Chemodivergent annulations of allenyl imides and β,γ-enones switched by nucleophilic phosphine and amine catalysts

Bingsen Xiang ,Yuhao Wang ,Chuqing Xiao ,Fengkai He ,Yiyong Huang

a Department of Chemistry,School of Chemistry,Chemical Engineering and Life Science,Wuhan University of Technology,Wuhan 430070,China

b Wuhan Britain China School,Wuhan 430022,China

Keywords:Chemodivergent Nucleophilic catalysis Allene Cyclopentenone Pyranone

ABSTRACT Nucleophilic phosphine and amine catalyst-switched chemodivergent [4+1] and [3+3] annulations of allenyl imides and β,γ-enones have been developed,furnishing highly substituted 2-cyclopentenone and 2-pyranone derivatives in moderate to excellent yields.Two plausible reaction mechanisms involving two different ketene intermediates have been proposed to explain the observed chemoselectivity.Moreover,by virtue of the α,β-enone substructure of the [4+1] adducts,1,3-dipolar cycloaddition of nitrile imines has been studied in one-pot to provide various fused pyrazoline derivatives.

2-Cyclopentenone and 2-pyranone derivatives bearing multiple substitutes have drawn tremendous interest since they are often found as structural cores for a variety of natural products and biologically active molecules (Fig.1) [1–12].They also have wide application as building blocks in catalytic reaction studies and natural product synthesis due to theα,β-enone or diene functional groups.As such,remarkable progress has been made in the development of synthetic methodologies for efficient construction of highly functionalized 2-cyclopentenone [13,14] including typical Pauson-Khand reaction [15–18] and Nazarov cyclization [19–21],or 2-pyranone cycles [22–26].However,the existing approaches accessing to two patterns of 2-cyclopentenone or 2-pyranone scaffolds are mainly limited by complicated process or harsh reaction conditions.Moreover,the synthetic protocol for the simultaneous assembly of 2-cyclopentenone and 2-pyranone structures has not been reported so far.Thus,developing novel synthetic methodology for installing both 2-cyclopentenone and 2-pyranone motifs from the same set of starting materials with simple variation of reaction condition is particularly interesting and significant.

Fig.1. Selected examples of biologically active 2-cyclopentenone and 2-pyranone derivatives.

Over the past two decades,Lewis base catalysis employing electron-deficient allenoates has emerged as a versatile tool for the construction of highly functionalized carbo-and heterocycles[27–33].In this context,allenyl imide bearing a 2-oxazolidinyl group,easily attacked at the C(sp) atom by nucleophiles,has been identified as an important component in diverse annulation reactions [34,35].For instance,the Lewis acid catalyzed intermolecular [2+2] cycloaddition/isomerization utilizing allenyl imides and non-activated aldimines provided a facial access to 1-azadiene derivatives (Scheme 1a) [36].Subsequently,we discovered that allenyl imides could be attacked by nucleophilic phosphine catalysts to afford 1,4-(bis)electrophilicα,β-unsaturated ketenyl phosphonium speciesA,which was further used as C4-synthons in the [4+1] cycloaddition of methyl ketimine,enamine,and primary amine (Scheme 1b) [34].Moreover,using P(4-F-Ph)3as the Lewis base catalyst,the annulation ofα-methyl substituted allenyl imide ando-aminotrifluoroacetophenones was realizedviathe zwitterionic intermediateBto afford highly valuable furo[3,2-b]indol-2-ones bearing a CF3-substituted quaternary stereogenic center (Scheme 1c) [37].Based on our earlier studies,it can be concluded that allenyl imides bearing a 2-oxazolidinyl group could undergo various novel annulations with activated methylene compoundsviathe key intermediateAin the presence of nucleophilic phosphine catalyst.And thus other types of nucleophilc substrates can be potentially explored to enrich the synthetic utility and diversity.Furthermore,we are curious about the application of nucleophilic amine catalyst,which may enable the discovery of novel key intermediate (likeC) and annulation reaction system [38].

Scheme 1. Working models based on previous works using allenyl imide.

As we all know,developing new organocatalytic chemodivergent synthesis remains a challenging task [39–42].Using allenyl imide as the first substrate,we attempt to explore the adequate second material to achieve the goal of chemodivergent synthesis of 2-cyclopentenone and 2-pyranone derivatives by switching the Lewis base catalyst type.Herein,we chooseβ,γ-enones [43–46] in terms of the following consideration: (1) the methylene C–H bonds are activated by the adjacent ketyl and alkenyl groups,and easily deprotonated twice to become bisnucleophilic under mild basic condition;(2) multiple functional groups can be decorated in the annulation adduct to the benefit of further derivatisation.To the best of our knowledge,this is the first example to construct both 2-cyclopentenone and 2-pyranone scaffolds from the common starting materials.

We began our study by investigating the model reaction of allenyl imide1aandβ,γ-enone2ausing PBu3(20 mol%) as the catalyst in (CH2Cl)2solvent.Indeed,the reaction occurred to afford the desired [4+1] annulation product3a,albeit in only 21%yield (Table 1,entry 1).Then we investigated the effect of different phosphine catalysts.When PPh3or P(4-Me-Ph)3was used,the yield of 2-cyclopentenone3awas not improved (entries 2 and 3).While P(4-MeO-Ph)3and MePPh2were employed,the yields were increased to 33% and 40% yields,respectively (entries 4 and 5).Fixing using MePPh2catalyst,the further investigation of solvent effect was performed including toluene,MeCN,CHCl3and CH2Cl2(entries 6?9);CH2Cl2was finally found to be the best choice of solvent (entry 9).In addition,base additive was examined (entries 10?15),and 1.2 equiv.of Na2CO3was proved to be the most effi-cient,resulting in the formation of product3ain 66% yield (entry 11).It should be noted that the lower catalyst loading (10 mol%)without Na2CO3additive provided an accept yield of 46% (entry 16).Finally,the optimized reaction conditions were established as following: 20 mol% of P(4-MeO-Ph)3and 1.2 equiv.of Na2CO3in CH2Cl2(0.1 mol/L) at 30 °C.

Table 1 Optimization of [4+1] annulation conditions.a

With the optimal reaction conditions being established (conditions A),the substrate scope ofβ,γ-enones2in the [4+1] annulation reaction was studied.All reactions proceeded smoothly to afford the 2-cyclopentenone products3in moderate yields,and the results were depicted in Scheme 2.Substrates2bearing electronrich aryl groups were well tolerated to give products3band3cin 64% and 46% yields,respectively.In addition,the yield of 2-cyclopentenone3dwas decreased to 46%,probably owing to the increased steric hindrance.The reaction was also compatible to the substrates bearing a heteroaryl (2-furyl and 2-thienyl) ketone moiety,and the target products3eand3fwere isolated in 66%and 58% yields,respectively.The structure of3ewas further determined by X-ray crystallography (CCDC: 2223668).For comparison,inorganic base-free and 10 mol% of P(4-MeO-Ph)3(conditionsB) were also checked.Although lower or compatible yields were observed in all cases,it proved that such type of reaction could proceed without additional Br?nsted base even in the presence of lower loading of phosphine catalyst [47].

Scheme 2. Substrate scope for the phosphine-catalyzed [4+1] annulation.

In order to explore the possible chemodivergent synthesis between allenyl imides1andβ,γ-enones2,we attempted the reaction using nucleophilic amine catalyst.To our delight,when DMAP or DBU was used,the tetrasubstituted 2-pyranone4aawas producedvia[3+3] annulation,albeit in low yields (Table 2,entries 1 and 2).Compound4aawas characterized by X-ray single crystallography (CCDC: 2155959).The only use of DABCO or Cs2CO3was unable to furnish the product4aa(entries 3 and 4).Then the combination of DBU and inorganic base was examined,and the isolated yield could be improved (entries 5 and 6).Pleasingly,2-pyranone4aawas isolated in 74% yield when using DABCO catalyst and 1.2 equiv.of Cs2CO3together (entry 7).The subsequent screening of the Cs2CO3loading and solvents revealed that 0.4 equiv.of Cs2CO3and ethyl acetate solvent were the best choice,and almost quantitative yield of4aawas observed within 2 h (entry 14).

Table 2 Optimization of [3+3] annulation conditions.a

Having the optimal [3+3] annulation reaction conditions in hand,the substrate scope and limitation were then explored,and the results were summarized in Scheme 3.Regardless of whether R3inβ,γ-enones2was an electron-rich or halide groupsubstituted phenyl ring,α-methyl-substituted allenyl imide1aunderwent [3+3] annulation to generate the corresponding 2-pyranones4aa?4ahin good to excellent yields (79%?99%).The scale-up experiment (1.0 mmol1aand 1.2 mmol2a) resulted in identical level of yield (4aa,97%).Introducing a more sterically bulky 2-naphthyl moiety resulted in a lower yield (4ai,70%).When R3was a heteroaromatic group,the yield of 2-thienyl product4ak(81%) is better than that of the 2-furyl case (4aj,66%).In addition,the annulation product4alwith a methyl group (R3) was also obtained in 76% yield.Next,the effect of R4(bearing an electronrich or halide group at the para-position of phenyl ring) linking to the alkene moiety was briefly investigated,and 2-pyranone products4am?4aowere delivered in 75%?90% yields.Finally,we turned our attention to the scope of allenyl imides1withγ-mono orα,γ-disubstituents.The corresponding products4ba?4eawere produced in 50%?88% yields,indicating that different alkyl substituents had an obvious influence on the yields.

Scheme 3. Substrate scope for the amine-catalyzed [3+3] annulation.

According to the above experimental results and our previous work,a plausible mechanism for the phosphine-catalyzed [4+1] annulation of allenyl imide andβ,γ-enone was outlined in Scheme 4.The reaction may be initiated by the addition of tertiary phosphine to allenyl imde1a,resulting in the formation of the zwitterionic intermediateI.Then the ketenyl vinyl phosphonium speciesIIis generatedviaeliminating a 2-oxazolidinyl anion fromI,which deprotonates theα-C?H ofβ,γ-enone2a(or by Na2CO3)to form the nucleophilic speciesIII.IIIattacks the electrophilic C(sp) center of speciesIIto generate the zwitterionic intermediateIV.Subsequently,the 1,3-proton transfer occurs to give speciesV,which undergoes intramolecular Michael addition to provide intermediateVI.VImight isomerizes to the more stable intermediateVII(1,2-proton transfer).Finally,product3ais producedviathe elimination of the phosphine catalyst.

Scheme 4. Possible catalytic cycle for the formation of 3a.

Besides,we also proposed a plausible mechanism for the tertiary amine catalyzed [3+3] annulation (Scheme 5).Initially,the 1,2-addition of DABCO to allenyl imide1agenerates the intermediateVIII,which then converts into the amide cationIXwith releasing the 2-oxazolidinyl anion.In parallel,Cs2CO3can deprotonate theα-C?H ofβ,γ-enone2ato give the nucleophilic intermediateIII,and it subsequently attacks the electrophilic C(sp) center of speciesIXto afford the zwitterionic intermediateX.Xundergoes 1,2-elimination to produce the ketenyl speciesXI,which may transform into the enolate anionXIIby Cs2CO3.Then the speciesXIIundergoes an intramolecular nucleophilic addition (6-endo-dig)to produce the intermediateXIII;XIIIundergoes isomerization and finally abstracts the proton ofα-C?H inβ,γ-enone2ato give the product4aa.

Scheme 5. Possible reaction mechanism for the formation of 4aa.

Towards demonstrating the practicality and synthetic utility of the [4+1] annulation,the scale-up experiment using substrates1a(1.0 mmol) and2awas firstly carried out under the standard conditions,producing compound3ain 67% yield (Scheme 6).By virtue of the electron-deficientα,β-enone substructure of3and the remaining inorganic base,1,3-dipolar cycloaddition of nitrile imines[48] was considered for the synthetic application.Eventually,the one-pot sequential process of [4+1] annulation and 1,3-dipolar cycloaddition has been completed to give a wide range of complex fused pyrazoline derivatives5in up to 52% yield.Based on the single crystal X-ray analysis of product5aa(CCDC: 2246606),heteroallenyl anion rather than heteropropargyl anion intermediate plays a key role in the regioselectivity (Table 3).

Table 3 Sequential [4+1] annulation and 1,3-dipolar cycloaddition of nitrile imines.a

Scheme 6. Scale-up [4+1] annulation experiment.

In summary,we have developed a novel nucleophilic catalystswitched chemodivergent strategy based on allenyl imides andβ,γ-enones under mild conditions.P(4-MeO-Ph)3catalyst enabled the [4+1] annulation to build 2-cyclopentenones bearing a qua-ternary carbon center (up to 66% yield),whereas the utilization of amine catalyst DABCO and Cs2CO3allowed for an exclusive [3+3]annulation to generate tetrasubstituted 2-pyranones in generally high yields (up to 99% yield).Two different ketenyl intermediates were considered as key reactive intermediates in both annulations,and two plausible mechanisms were proposed on the basis of experimental data.Further efforts have been made to develop the one-pot sequential [4+1] annulation/1,3-dipolar cycloaddition for the synthesis of various fused pyrazoline derivatives.Further advancing the synthetic concept in asymmetric manner is on-going in our laboratory.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Y.Y.Huang gratefully acknowledges the financial support for this investigation from the National Natural Science Foundation of China (No.22072111),and the Fundamental Research Funds for the Central Universities (No.2023IVA055).

Supplementary materials

Supplementary material associated with this article can be found,in the online version,at doi:10.1016/j.cclet.2023.108777.