Non-Palladium-Catalyzed Approach to the Synthesis of (E)-3-(1,3-Diarylallylidene)Oxindoles

Two novel synthetic approaches for synthesizing (E)-3-(1,3-diarylallylidene)oxindoles from oxindole were developed. All previously reported methods for synthesizing 3-(1,3-diarylallylidene)oxindoles utilized palladium-catalyzed reactions as a key step to form this unique skeleton. Despite high efficiency, palladium-catalyzed reactions have limitations in terms of substrate scope. Especially, an iodoaryl moiety cannot be introduced by the previous methods due to its high reactivity toward the palladium catalyst. Our Knoevenagel/allylic oxidation/Wittig and Knoevenagel/aldol/dehydration strategies complement each other and show broad substrate scope, including substrates with iodoaryl groups. The current methods utilized acetophenones, benzylidene phosphonium ylides, and benzaldehydes that are commercially available or easily accessible. Thus, the current synthetic approaches to (E)-3-(1,3-diarylallyldiene)oxindoles are readily amendable for variety of oxindole derivatives.


Introduction
3-(Diarylmethylene)oxindoles belong to a major oxindole family that has recently been reported to have novel biological activities, such as AMPK activation [1] and estrogen receptor-related anticancer activity against breast cancer [2]. As valuable derivatives of 3-(diarylmethylene)oxindoles in the field of medicinal chemistry, 3-(1,3-diarylallylidene) oxindoles, which have a vinyl linker at the 3-methylene position, have attracted considerable attention from synthetic chemists, and several synthetic methods have been reported (Scheme 1) [3][4][5][6]. In 2005, a 3-(1,3-diarylallylidene)oxindole was first synthesized by Takemoto et al., utilizing double Heck reactions [3]. Recently, Sekar et al., improved this approach using palladium binaphthyl nanoparticles (Pd-BNPs) as a catalyst to broaden the substrate scope and allow easy separation [4]. In 2008, Murakami et al., developed another synthetic method featuring palladium-catalyzed oxidative cyclization of 2-(alkynyl)isocyanate, followed by the Suzuki-Miyaura reaction with styrylboronic acid [5]. As part of our ongoing efforts to identify novel synthetic methods for 3-methyleneoxindole derivatives [6][7][8][9][10], we recently reported a palladium-catalyzed multicomponent tandem reaction, which allowed a stereoselective approach to (E)-and (Z)-isomers of 3-(1,3diarylallylidene)oxindoles by changing phosphine ligands, reaction temperature, and time [6]. Although several synthetic methods for 3-(1,3-diarylallylidene)oxindoles have already been developed, as described above, the narrow substrate scope and/or limited accessibility of reagents when using these methods necessitate the development of a more general approach to this unique skeleton. In all previous methods palladiumcatalyzed reactions were the key reactions, which greatly limited the range of products to which these procedures could be applied. A few non-palladium-catalyzed approaches to 3-allylideneoxindoles have been reported, but they cannot be applied to the synthesis of 3-(1,3-diarylallylidene)oxindoles [11,12]. Therefore, we attempted to

Stepwise Approach 1 (Knoevenagel/Allylic Oxidation/Wittig)
The disappointing results of the direct Knoevenagel strategy prompted us to apply a stepwise approach (Scheme 3). Using an acetophenone as a "partner" of Ti(O i Pr) 4 /pyridinemediated Knoevenagel condensation, 3-methyleneoxindole 5 was easily obtained from oxindole 1 in 93% yield with good Z-stereoselectivity (Z:E = 5:1). The preference for the Z-isomer could be explained by a chelation-controlled transition state [14]. The geometry of each isomer was confirmed by comparing 1 H NMR data for (E)-5a [19] and the chemical shift of H 4 [6.84 ppm (Z-isomer), 6.14 ppm (E-isomer)]. On 1 H NMR analysis of known 3-arylmethylenoxindoles, the chemical shift of H 4 is upfield (generally 6.50-6.00 ppm) compared to the usual aromatic area when the aryl group attached to the 3-methylene position of oxindole is located close to H 4 [6,9]. Next, the methyl group should be transformed into a proper functional group to introduce the second olefin. Under radical bromination conditions [20], allylic bromide 6 was obtained as a single geometric isomer, regardless of the geometry of 5a. The structure of 6 was elucidated by intensive NMR studies, including HSQC, HMBC, COSY, and ROESY. In addition, the chemical shift of H 4 was 6.11 ppm, which supported the (Z)-geometry of 6. The Krische group reported similar scrambling of olefin geometry during radical allylic bromination [21]. Unfortunately, the Wittig reaction of the corresponding ylide derived from 6 did not afford the desired 3aa. Given these disappointing results, we exchanged the positions of the functional groups in the Wittig reaction. Therefore, the second functionalization of the methyl group was allylic oxidation. After analyzing several oxidation conditions, we found that SeO 2 oxidation [22] afforded aldehyde 7a in 84% yield, including as a single geometric isomer from both (Z)-and (E)-5a. Interestingly, the olefin geometry of 7a had the Z-configuration, which was confirmed by comparison with previously reported 1 H NMR data for 7a [23]. In addition, the chemical shift of H 4 for 7a also appeared at 6.26 ppm. The Z-stereoselectivity of allylic oxidation may have been due to coordination of the oxindole carbonyl group to selenium [24]. However, considering the high reaction temperature, the possibility of isomerization of (E)-7a to the more stable (Z)-7a during the reaction could not be excluded. Then, the Wittig reaction of aldehyde 7a with the ylide proceeded smoothly and provided the desired 3aa in 84% yield. The 1 H and 13 C NMR data of 3aa exactly matched the results obtained in our previous study [6]. By applying the successful stepwise approach to 3-(1,3-diphenylallylidene)oxindole, we investigated the substrate scope of aldehyde 7 ( Table 1). The Knoevenagel condensation of oxindole 1 and acetophenones with chloro, nitro, and methoxy substituents proceeded well, affording 5b-d in good yield (77-95%) with Z-stereoselectivity (Z:E = 4-10:1) (Entries 1-3). SeO 2 -mediated allylic oxidation of 5b and 5c also proceeded smoothly to afford the corresponding 7 in 85% and 87% yield, respectively. However, the oxidation of 5d, bearing a methoxy substituent at the aryl group, was unsuccessful and resulted in complete decomposition. Unfortunately, neither a lower reaction temperature nor other oxidation conditions overcame this decomposition problem. Setting aside the problematic 5d, we assessed the substrate scope of the final Wittig reaction of 5a-c with ylides bearing various substituents on the aryl group (Table 2). Fortunately, all reactions afforded 3-(1,3-diarylallylidene)oxindoles 3, regardless of the substituent combination, in moderate to good yield (53-95%) (Entries 1-12).

Stepwise Approach 2 (Knoevenagel/Aldol/Dehydration)
As shown above, the allylic oxidation/Wittig reaction strategy allowed synthesis of various 3-(1,3-diarylallylidene)oxindoles 3 from Knoevenagel adducts 5. However, decomposition of 5d in SeO 2 oxidation limited the application scope of this strategy. Therefore, we investigated another stepwise approach, which could be applied to 5d and overcome the limitation of the first strategy. Based on the fact that the functional handle of the methyl group was located at the γ-position of the α,β-unsaturated carbonyl moiety, we assumed that aldol reaction may be feasible. In addition, several examples of similar aldol reactions were found in the literature [24][25][26]. According to the results of base screening, only n-BuLi could provide the desired aldol product, 8aa, in good yield (Scheme 4). The olefin geometry of 8aa was assigned as E, as the chemical shift of H 4 appeared at 6.14 ppm. Notably, unlike bromination and allylic oxidation, the olefin geometry of 5a significantly affected the aldol reaction rate. Under optimized conditions, (Z)-5a was rapidly converted to 8aa in 91% yield, while the reaction of (E)-5a afforded 8aa in 55% yield. A longer reaction time and/or elevated reaction temperature did not increase product yield. The difference in reaction rate may have been caused by the lithiated intermediate from (E)-5a assuming a stable chelated form via coordination of the oxindole carbonyl group. Dehydration of 8aa proceeded smoothly under acidic conditions to provide 3aa in 95% yield [27,28]. Next, we examined whether the second stepwise approach (aldol/dehydration) was applicable to 5d ( Table 3). The first aldol reaction of 5d proceeded well with various benzaldehydes, giving aldol adduct 8 in moderate to good yields (Entries 1-3 and 5). With the exception of 8dc, TFA-mediated dehydration of 8 also proceeded well to afford 3 in excellent yields (Entries 1, 2, and 5). The strong electron-withdrawing action of the nitro group in 8dc may hamper dehydration under acidic conditions. Even under reflux conditions, the desired 3dc was produced in only 45% yield (Entry 3). After several tests, we found that, under basic conditions (TsCl, DMAP, NEt 3 , CH 2 Cl 2 , room temperature, 3 h), 3dc formed in 79% yield (Entry 4). The aldol/dehydration approach could serve as an additional option for synthesis of 3-(1,3-diarylallylidene)oxindoles 3 with the previous allylic oxidation/Wittig strategy.

Application of Stepwise Approach to An Iodoaryl Compound
To demonstrate that our stepwise approach is useful for synthesis of 3-(1, 3-diarylallylidene)oxindoles 3, which are not accessible by previous palladium-catalyzed methods, we synthesized 3 with an iodoaryl moiety using a Knoevenagel/allylic oxidation/Wittig strategy (Scheme 5). Due to its high reactivity toward the palladium catalyst, the iodoaryl group was not compatible with palladium-catalyzed reactions. Ti(O i Pr) 4 /pyridinemediated Knoevenagel condensation of oxindole 1 with p-iodoacetophenone gave 3methyleneoxindole 5e in 89% yield, with a preference for the Z-isomer (Z:E=10:1). Allylic oxidation of 5e afforded aldehyde 7e in 78% yield. In addition, the last Wittig reaction of 7e produced 3ea (80% yield), which could not be formed using previous methods. The iodoaryl group of 3ea could be used as a functional handle for further molecular modifications. For example, Suzuki-Miyaura reaction of 3ea introduced another phenyl group to give 9 in 84% yield. Scheme 5. Synthesis of iodoaryl compound 3ea and its Suzuki-Miyaura reaction.

General Information
All reactions were performed under an argon atmosphere with dry solvents, unless otherwise stated. Dry tetrahydrofuran (THF) and methylene chloride (CH 2 Cl 2 ) were obtained from Ultimate Solvent Purification System (JC Meyer Solvent System, Laguna Beach, CA, USA). Other dry solvents were purchased as anhydrous grade. All glassware is oven-dried and/or flame-dried before use. All commercially available reagents were purchased and used without further purification. Reactions were monitored by thin-layer chromatography (TLC) on silica gel plates (Merck TLC Silica Gel 60 F254, Darmstadt, Germany) using UV light, PMA (an ethanolic solution of phosphomolybdic acid) or ANIS (an ethanolic solution of para-anisaldehyde) as visualizing agent. Purification of products was conducted by column chromatography through silica gel 60 (0.060−0.200 mm). Melting points of all solid compounds were determined by Buchi M-565. NMR spectra were obtained on Bruker AVANCE III 500 MHz (Bruker Corporation, Billerica, MA, USA) at 20 • C using residual undeuterated solvent or TMS (tetramethylsilane) as an internal reference. High-resolution mass spectra (HR-MS) were recorded on a JEOL JMS-700 (JEOL, Tokyo, Japan) using EI (electron impact).