Facile and innovative catalytic protocol for intramolecular Friedel–Crafts cyclization of Morita–Baylis–Hillman adducts: Synergistic combination of chiral (salen)chromium(III)/BF3·OEt2 catalysis

The chiral (salen)Cr(III)/BF3·OEt2 catalytic combination was found to be an effective catalyst for intramolecular Friedel–Crafts cyclization of electron-deficient Morita–Baylis–Hillman adducts. In presence of mild reaction conditions the chiral (salen)Cr(III)/BF3·OEt2 complex affords 2-substituted-1H-indenes from unique substrates of Morita–Baylis–Hillman adducts via an easy operating practical procedure.

ported Friedel-Crafts reactions utilize either strong Lewis acid catalysts or severe reaction conditions resulting in low yield, unwanted byproducts and tedious workup methodologies [15,16]. Therefore, developing an efficient, novel and efficient Friedel-Crafts reaction methodology in presence of novel catalysts will widely serve its purpose in synthesising molecules of biological interest. Thereby with the goal of operating FC reactions in terminal allylic units of Morita-Baylis-Hillman adducts we sought to screen the M(salen) complexes.
Intramolecular Friedel-Crafts cyclizations in Morita-Baylis-Hillman adducts are known to undergo annulations generating cyclic frameworks of indene. To the best of our knowledge, five reports are cited for the intramolecular FC reaction in MBH adducts. The first report was by Basavaiah et al. [10] on the phosphorous pentoxide-catalysed synthesis of indene using alkoxy-substituted MBH adducts. Later Shanmugam et al. [11] reported a Mont. K10-catalysed synthesis of indenes from similar alkoxy MBH adducts. Thereafter Lee et al. [12] and Xu et al. [13] synthesised indenes in presence of a palladium catalyst from allylic acetates of MBH adducts. Recently Anas et al. [14] has reported the palladium-catalysed synthesis of indene from MBH adducts at 120 °C under N 2 atmosphere. The methodologies referred in Scheme 1 access indenes either relying on harsh reaction conditions or on the dialkoxy and ortho-halidesubstituted MBH adducts. Thereby alternative synthetic routes should be accessed to overcome the harsh reaction conditions, structural requirements and scalability issues intrinsically associated with the literature reported procedures. Hence chiral catalysts could possibly be utilized for the current investigation with expectations to minimize the formation of regioisomers, dimer-ized side products and overcome the usage of allylic-OH protected MBH adducts.
Metallosalen complexes can be easily prepared and safely handled. The stability of metallosalen complexes convinced us to explore them as suitable chiral Lewis acid catalysts for the Friedel-Crafts cyclization of MBH adducts. Mononuclear(salen) complexes of aluminium, chromium, manganese and cobalt were chosen and screened for the current investigation.

Results and Discussion
To evaluate the scope of the intramolecular Friedel-Crafts cyclization protocol the Morita-Baylis-Hillman adduct 5a, was surveyed as the model substrate. The optimization experiments are listed in Table 1. The cyclization of MBH adduct 5a was examined in presence of metal(III)-salen complex (5 mol %) as catalysts and BF 3 ·OEt 2 (2.5 mol %) as co-catalyst. Though all metal-salen complexes catalysed the reaction ( . In absence of co-catalyst or additives Cr(III)salen complexes are known to effectively promote cyclization reactions [17,18]. In contrast to the literature reports the Cr(III)-salen complex in absence of co-catalyst BF 3 ·OEt 2 provides the expected product at a very low yield of 21% (Table 1, entry 6). Therefore, the consequence of increasing [Cr(salen)Cl] catalyst loading from 10 mol % to 20 mol % (Table 1, entries 7-9) in presence of co-catalyst BF 3 ·OEt 2 was By considering the efficiency and ease of the transformation, the optimized reaction conditions were attempted for a series of structurally distinct MBH adducts (1 mmol), at a catalyst load of 3a (15 mol %)/BF 3 ·OEt 2 (2.5 mol %) in 10 mL dichloromethane (Table 2). A series of indene derivatives were obtained from moderate to excellent yield (58-85%). The steric hindrance and electronic effect of electron-withdrawing substituents such as nitriles and methyl/ethyl esters did not significant-ly affect the scope of the reaction. On contradictory to the literature reports [Cr(III)salenCl] complex surprisingly catalysed the intramolecular Friedel-Crafts reaction in electron deactivated arenes of MBH adducts [10][11][12][13][14]. However, ortho/meta-substituted arenes of MBH adducts were inert to the Cr(salen)/ BF 3 ·OEt 2 catalytic system (5m-r, Table 2). This could be an outcome of steric hindrance exerted by the substitutents at the arene moiety of the MBH adducts.   Thereafter, to inspect the utility of the reaction for a gram-scale reaction, we endeavoured a model reaction using the optimized standard reaction conditions. Convincingly MBH adduct 5h (10 mmol) delivered the desired product 6h in 73% yield (1.28 g). The outcome of this practical scale synthesis demonstrates the synthetic utility of the stabilized reaction for large scale synthesis. The structure of the synthesised indene compounds (6a-f) were deduced from 1 H NMR, 13 C NMR, elemental analysis and high-resolution mass spectrometry.
To account for the observed synthesis of indene from MBH adducts a model was suggested based on the reports of Rawal et al. [17,19], Katsuki et al. [20,21] and Jurczak et al. [22]. The proposed model is an outcome of interaction between the Mortia-Baylis-Hillman adduct and the Cr(salen) complex (Scheme 2), The hydroxyl lone pair of the MBH adduct is expected to coordinate with the Cr(salen) complex in a position of minimized steric strain to that of the cyclohexyl group. We anticipate that this arrangement would facilitate the intramolecular Friedel-Crafts cyclization of the MBH adducts.

Conclusion
In summary we have developed an efficient synthetic protocol for intramolecular Friedel-Crafts cyclization in electron-deficient Morita-Baylis-Hillman adducts. The present methodology is attractive because it directly utilizes MBH adducts over the possible reports on utilizing allylic-OH protected MBH adducts [12,13] to access indenes. The chiral Cr(III)(salen)/ BF 3 ·OEt 2 -catalyzed synthesis of indenes from MBH adducts restricts the formation of regioisomers [10] and hinders the formation of dimerised side products [11]. In addition, the reaction smoothly accesses substituted indenes from MBH adducts at room temperature. In conclusion, the methodology is attractive for its easy transformation of multifaceted MBH adducts into 2-substituted indenes. We have also envisaged that the octahedral complex derived from Cr(salen) and MBH adduct to facilitate intramolecular Friedel-Crafts cyclization.

Experimental
Typical procedure for the synthesis of indenes 6a-l The Morita-Baylis-Hillman adduct 5a (1 mmol) and chromium(salen)(III) complex 3a (15 mol %) were dissolved in 10 mL of dichloromethane in a flame dried 50 mL RB flask. To the reaction mixture BF 3 ·OEt 2 (2.5 mol %) was added dropwise over 10-15 min using a well-dried glass syringe. The reaction mixture was stirred for 12 hours at room temperature, followed by thin-layer chromatography. The resulting solution was quenched with sodium bicarbonate (20 mL) and the aqueous layer was extracted with dichloromethane (3 × 20 mL). The combined extracts were washed with brine and the organic layer was dried (anhydrous MgSO 4 ). After filtration, the solvent was removed under reduced pressure and the crude product was purified on silica gel (using hexane/EtOAc) to afford the desired product 6a as a white solid (81%). Typical procedure for synthesis of compounds 8a and 8b

Methyl 1H-indene
Indene 6b (1 mmol) in 2 mL of toluene was successively added to 1-benzylidene-3-oxopyrazolidin-1-ium-2-ide (1.2 mmol). The reaction mixture was stirred at 70 °C for 6 h until the dipolarophile was consumed. After completion of the reaction, toluene was evaporated and extracted using CHCl 3 and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. Finally, the crude reaction mixture was purified by column chromatography to afford the corresponding [3 + 2] cycloaddition product 8a in 61% yield.