Silicon-assisted O-heterocyclic synthesis: mild and efficient one-pot syntheses of ( E )-3-benzylideneflavanones, coumarin-3-carbonitriles / carboxamides, and benzannulated spiropyran derivatives

A new general and efficient method for the one-pot synthesis of ( E )-benzylideneflavanones, dibenzospiropyrans and coumarin-3-carbonitriles/carboxamides is achieved through tandem aldol-cyclocondensation of o -hydroxyaryl carbonyl compounds with aryl aldehydes or enolisable ketones or through Knoevenagel reaction by the aid of SiCl 4 /EtOH at ambient temperature.


Introduction
3-Benzylideneflavanones, termed as flavindogenides, are important building blocks in synthesis and their skeleton is common in some natural products. 1For example, they are precursors of spiroheterocycles, 2 as well as biologically important flavones. 3Moreover, a number of 3-benzylideneflavanones possess pharmacological activity such as anti-inflammatory, antioxidant, analgesic and anti-bacterial properties. 43-Benzylideneflavanones are commonly synthesized either by acid or base catalyzed condensation of flavanones with aromatic aldehydes. 5They have also been isolated as co-products during the preparation of flavanones through the acid or base catalyzed condensation of aromatic aldehydes and substituted o-hydroxyacetophenones. 6 Chawla et al. 7 reported the synthesis of 3-benzylideneflavanones by condensing 2-hydroxyacetophenones with aromatic aldehydes in aqueous alkaline medium, along with corresponding chalcones.According to these authors benzylideneflavanones were accessible only by a low-yielding circuitous route.To the best of our knowledge, only one protocol claimed a one-pot synthesis of (E)-3-benzylideneflavanones through base catalyzed condensation of aromatic aldehydes with o-hydroxyacetophenones over a relatively long time (i.e. the reaction mixture had to be kept under stoppered condition for four days with occasional shaking). 4,8n the other hand, coumarin-3-carbonitriles are important compounds as they are required for the synthesis of methine dyes, 9 3-carboxycoumarins that are used for the synthesis of cephalosporins, 10 modified penicillins 11 and oxygen-bridged tetrahydropyridones. 12 The amides obtained from 3-cyanocoumarins exhibit specific inhibitors of α-chemotripsin 13 and leukocyte elastase. 14Coumarin-3-carbonitriles have been synthesized by reaction of salicylic aldehydes with malononitrile or ethylcyanoacetate, in the presence of bases 15 such as pyridine, 15c pyridinepiperidine, 15d triethylamine, 15e or under phase-transfer catalysis. 16However, in most of reported procedures, coumarin-3-carbonitriles are obtained along with 2-imino-2H-benzopyran-3carbonitriles which are hydrolyzed in HCl/MeOH to give the desired products.][18] Nevertheless, some of these protocols are disadvantageous in terms of the limited availability of catalyst (ZrCl4/[bmim]BF4), 16 the large quantities of solid support used (alumina, 0.3 g/1 mmol of hydroxyaldehyde), 17 or the long reaction times under reflux conditions (KSF, 160 o C/24 h, solvent-free.KSF, 100 o C/24 h, H2O, 17 cat.NaOH, 100 o C/24 h, H2O 18 ).The development of novel synthetic strategies for O-heterocycles which have advantages with respect to using less expensive and readily available reagents, mild reaction conditions, cleaner reactions, and simple isolation of the product are of interest.Within this context and in conjunction with our interest 19 in exploring the utility of in situ reagents based on tetrachlorosilane (TCS, SiCl4) 20 in organic synthesis, we report herein the use of SiCl4 as an efficient dehydrating agent in achieving cyclocondensation as well as Knoevenagel reactions resulting in the formation of various Oheterocycles.The process involves sequential reaction of the o-hydroxycarbonyl compounds with aromatic aldehydes, malononitrile or cyanoacetamide in the presence of the inexpensive and readily available SiCl4/EtOH mixture to furnish (E)-benzylideneflavanones, coumarin-3carbonitriles/carboxamides, respectively at room temperature.Under these very mild conditions, the reaction was explored to synthesize benzannulated spiropyrans quantitatively via cyclocondensation of salicylaldehyde with cycloalkanones.

Results and Discussion
A convenient one-pot synthesis of (E)-3-benzylideneflavanones through the reaction of o-hydroxyacetophenone with aromatic aldehydes in the presence of tetrachlorosilane in absolute ethanol at ambient temperature has been achieved.Stirring a mixture of o-hydroxyacetophenone (1 equiv.)and aromatic aldehyde (2.5 equiv.) in the presence of tetrachlorosilane (6 equiv.) in absolute ethanol as a solvent at ambient temperature led to the formation of (E)-3benzylideneflavanones 3a-d in good yield (Scheme 1, Table 1).Although only two moles of aldehydes are needed for this reaction, the best results were obtained through the use of 2.5 equivalents of aldehydes.This observation seemed reasonable as the formation of flavindogenides is a reaction which is achieved under equilibrating conditions when starting with o-hydroxyacetophenone and aldehydes. 8Thus, higher concentration of aromatic aldehyde would displace the final equilibrium to the forward direction.It is significant that the yields of benzylideneflavanones in the present procedure are strongly dependent upon the amount and the manner of addition of tetrachlorosilane to the reactants.The best yields were obtained by using six equivalents (3 × 2 equiv.) of tetrachlorosilane added during the reaction period, otherwise many side products were obtained.The results summarized in Table 1 showed that the formation of 3-benzylideneflavanones proved to be general and quite efficient for aryl aldehydes and tolerated a variety of functional groups on the phenyl ring regardless of whether electron-donating or electron-withdrawing in character.Thus, chloro, bromo, methyl, and methoxy-containing aromatic aldehydes reacted smoothly at room temperature to give the respective 3-benzylideneflavanones in good yields.The identification of 3-benzylideneflavanones was carried out by spectroscopic analyses as well as by comparing their properties to those reported.The stereochemistry of the 3-benzylidene-flavanone derivatives was unambiguously determined from the 1 H NMR spectra which showed that the product 3 exists only in the E form. 5The E isomers are crystalline solids and an examination of their purity using thin layer chromatography showed no trace of a second isomer.For example, the 1 H NMR spectra of the E-flavindogenides 3a and 3c obtained by the present method showed two broadened singlets at δ 7.96, 8.05 and 6.43, 6.61 ppm, respectively.The two singlets are due to the proton at β-carbon (vinylic proton) and the proton at C-2 (H-2), respectively.The observed broadening of the signal is attributed to a small long range allylic coupling 21 between the two protons or most likely due to hindered rotations of the bulky aromatic groups.An absorption, for example, at δ 8.05 (for H β in 3c) is much lower than expected for an ordinary vinyl proton and indicates the E configuration of the flavindogenides 3a and 3c in which the vinylic proton lies well in the deshielding zone of the carbonyl group.In addition, the H-5 protons of 3a and 3c absorb at a lower field (δ = 7.86-7.90)than the other aromatic protons.The shift of the aromatic H-5 proton downfield arises from the deshielding effect of the carbonyl group and is characteristic of flavanone and flavone systems.Mass spectral (MS) measurements of 3a and 3d displayed their corresponding molecular ions (M + ) m/z 380 and 372, respectively.However, the spectral data of the product from the reaction of o-hydroxyacetophenone with 3′,4′,5′-trimethoxybenzaldehyde under the same reaction conditions (entry 5) and as judged by the melting point, 22 showed it to be 3′,4′,5′-trimethoxyflavone (4) instead of the anticipated benzylideneflavanone.The formation of compound 4 is the result of condensation of only one mole of the aldehyde 2e with one mole of o-hydroxyacetophenone which may be attributed to the steric factor and/or to the lower reactivity of 2e attributed to the three electrondonating groups.3b Such flavones were synthesized in the literature through oxidative cyclization of the corresponding o-hydroxychalcones. 23 reasonable pathway for the formation of 3-benzylideneflavanones 3 may agree with that depicted in Scheme 3. SiCl 4 may react with ethanol to form the reagent system A 24 which may form siloxy species B as well silyl enolate C via its reaction with aldehydes and o-hydroxyacetophenone, respectively.Attack of C on B in an aldol-type condensation 25 followed by cyclisation would produce D which reacts with another mole of aldehyde to give the desired product after aqueous work-up.Following our interest concerning the use of tetrachlorosilane as dehydrating agent in heterocyclic synthesis, we investigated the Knoevenagel synthesis of coumarin derivatives in the presence of SiCl4/EtOH.To study this process, we examined the reaction of salicylaldehyde (10 mmol) with malononitrile (10 mmol) in the presence of two equivalents of tetrachlorosilane (2.4 mmol) in ethanol (15 mL) at room temperature.We observed that tetrachlorosilane promoted the process affording the coumarin 6a within 15 min.Various o-hydroxycarbonyl compounds were reacted under similar conditions, allowing the easy synthesis of coumarin-3-carbonitriles 6 in quantitative yield without chromatography (Scheme 2, Table 2).With respect to reports that utilize SiCl4/EtOH as a dehydrating 25 and hydrolyzing agent, 26 the reaction path may include steps involving a typical Knoevenagel condensation of o-hydroxycarbonyl compound and malononitrile or cyanoacetamide.Hydrolysis of a cyano group gives the intermediate E which furnishes coumarin derivatives 6 after an aqueous work-up.31 Scheme 3 Spiroketals are crucial substructures in a wide variety of natural compounds of diverse origins 27a and owing to their broad spectrum of biological activities, 27b these moieties have therefore attracted considerable synthetic interest.28 The main approach for the synthesis of spiroketal units involves elaboration of a key acyclic keto-diol or its equivalent via intermolecular C-C bond formations followed by an intramolecular acid-catalyzed dehydrative ketalization.29 Exploring the utility of the dual function of tetrachlorosilane/ethanol as a dehydrating agent and inducing aldol condensation in heterocyclic synthesis, we have investigated the reaction of salicylaldehyde with some bis-active methylene containing ketones such as cycloalkanones and dibenzalacetone envisaging that the reaction may proceed to yield the bis-chalcones, keto-diol type products which then, may undergo an intramolecular dehydrative ketalization under the reaction conditions yielding spiroketal derivatives.Thus, stirring a mixture of salicylaldehyde (20 mmol) and cyclohexanone (10 mmol) in ethanol (20 mL) for 2 h at room temperature in the presence of tetrachlorosilane (2 equiv.)gave the dibenzospiroketal derivatives 8b in quantitative yield after an aqueous work up.The reaction was successfully extended to substituted cyclohexanones such as 4-methylcyclohexanone to give the corresponding dibenzospiropyran derivative in good yield. Uner similar conditions, the reaction has proved to be quite efficient with either lower or higher members of cycloalkanones.Thus, the reaction with cyclopentanone, cycloheptanone and cyclooctanone yielded the respective dibenzospiropyran derivatives.The reaction of salicylaldehyde with acyclic active methylene ketones such as 1,3-diphenylacetone yielded products 10 and 9 as a result of condensation of one mole of 1,3-diphenylacetone with either one or two moles of salicylaldehyde, respectively.Scheme 4. All isolated compounds are solids and readily crystallized from either ethanol or acetone.The structure elucidation of dibenzospiropyrans 8 was assigned on the basis of both elemental and spectral analyses.In the IR spectra, no hydroxyl group (OH) stretching frequency was observed but, rather, all products displayed a characteristic ether-linkage (C-O) stretching band at νmax 1227-1213 cm -1 , supporting the cyclization step.Mass spectral measurements (MS) for 8b displayed the m/z 288 peak corresponding in mass to the molecular ion (M + ).The 1 H-NMR spectra of dibenzospiropyrans contain several notable features: no absorption bands for the hydroxyl group protons, the spectra were in agreement with the depicted structures, and the resemblance of the aromatic and olefinic protons as well as carbon skeleton system in dibenzospiropyran derivatives.The formation of 8 may proceed through an intramolecular dehydrative ketalization of the formed bis-chalcone intermediates.Similar transformation of keto-diols to spiroketals under acid catalysis is well documented.29

Conclusions
In summary, we have developed a simple, mild and efficient protocol for the one-pot syntheses of various O-heterocycles from readily available substrates, employing the cheap tetrachlorosilane-ethanol mixture at ambient temperature.(E)-3-Benzylideneflavanones as well as dibenzospiropyran derivatives were prepared through tandem aldol-cyclocondensation / ketalization reaction sequence.Knoevenagel synthesis of coumarin-3-carbonitriles / carboxamides has been developed under the same reaction conditions.This protocol has a few noteworthy features: Good yields can be obtained, great operational simplicity at ambient temperature, and applicability of this protocol for various substrates.Exploring this protocol for preparation of biologically important spiroketals is on-going project in our laboratory.

Experimental Section
General.Melting points were determined using a Griffin melting point apparatus.The IR spectra were recorded with Mattson FTIR spectrometer 5000.Absorption maxima were measured in cm -1 .The 1 H NMR and 13 C NMR spectra were recorded with Bruker 200, 300, 400 MHz spectrometer instruments in CDCl3.The chemical shifts (δ) were measured in ppm and with the solvents as references (For CDCl3, 1 H: δ = 7.26 ppm, 13 C: δ = 77.0ppm).MS spectra were recorded on GC-MS QP-1000 EX Shimadzu mass spectrometer.Column chromatography was performed on silica gel (100-200 or 200-300 mesh) using petroleum ether and ethyl acetate as eluent.Thin layer chromatography (TLC) was performed on Merck silica gel GF254 plates and visualized by UV-light (254 nm).Tetrachlorosilane was used as obtained from commercial sources.Ethanol was purified and dried according to standard procedures.

9, 33 10 33
are known compounds and all physical data were in agreement with literature while compound 8e is unknown.Data for some representative examples are listed below.