Catalyst-Controlled Selectivity Switch in Three-Component Reaction: An NHC-Catalyzed Strategy for the Synthesis of δ-Lactone-Fused Spirobenzofuran-3-ones

An efficient, three-component reaction of aldehydes and benzofuran-3-ones was developed. This process provides a new approach for the preparation of synthetically and biologically important spirobenzofuran-3-one derivatives with moderate-to-good yields under mild conditions. A switch of intramolecular to intermolecular domino Michael–aldol–lactonization leading to differential product formation was achieved by different NHCs catalysis.


Results and Discussion
We initiated our studies with the readily available benzofuran-3-one 1a and two molecules of α-bromoenal 2a as the starting materials in the presence of 20 mol % of NHC in toluene at room temperature for optimizing the reaction conditions (Table 1, entries 1-10). Various NHC precursors were investigated by using Cs 2 CO 3 as a base. In the presence of the precatalyst A, the desired product 3a was formed in only 32% yield. In some cases, such as when F, H and I were employed, the degradation of the reactant was observed along the traces of the targeted compound (Table 1, entries 6,8,9); in other cases, the reactions were complicated and only small amounts of products were isolated (Table 1, entries 7, 10). Further adjustment of other NHC catalysts revealed that precatalyst B exhibited the highest catalytic activity, and the desired spirobenzofuranone derivative 3a was isolated in 55% yield (Table 1, entry 2 vs. entries 1, 3-10). These results show that precatalyst B exhibited the highest catalytic activity. It is possible that due to the partially non-aromatic ring structure of B, the electrophilicity of the carbonyl attached to the partially aromatic ring structure of B was not as strong as that of other NHCs, which resulted in intermolecular aldol reaction rather than intramolecular cyclization [59]. Then, a wide range of organic and inorganic bases were investigated. DABCO, DIPEA and NaOAc could not push the reaction forward effectively and gave the isolated product in poor yields. The screening of various bases revealed that Cs 2 CO 3 was the optimal choice (Table 1, entry 2 vs. entries [11][12][13][14][15][16][17][18]. Subsequently, several solvents were further screened, but no better result was obtained (Table 1, entry 2 vs. entries [19][20][21][22][23]. The use of 4 Å MS did give some improvement in reactivity (Table 1, entry 24). It should be noted that the desired product 3a that we obtained in these screening cases are single diastereomers (dr >20:1). Finally, the optimal reaction conditions with respect to yield was established (see Figure S1 in Supplementary Materials).
With the optimized reaction conditions, the generality of the reaction was further evaluated using enals 2 with various substitution patterns (see Figure S3 in Supplementary Materials). As can be seen from Scheme 2, both electron-donating and electron-withdrawing substituents all proceeded smoothly to give the desired spiro products in moderate-to-good yields under the optimized conditions (3a-3o). In addition, enals 2 bearing different halogen groups, e.g., I, Br and Cl, were all tolerated in the reaction (3a-3c). Enals bearing strong electron-withdrawing substituents, such as 4-NO 2 , could be well-tolerated to give a high yield of the corresponding product 3f. Moreover, enals with a meta-substituent on the phenyl ring did not affect the reaction outcome and gave the cycloadduct in good yield (3h); however, the ortho-substituent of the enal gave the corresponding product in quite a low yield. Due to the electronic properties of naphthalene, 1-naphthaleneacrolein resulted in higher reactivity (3i-3j). Subsequently, the easily accessible benzofuran-3-ones 1 also underwent a smooth cascade reaction leading to the formation of the desired products in good yields (3k-3o). In addition, when the enals were heterocyclic-substituted, the protocol could still work well with a moderate yield (3p).
To further extend the substrate scope of this methodology, we turned our attention to the three-component annulation with two different aldehydes. It was found that this method was successful in the preparation of spiro-bicyclic benzofuran-3-ones in moderate yields (Scheme 3). Substitution at the 4-position with electron-withdrawing groups gave the products 5d to 5g with moderate yields. The same result of 3,5-Dichlorobenzaldehyde could work in this cycloaddition reaction, with the corresponding product 5h. Probably affected by steric hindrance, the ortho-substituents were not effective for this transformation.
Based on the above results of the study and previous reports [60][61][62], we propose a mechanistic rationalization for the construction of spiro-bicyclic benzofuran-3-one as follows (Scheme 4). Initially, the reaction proceeds via the free carbene nucleophilic attack on α-bromoenal 2a and the debromination to generate the key α,β-unsaturated acylazolium

Materials and Methods
NMR spectra were obtained on a Bruker Avance 400 spectrometer (Bruker Corporation, Billerica, MA, USA); 400 for 1 H NMR or 100 MHz for 13 C NMR. 1 H NMR spectra J-values were reported in Hz. Toluene was dried and fractionally distilled from CaH 2 . Commercially obtained reagents were used as received. Column chromatography was performed using Huanghai 300-400 mesh silica gel (Huanghai Corporation, Yantai, China) at increased pressure. HRMS (m/z) was measured using a Thermo Scientific™ Q Exactive (Thermo Scientific, New York, NY, USA).

Conclusions
In conclusion, we accomplished a novel NHC-catalyzed three-component annulation reaction for the efficient synthesis of the medicinally important spirobenzofuranone derivatives containing three contiguous stereocenters and one all-carbon quaternary spirocenter. The interception of the α-bromoenals with the catalytically generated α,β-unsaturated acylazoliums proceeds in a Michael addition-aldol reaction-cyclization sequence. This protocol can tolerate a series of available substrates and spiro-bicyclic benzofuran-3-ones were obtained in moderate-to-good yields with excellent diastereoselectivities (all products > 20:1 dr). Given the importance of the spirobenzofuranone derivatives, it is conceivable that the method outlined here may be a practical way to access these relevant molecules.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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