5 equivalents of 2a in the presence of Pd(OAc)2 as the catalyst, dpp K2CO3 as base in THF at 60 °C. After 12 h, we could isolate the expected 3( appended hydrazino cyclopentene 3a in 10% yield from the reaction mixt The structure of 3a was assigned based on 1 H NMR, 13 C NMR, high re spectral analyses and on comparison with literature reports [43][44][45]. In the HMBC spectrum of 3a (spectrum in SI), the proton signal at 3.40 showed correlations with C5, C4 and C3 carbons ( Figure 4). These relations connectivity of cyclopentene moiety with 3(2H)-furanone core. The cis ster the 1′ and 4′ positions was confirmed through the NOE analysis (spectrum comparison with the literature reports [43][44][45]. When we irradiated the sign ppm, a signal enhancement in the opposite phase was observed at 5 confirmed the stereochemistry of protons at 3.40-3.42 and 5.32 ppm as in th  In the HMBC spectrum of 3a (spectrum in SI), the proton signal at 3.40-3.42 ppm (1 ) showed correlations with C5, C4 and C3 carbons ( Figure 4). These relations confirmed the connectivity of cyclopentene moiety with 3(2H)-furanone core. The cis stereochemistry at the 1 and 4 positions was confirmed through the NOE analysis (spectrum in SI) and in comparison with the literature reports [43][44][45]. When we irradiated the signal at 3.40-3.42 ppm, a signal enhancement in the opposite phase was observed at 5.32 ppm. This confirmed the stereochemistry of protons at 3.40-3.42 and 5.32 ppm as in the same phase.
Organics 2023, 4, FOR PEER REVIEW 6 furanone-substituted hydrazino-spiro [2.4]hept-5-enes 5a to 5d in good to excellent yields. The reactions of 4-chloro-3-oxopentanoate 2d with spirotricyclic olefins 4a & 4b also afforded the expected products 5e and 5f (as a mixture of diastereomers) in 52% and 45% yields, respectively.  We propose a mechanism for the Pd-catalyzed synthesis of 3(2H)-furanoneappended hydrazino cyclopentene from diazabicyclic olefin and 4-halo acetoacetate based on literature precedents (Figure 8) [43][44][45][46].  The reaction proceeds through three stages; the first one being the attack of Pd(0) species to the double bond (through exo-face) of the diazabicyclic olefin 1a to form the π-allylpalladium intermediate B (via A) by the cleavage of one C-N bond (endo phase). The second stage involves the attack of the anionic species C or D (generated from 2a) to one end of the π-allylpalladium intermediate (through the opposite side of that of Pd) B generating the species E. Then, the decomplexation of Pd-species from the cyclopentene ring occurs, followed by the oxidative addition of Pd(0)Ln to the C-Cl bond to form F. The intermediate F is easily converted into oxy-π-allylpalladium intermediate G and the ester enolate formed by the abstraction of the acidic proton attacks the carbon end of the oxy-π-allyl Pd-intermediate resulting in the 3(2H)-furanone ring. The classical double inversion mechanism is the reason for the cis-stereochemistry in the product.
Our next attempt was to utilize the synthesized 3(2H)-furanone-appended hydrazino cyclopentenes for the generation of biologically relevant furanone-analogues [47,48]. This transformation was effected by treating the 3(2H)-furanone-appended hydrazino cyclopentene 3 with an amine 6 in MeOH at 40 • C. These reactions were found to be completed in 12 to 24 h, from which the respective furanone-analogues 7a-d were isolated in moderate to excellent yields ( Figure 9).
Organics 2023, 4, FOR PEER REVIEW 7 The reaction proceeds through three stages; the first one being the attack of Pd(0) species to the double bond (through exo-face) of the diazabicyclic olefin 1a to form the πallylpalladium intermediate B (via A) by the cleavage of one C-N bond (endo phase). The second stage involves the attack of the anionic species C or D (generated from 2a) to one end of the π-allylpalladium intermediate (through the opposite side of that of Pd) B generating the species E. Then, the decomplexation of Pd-species from the cyclopentene ring occurs, followed by the oxidative addition of Pd(0)Ln to the C-Cl bond to form F. The intermediate F is easily converted into oxy-π-allylpalladium intermediate G and the ester enolate formed by the abstraction of the acidic proton attacks the carbon end of the oxy-π-allyl Pd-intermediate resulting in the 3(2H)-furanone ring. The classical double inversion mechanism is the reason for the cis-stereochemistry in the product.
Our next attempt was to utilize the synthesized 3(2H)-furanone-appended hydrazino cyclopentenes for the generation of biologically relevant furanone-analogues [47,48]. This transformation was effected by treating the 3(2H)-furanone-appended hydrazino cyclopentene 3 with an amine 6 in MeOH at 40 °C. These reactions were found to be completed in 12 to 24 h, from which the respective furanone-analogues 7a-d were isolated in moderate to excellent yields ( Figure 9).  During the synthesis of amine-functionalized 3(2H)-furanone derivatives, we chose different ortho-bromo-benzylamines to access scaffolds that can be subjected to further transformations towards complex fused moieties. We hypothesized that, by subjecting compound 7c to intramolecular Heck coupling conditions, a tri-ring-fused azocine moiety, namely 3(2H)-furanone-fused cyclopetano-benzoazocine could be synthesized. The first trial run of the intramolecular Heck coupling of 7c was carried out with Pd(OAc)2 as the catalyst, P(o-tol)3 as the ligand, and Et3N as the base in CH3CN at 100 °C ( Figure 10). After 12 h, to our dismay, we isolated the dehalogenated 3(2H)-furanone 7b. We then changed different conditions to see if the expected 3(2H)-furanone-fused cyclopetanobenzoazocine could be synthesized [49]. All the attempts were in vain, furnishing the dehalogenated product. The reason for failure might be due to the fact that oxidatively added palladium species might not be in a bonding distance with that of the alkene (of cyclopentene) for insertion reaction. During the synthesis of amine-functionalized 3(2H)-furanone derivatives, we chose different ortho-bromo-benzylamines to access scaffolds that can be subjected to further transformations towards complex fused moieties. We hypothesized that, by subjecting compound 7c to intramolecular Heck coupling conditions, a tri-ring-fused azocine moiety, namely 3(2H)-furanone-fused cyclopetano-benzoazocine could be synthesized. The first trial run of the intramolecular Heck coupling of 7c was carried out with Pd(OAc) 2 as the catalyst, P(o-tol) 3 as the ligand, and Et 3 N as the base in CH 3 CN at 100 • C ( Figure 10). After 12 h, to our dismay, we isolated the dehalogenated 3(2H)-furanone 7b. We then changed different conditions to see if the expected 3(2H)-furanone-fused cyclopetano-benzoazocine could be synthesized [49]. All the attempts were in vain, furnishing the dehalogenated product. The reason for failure might be due to the fact that oxidatively added palladium species might not be in a bonding distance with that of the alkene (of cyclopentene) for insertion reaction.

Materials and Methods
All chemicals were of the best grade commercially available and were used further purification. All solvents were purified according to the standard procedu solvents were obtained according to the literature methods and stored over m sieves. Analytical thin-layer chromatography was performed on polyeste precoated with silica gel containing fluorescent indicator (POLYGRAMSIL G/ Gravity column chromatography was performed using silica, and mixtures acetate hexanes were used for elution. Melting points were measured with a Fis melting point apparatus and are uncorrected. NMR spectra were recorded with Avance-500 (500 MHz for 1 H NMR, 125 MHz for 13 C NMR) spectropho instruments. All spectra were measured at 300 K, unless otherwise specified. The c shifts δ are given in ppm and referenced to the external standard TMS or interna standard. 1 H NMR coupling constants (J) are reported in Hertz (Hz) and multiplic indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), (doublet of doublets). Mass spectra were performed with a Thermo Finnigan MA a Thermo Fisher Scientific LTQ Orbitrap Velos, and an Agilent 6890 gas chroma with JMS-T100GC spectrometer or with a ESI/HRMS at 60,000 resolution using Scientific Exactive mass spectrometer with orbitrap analyzer.

Materials and Methods
All chemicals were of the best grade commercially available and were used without further purification. All solvents were purified according to the standard procedures; dry solvents were obtained according to the literature methods and stored over molecular sieves. Analytical thin-layer chromatography was performed on polyester sheets precoated with silica gel containing fluorescent indicator (POLYGRAMSIL G/UV254). Gravity column chromatography was performed using silica, and mixtures of ethyl acetate hexanes were used for elution. Melting points were measured with a Fisher John melting point apparatus and are uncorrected. NMR spectra were recorded with Bruker Avance-500 (500 MHz for 1 H NMR, 125 MHz for 13 C NMR) spectrophotometer instruments. All spectra were measured at 300 K, unless otherwise specified. The chemical shifts δ are given in ppm and referenced to the external standard TMS or internal solvent standard. 1 H NMR coupling constants (J) are reported in Hertz (Hz) and multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and qdd (doublet of doublets). Mass spectra were performed with a Thermo Finnigan MAT95XL, a Thermo Fisher Scientific LTQ Orbitrap Velos, and an Agilent 6890 gas chromatograph with JMS-T100GC spectrometer or with a ESI/HRMS at 60,000 resolution using Thermo Scientific Exactive mass spectrometer with orbitrap analyzer.
Synthesis and characterization of 3(2H)-furanone-appended hydrazino cyclopentenes 3a to 3k: Diethyl  to stir at 100 • C for 12h. Upon completion of the reaction, the solvent was removed, and the residue was subjected to column chromatography on silica gel (100-200 mesh) using hexanes/ethyl acetate mixture as eluent (70% ethyl acetate in hexanes) to afford the 8c as pale-yellow viscous liquid (18 mg, 65%). Analytical data was the same as 7b.

Conclusions
We have developed a methodology for the ring-opening of diazabicyclic olefins via a Pd-catalyzed reaction with 4-halo-1,3-dicarbonyl compounds. This reaction has resulted in the generation of a new class of 3(2H)-furanone-appended hydrazino cyclopentenes. This ring opening reaction of diazabicyclic olefins was found to be general with different 4halo-1,3-dicarbonyl compounds and we could also synthesize another interesting scaffold, namely, 3(2H)-furanone-substituted spiro [2.4]hept-5-ene from cyclopropane-appended spirotricyclic olefin. We have proposed a mechanism which proceeds via the formation of a π-allylpalladium intermediate, which is quenched by the active methylene moiety generated from 4-halo1,3-dicarbonyl moiety, and an intramolecular cyclization in the intermediate then generates the product. We then utilized the synthesized 3(2H)-furanoneappended hydrazino cyclopentenes for the generation of amine-functionalized 3-(2H)furanone-appended hydrazino cyclopentenes. Finally, we tried to generate a new family of 3(2H)-furanone-fused tetrahydroazocine derivatives which did not result in the expected outcome.