Silver Catalyzed Decarbonylative [3 + 2] Cycloaddition of Cyclobutenediones and Formamides

As an important moiety in natural products, N,O-acetal has attracted wide attention in the past few years. An efficient method to construct N,O-acetal has been developed. Using silver catalyst, cyclobutenediones were smoothly converted to the corresponding γ-aminobutenolides in the presence of formamides, in which cyclobutenediones likely proceed with a key decarbonylative [3 + 2] cycloaddition process. In this way, a series of products with varied substituents were isolated in moderate yield and fully characterized.

As part of the transformation of small ring compounds, especially squaric acid in our group, we wish to establish an alternative approach for the construction of N,O-acetal from squaric acid or other four-membered cyclic compounds. Although the transformation of squaric acid and other cyclobutenediones to cyclopropenones under photolysis is known [26][27][28], the investigation of their thermal stability is still lacking. Based on this, we anticipated that the strained ring compound cyclobutenediones [29][30][31] could proceed with a decarbonylation process under metal-catalyst to form cyclopropenone intermediate similar to their photochemical nature, and thus achieve N,O-acetal/ketal skeleton. Scheme 1. Pathways to construct N,O-acetal/ketal.

Results
We initiated our studies by probing various reaction conditions for the cycloaddition of diphenylcyclobutenedione [32] (1a) with N,N-dimethylformamide (DMF, 2a), and the results are given in Table 1. Heating the reaction mixture at 170 • C in the absence of catalyst, no reaction occurred ( Table 1, entry 1). Considering the wide catalytic applications of transition metals in carbonylation and/or decarbonylation reaction, rhodium [33] and palladium [34] salts were firstly adopted in our decarbonylative [3 + 2] cycloaddition. Fortunately, the reaction occurred under the rhodium catalyst [Cp*RhCl 2 ] 2 or Rh(PPh 3 ) 3 Cl (Entries 2 and 3). Due to the low yield of 3aa under rhodium catalyst, we thus turn our attention to the palladium catalyst such as Pd(OAc) 2 or Pd(PPh 3 ) 4 . It was found that Pd(II) leads to the decomposition of cyclobutenedione, and Pd(0) catalyzes the formation of 3aa (Entries 4 and 5). Based on these results, other transition metals without obvious coordination effect with CO were screened. Most of the metals yielded similar results as Cu(OTf) 2 , and gave no desired product during the reaction (Table 1, entry 6). According to the [3 + 2] cycloaddition of cyclopropenone, various Ag salts were then investigated and proved effective for this transformation. When AgSbF 6 was employed as the catalyst, the desired product 3aa was isolated in only 21% yield (Entry 7). Further examination demonstrated that the reaction proceeded most efficiently with AgNTf 2 catalyst and the product 3aa was offered in 60% yield (Entries 8-10). It should be mentioned that longer reaction time proved ineffective for this transformation (Entry 11). Moreover, no annulation reaction took place upon lowering the temperature to 160 • C (Entry 12). Other solvents such as chlorobenzene were also investigated for the reaction and the product 3aa was obtained in 52% yield, which was slightly lower than o-dichlorobenzene (Entry 13). Copies of 1 H and 13 C NMR spectra for 3aa and its crystallographic data are available in the Supplementary Materials.
With the optimized [3 + 2] cycloaddition conditions in hand, the scope and generality of the annulation reactions for the formation of products 3 were then investigated ( Table 2). We firstly examined the reaction of various formamides (2a-f) with diphenylcyclobutenedione (1a) under standard conditions. The experiment results demonstrated that the steric hinerance of formamides had an obvious effect on the reaction. Compared with the yield of N,N-dimethylformamide (2a), the coupling product (3ab) of N,N-diethylformamide (2b) with 1a was isolated in only 36% yield. In addition, the extension of N-methyl-N-phenylformamide (2c) was unsuccessful, and only a few products (3ac) could be detected. Although the increasingly steric hindrance led to the lower yield, the various cyclic formamides (2d-2f) could be converted smoothly to give the corresponding products (3ad-3af) in moderate yield. Further exploration demonstrated that various aromatic substituted cyclobutenediones were suitable for this reaction ( Table 2). As indicated, diarylcyclobutenediones bearing electron-donating groups on the phenyl rings such as 4-methyl, 4-ethyl and 4-methoxy, respectively, provided the corresponding annulation products (3ba, 3ca and 3da) in higher yields, thus broadening the application of current methodology. Meanwhile, this transformation can be extended to the halogen substituted cyclobutenediones, although the isolated yields of products (3ea, 3fa and 3ga) were decreased slightly. Moreover, when the position of the substituent on the phenyl rings changed, the corresponding products (3ha, 3ia) were still isolated in good yields.
To further expand the application of the Ag-catalyzed [3 + 2]-cycloaddition reaction, cross experiments with various substituent groups on formamides or the phenyl rings were screened. Results are given in Table 3; ten new corresponding annulation products were obtained in moderate yield.

Scheme 2. Derivatization experiments.
A possible mechanism for the decarbonylative [3 + 2] cycloaddition of cyclobutenedione 1a with formamide 2a is tentatively proposed. As shown in Scheme 3, following the initial chelation of Ag + with the carbonyl group to generate A, the ring-reducing process is occurred and lead to the formation of intermediate B [36]. After the extrusion of CO, the cyclopropenone intermediate C is formed. The next steps involving ring-opening, nucleophilic addition of formamide, and regeneration of silver catalyst are the same with the literatures [24,25].

General Methods
Unless otherwise stated, all reactions were carried out under argon atmosphere. All commercial available reagents (Energy Chemical, Shanghai, China) were used without further purification. Anhydrous solvents including chlorobenzene and o-dichlorobenzene were commercially available. Tetrahydrofuran (THF) was distilled from sodium. Column chromatography was performed on silica gel (200-300 mesh). 1 H NMR spectra (Bruker, Fällanden, Switzerland) were recorded on a 500 MHz NMR spectrometer and 13 C NMR spectra were recorded on a 125 MHz NMR spectrometer. HRMS data were recorded on Thermo Scientific LTQ Orbitrap XL. Melting points were uncorrected.

Experiment Procedures
General procedure for the synthesis of cyclobutenedione. THF (150 mL) was added to a mixture of Fe 2 (CO) 9 (5.457 g, 15.00 mmol) and t-BuOK (2.245 g, 20.00 mmol) at room temperature under argon. The resulting mixture was stirred for 0.5 h at room temperature and another 15 min at 65 • C. Diphenylacetylene (0.892 g, 5.00 mmol) was added and then further stirred for 12 h at 75 • C. The mixture was cooled to room temperature, and CuCl 2 ·2H 2 O (12.786 g, 75.00 mmol) in acetone (50 mL) was added. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (petrol ether/EtOAc = 20:1) to give products. The NMR data are consistent with previous reports in the literature (1a [32,37], 1b, 1d, 1f-1h [37], 1e [38]).
Procedure for the synthesis of product 4. To a solution of 3aa (0.144 g, 0.51 mmol) in THF (3 mL) was added 0.5 M H 2 SO 4 (3mL). The reaction mixture was heated at 65 • C for 36 h. After cooled to room temperature, the mixture was quenched with saturated NaHCO 3 solution. The separated layer was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na 2 SO 4 , and then concentrated under reduced pressure.
The crude product was purified by flash chromatography (petrol ether/EtOAc = 3:1) to give product 4. The NMR data are consistent with previous reports in the literature. [40] Procedure for the synthesis of product 5. To a solution of 4 (0.032 g, 0.13 mmol) in THF (3 mL) at −78 • C under argon was added a solution of allylmagnesium bromide in diethyl ether (0.39 mL, 1.0 M, 0.39 mmol) via syringe. The reaction was stirred at room temperature for 1.5 h, and then quenched with saturated NH 4 Cl solution. The separated aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous Na 2 SO 4 , and then concentrated. The crude product was purified by flash chromatography (petrol ether/EtOAc = 10:1) to give product 5.

Conclusions
We have successfully presented a silver catalyzed ring-opening [3 + 2] cycloaddition of cyclobutenediones with formamides to prepare γ-aminobutenolide, in which cyclobutenediones likely proceed with a key decarbonylative process. In addition, harsh reaction conditions showed the thermochemical stability of cyclobutenedione and made us pay more attention to its mechanism. Further studies including DFT calculations about the decarbonylative process and the applications to address complex synthetic issues are in progress.