Efficient Method for the Synthesis of α,α′-Bis(arylmethylidene) Cycloalkanones Catalyzed by Bromodimethylsulfonium Bromide

Abstract Bromodimethylsulfonium bromide (BDMS)–catalyzed crossed aldol condensation between aromatic aldehydes and ketones is reported to access α,α′-bis(arylmethylidene) cycloalkanones at room temperature in good yields within 3–10 min. The salient features of this method are the simplicity of the procedure, the ready accessibility of the catalyst, and greater yields in relatively short reaction times. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT

Bromodimethylsulfonium bromide (BDMS) is a readily accessible, cheap, and highly effective reagent [31] as well as a catalyst for various organic transformations. [32] Recently, Yadav et al. reported the efficiency of BDMS in Beckmann rearrangement (BKR). [33] In addition, very recently they have demonstrated the virtue of this catalyst for multicomponent synthesis of 3-aminoalkylated indoles. [34] In continuation of our work on the development of new synthetic methodologies, [35] we sought to explore the advantages of this reagent further for other important transformations. Here we report an efficient, convenient, and facile method for the condensation of aldehydes with cycloalkanones leading to the corresponding a,a 0 -bis(arylmethylidene) cycloalkanones in the presence of BDMS as a catalyst Scheme 1.

RESULTS AND DISCUSSION
The condensation reaction of benzaldehyde (2 mmol) with cyclohexanone (1 mmol) was carried out at room temperature. In the study of catalyst loading, 0, 1, 5, 10, and 15 mol% of BDMS were tested. Reactions with both 10% and 15% catalysts both gave quantitative yields in 4 min ( Table 1, entries 4 and 5), while the reaction with 5 mol% loading only gave 85% yield even after a long reaction time of 25 min. In the absence of catalyst, the reaction did not yield any product at room temperature even after a long reaction time. This result suggests that BDMS plays a critical role in this reaction. Scheme 1. Crossed-aldol condensation catalyzed by BDMS.
To demonstrate the generality and scope of this method, various aromatic aldehydes such as 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, and 4-chlorobenzaldehyde were treated with cycloalkanones in the presence of catalytic amounts of BDMS (10 mol%) under solvent-free conditions, and the obtained results are summarized in Table 2. All the yields were excellent, including the heteroaromatic aldehydes such as 2-furaldehyde and 2-thiophenecarboxaldehyde. Aromatic aldehydes containing both electron-donating (Me, MeO, OH) and electron-withdrawing (NO 2 , Cl) groups underwent the conversion smoothly. Both cyclopentanone and cyclohexanone showed similar activity toward the condensation with aromatic aldehydes. All the reactions were free from by-products usually found in classical reaction conditions. [6] The purification of these compounds was easily performed by simple filtration and recrystallization with alcohol.
The EE geometry of the double bonds in these compounds (3a-t) was based on earlier literature reports. [36][37][38] It is reported that the vinylic protons are in close proximity to the carbonyl group, which exerted an anisotropic effect, resulting in the downfield shifting and overlapping of the vinylic protons with the aromatic protons and the appearance of vinylic protons in the region of d 7.15-7.95 ppm is an indication of such compounds with E-configuration and in the region of d 6.8 ppm indicates Z-configuration. [36,37] For example, the olefinic protons of Z-2-phenyl methylenecyclohexanones and Z-2-phenyl methylene-6,6-diphenyl cyclohexanones are generally observed at d 6.27 and 6.22 ppm. [38] We used BDMS as a source of HBr to catalyze this reaction and found it to be an excellent catalyst for preparation of a,a 0 -bis(arylmethylidene) cycloalkanones. A plausible mechanism is shown in Scheme 2. Accordingly, BDMS (10 mol%) reacts with the aromatic aldehyde and releases 2 mol of HBr and 1 mol of DMSO (removable by washing with water) as the by-products. The in situ-generated HBr acts as a protic acid and activates the carbonyl oxygen to promote the condensation to give the products.
Some critical mechanistic information for the reaction of benzaldehyde with cyclopentanone was collected by experimental investigations (Scheme 3). The benzaldehyde could efficiently react with cyclopentanone with the aid of HBr (20 mol%) as catalyst, giving the corresponding product 3a in 95% yield. This result suggests that HBr plays the critical role in this reaction. In comparison with other catalysts such as Yb(OTf) 3 , Cp 2 TiPh 2 , RuCl 3 , I 2 , ABM, Na=animal bone meal (Na=ABM), and TCT, which were recently used in the synthesis of a,a 0 -bis(arylmethylidene) cycloalkanones, BDMS employed here exhibits more effective catalytic activity than those previously reported in terms of the reaction temperature, yields, and reaction time ( Table 3). All the products obtained were fully characterized by infrared (IR), 1 H NMR, 13 C NMR, and elemental analyses. The spectral data were also compared with the reported values.

EXPERIMENTAL
All chemicals were purchased from Aldrich Co. and used as received. Melting points were measured using a X-4 apparatus and are uncorrected. IR spectra were obtained using Shimadzu FTIR-8900 spectrometer instrument. NMR spectra were taken with a Varian 400 spectrometer. Elemental analyses were carried out on MT-3 analyzer. Physical and spectral characterization of the products was confirmed by comparison with available literature data. [10,13]   A mixture of aromatic aldehyde (2.0 mmol), cycloalkanone (1.0 mmol), and bromodimethylsulfonium bromide (0.1 mmol) was stirred at room temperature for an appropriate time (Table 2). After completion of the reaction as indicated by thin-layer chromatography (TLC), the mixture was diluted with water (10 mL), which precipitated the solid product. The product obtained was pure as found by TLC and 1 H and 13 C NMR spectroscopy. However, the products were further purified by recrystallization from ethanol.

CONCLUSION
In conclusion, we have developed an expeditious, novel, and efficient method for the synthesis of a,a 0 -bis(arylmethylidene) cycloalkanones from aromatic aldehydes with ketones using a catalytic amount of bromodimethylsulfonium bromide at room temperature. The advantages of the current protocol include experimentally operational ease, mild reaction conditions, ready accessibility of the catalyst, and high efficiency, all of which make it a useful and attractive strategy for the preparation of various a,a 0 -bis(arylmethylidene) cycloalkanone derivatives simply by changing different substrates.

SUPPORTING INFORMATION
Full experimental detail and 1 H and 13 C NMR data can be found via the Supplementary Content section of this article's Web page.

ACKNOWLEDGMENTS
This work was supported financially by Tianjin Normal University (Grant No. 5RL090), the Natural Science Foundation of Tianjin (Grant, Nos. 12JCZDJC34300, 11JCYBJC03600), and the Young Scientist Fund (Grant No.21001080).