Phosphine-promoted [4 + 3] annulation of allenoate with aziridines for synthesis of tetrahydroazepines: phosphine-dependent [3 + 3] and [4 + 3] pathways

In this manuscript, phosphine-dependent [3 + 3] and [4 + 3] annulation reactions of allenoate with aziridines were disclosed. The alkyldiphenylphosphine-promoted [4 + 3] annulation of allenoate with aziridines has been achieved under mild conditions, providing biologically interesting functionalized tetrahydroazepines in moderate to excellent yield with moderate to excellent regioselectivity and diastereoselectivity.

Nitrogen-containing heterocyclic compounds are widely present in biologically active natural products and synthetic pharmaceuticals.Among them, tetrahydropyridines which can be converted into pyridines and piperidines are intriguing synthetic targets due to their signicant biological activities. 1 In addition, azepines are widely found as the core structure in a large number of compounds that possess important pharmaceutical activities.The compounds containing the azepine moiety are important targets in synthetic and medicinal chemistry. 2mong these compounds (Fig. 1), azelastine is an effective and safe treatment agent for urticaria. 3Meptazinol is a new opioidtype analgesic with mixed agonist/antagonist properties. 4À)-Balanol is a fungal metabolite with potent protein kinase C inhibitory properties. 5An anticonvulsant, carbamazepine, is known to show incidences of cutaneous adverse drug reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug-induced hypersensitivity syndrome. 6Epinastine is a potent antiallergic agent that not only has antihistaminic property but also provides antileukotriene, anti-PAF and antibradykinin activities. 7The tetracyclic natural product, (À)-tetrapetalone A is a novel lipoxygenase inhibitor from Streptomyces sp. 8 Therefore, new synthetic methodologies for the synthesis of azepine derivatives have attracted much attention.Among various methods, the cycloaddition reactions are practical and efficient methods, and have been extensively investigated.
Nucleophilic phosphine-catalyzed cycloaddition reactions of allenoates have evolved as a very useful tool to access various complex ring systems of organic molecules. 9,10Since Lu and coworkers reported the rst phosphine-catalyzed [3 + 2] cycloaddition of allenoates with electron-decient alkenes in 1995, 11 various types of cycloaddition reactions have been developed to afford different sizes of carbocycles or heterocycles. 9In spite of these advances, developing new cycloaddition reaction of allenoates is still of great signicance to construct novel ring frameworks with functional groups.
Aziridines are an important type of versatile building blocks for synthesis of diverse nitrogen-containing heterocyclic compounds and natural products. 12In the presence of Lewis acid or organocatalyst, aziridines may undergo a ring-opening reaction through C-N bond cleavage and work as a masked  annulation of aziridines with a-substituted allenoates to generate highly functionalized tetrahydropyridines by release of SO 2 .17a During the process, aziridines undergo a ring-opening reaction through the breakage of the C-N bond upon the attack of the zwitterionic adduct formed by the addition of PPh 3 to an allenoate, and the resulting amide anion attacks the bcarbon of the allenoate aer an intramolecular desulfonation to realize the [3 + 3] annulation (Scheme 1). 17The reaction is operationally simple and produces highly functionalized tetrahydropyridines in good to excellent yields with high levels of diastereoselectivity.In theory, however, the amide anion without the desulonation could attack the g-carbon of the allenoates to result in a [4 + 3] annulation (Scheme 1). 18With this query in mind and our continuing interest in phosphinecatalyzed cycloaddition reactions, 19 we herein report the rst alkyldiphenylphosphine-promoted [4 + 3] annulation of aziridines with an allenoate to afford functionalized tetrahydroazepines under simple and mild reaction conditions (Scheme 1).
As shown in Scheme 1, in our previous work, in the presence of Ph 3 P, aziridines and a-substituted allenoates performed [3 +  3] annulation in dichloromethane at room temperature.Through revisiting the catalyst screening, we found that alkyldiphenyl-phosphines can reverse the regioselectivity, leading to [4 + 3] annulation, as shown in Table 1.The best result for [4 + 3] annulation of aziridine 1a and allenoate 2 was  obtained when 1 equivalent of EtPPh 2 was added, with 93% yield of the cycloadducts, 92 : 8 of regioselectivity and 81 : 19 of diastereoselectivity (Table 1, entry 3).n-PrPPh 2 is also an effective catalyst compared to PPh 3 , and gave similar result to that with EtPPh 2 (entry 4).MePPh 2 , i-PrPPh 2 , n-BuPPh 2 , CyPPh 2 , DPPB, and DPPP gave good yield of cycloadducts with poor to moderate regioselectivity (entries 2, 5, 6, 8-11).t-BuPPh 2 afforded much lower yield of cycloadducts although with excellent regio-and diastereoselectivity (100 : 0) (entry 7).Subsequently, the effect of solvents was evaluated with the model reaction using EtPPh 2 as the catalyst.The results showed that the aprotic CH 2 Cl 2 remained to be the best solvent, while MeOH gave excellent reaction selectivity but low yield of cycloadducts (entry 16).Other solvents, such as THF, CH 3 Cl, Cl(CH 2 ) 2 Cl, and toluene afforded low to moderate yield of cyloadducts and lower reaction selectivity (entries 12-15).As such, CH 2 Cl 2 was selected as the best solvent for the reaction.The relative conguration of the product 4a was determined by single-crystal X-ray analysis. 20nder the optimized conditions, the annulation reactions of different aryl substituted aziridines with diethyl 2-vinylidenesuccinate were evaluated (Table 2).In most cases, regardless of the electronic nature of the substituent of the aryl group, using EtPPh 2 or n-PrPPh 2 as the catalyst, moderate to good yield and moderate to good selectivity of cycloadducts were obtained, and the yields are usually lower than that having the simple phenyl ring.The position of substituents on the benzene ring seems to have no signicant inuence on reactivity and selectivity.For example, substituents such as 4-MeC 6 H 4 and 2,4,6-Me 3 C 6 H 2 gave the desired products 4d and 4g in similar yields (entries 4 and 7).
The annulation reaction also worked well with 2-naphthyl substituted aziridine (1n), affording the corresponding product in 58% yield (entry 14).Unfortunately, the alkyl substituent gave no desired product, due to the weak electrophilic properties of alkyl aziridines.All these products (4) are new compounds.
Two plausible pathways for the reactions of the aziridines 1 and the allenoate 2 are presented in Scheme 2. PPh 3 and EtPPh 2 or n-PrPPh 2 were found to mainly lead to [3 + 3] and [4 + 3]  annulations, respectively.The reaction starts with a nucleophilic addition of the catalyst to the allenoate 2. A subsequent proton transfer then occurs to neutralize the negative charge on the terminal g-carbon atom of 5.The newly formed secondary carboanion 6 is nucleophilic, and may attack the electron-decient C atom of the aziridine to give a zwitterionic intermediate 7.
When PPh 3 is used as catalyst, a proton transfer ensues to neutralize the negative charge on N atom and results in a primary carboanion 8.The formation of 8 may be followed by a desulfonylation step and the p-nitrophenyl group is migrated to the terminal g-carbon, releasing a molecule of SO 2 and leaving the negative charge on the N atom.

Conclusions
In conclusion, we disclosed phosphine-dependent [3 + 3] and [4  + 3] annulations of allenoate with aziridines and developed the rst phosphine-promoted [4 + 3] annulation involving aziridines.The reaction works efficiently under mild conditions to give functionalized tetrahydroazepines in moderate to excellent yield with moderate to excellent diastereoselectivity.

General methods
All reactions were performed under N 2 atmospheres in ovendried glassware with magnetic stirring.Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purication.All solvents were puried and dried according to standard methods prior to use.Organic solutions were concentrated under reduced pressure on a rotary evaporator or an oil pump.Reactions were monitored through thin layer chromatography (TLC) on silica gel-precoated glass plates (0.25 mm thickness, silica gel).Chromatograms were visualized by uorescence quenching with UV light at 254 nm.Flash column chromatography was performed using ash silica gel (200-300 mesh). 1 H and 13 C NMR spectra were recorded in CDCl 3 using a 300 MHz NMR instrument (referenced internally to Me 4 Si).Data for 13 C NMR spectra are reported in terms of chemical shi.Melting points were determined on a melting point apparatus.

Preparation of aziridines 1
The 2-aryl-1-(4-nitrobenzenesulfonyl) aziridines were prepared according to procedures described previously in the literature.17a Preparation of allenoate 2 The diethyl 2-vinylidenesuccinate 2 was prepared according to procedures described previously in the literature.17a,c General procedure for the annulation of aziridines 1 and allenoate 2 An oven-dried 10 mL ask was charged with diphenylethylphosphine or diphenyl-n-propylphosphine (0.125 mmol), the N-4-nitrobenzenesulfonyl-protected aziridine (0.125 mmol), and CH 2 Cl 2 (5 mL) at room temperature.Aer adding diethyl 2vinylidenesuccinate (0.15 mmol) to this solution, the mixture was stirred at room temperature for 48 h.The reaction mixture was concentrated and the residue puried through ash column chromatography (EtOAc/hexane, 1 : 5) to afford the corresponding tetrahydroazepine product.
A nucleophilic step then occurs to close the six-membered ring and the elimination of triphenylphosphine gives the [3 + 3] annulation product 3 with the catalyst being regenerated.Compared with PPh 3 , when alkyldiphenylphosphine is used as catalyst, the primary carboanion 11 isomerizes into intermediate 12, which performs a proton transfer from N atom to C atom to give the intermediate 13.The cyclization of 13 furnished the ylide 14, which undergoes a proton transfer to produce the intermediate 15.Through elimination of the phosphine, the b-phosphonium ester 15 was converted to the

[ 4 + 3 ] annulation product 4 .
The carbon-carbon single bond between C 4 and C 5 in the intermediates 11, 12 and 13 might rotate, thus resulting in moderate diastereoselectivity.

Table 1
Screening of the reaction conditions a a Unless otherwise stated, all reactions were performed using 0.125 mmol of 1a and 0.150 mmol of 2 in 5 mL of CH 2 Cl 2 at room temperature for 48 h.b Sum of the isolated yields of 3a and 4a.c Ratio of isolated yields.d React time is 72 h.DPPB: 1,4-bis(diphenylphosphino)butane; DPPP: 1,3bis(diphenylphosphino)propane.

Table 2
Substrate scope with respect to aziridines a b (%) of 4 + 3 4: 3 c 4 dr (trans : cis) for 4 c a All of the reactions were performed using 0.125 mmol of 1a, 0.150 mmol of 2, and 0.125 mmol of catalyst in 5 mL of CH 2 Cl 2 for 48 h.b Sum of the isolated yields of 3 and 4. c Ratio of isolated yields.