Salicylaldehydes as privileged synthons in multicomponent reactions

Salicylaldehyde (2-hydroxybenzaldehyde) bearing two different active functional groups, namely, a hydroxy group and an aldehyde group, finds wide application as a key chemical in a variety of industrial processes, especially in the large-scale production of pharmaceuticals. Salicylaldehyde and most of its derivatives are commercially available or readily accessible, and hence are ideal starting materials for multicomponent reactions (MCRs), mostly in pseudo-three and four-component ones, giving rise to a plethora of heterocyclic systems. The importance of salicylaldehyde and an impressive amount of studies concerning its applications in MCRs prompted us to highlight in this review the important role of this compound as a privileged synthon in the synthesis of heterocycles. The bibliography includes 276 references.


Introduction
A multicomponent reaction (MCR) is a synthetic approach in which three or more commercially available or easily accessible starting materials are reacted in a one-pot fashion to produce a compound where almost all the parent entities contribute to this newly formed compound. This strategy provides many advantages over the traditional multi-step reactions such as shorter reaction times, higher yields as well as a wide scope for molecular diversity and atom economy. 1 On the other hand, a MCR is a domino or cascade reaction. A cascade reaction is a chemical process involving at least two consecutive reactions wherein each subsequent reaction takes place only in virtue of the chemical functionality generated in the previous step. 2,3 MCRs are currently on the top of the most valuable synthetic processes since they provide facile and rapid access to large combinatorial libraries of organic molecules, what is of particular importance in drug design. The most advantageous and promising drug nominees are small organic molecules, since common peptides and standard oligonucleotides have certain restrictions in terms of bioavailability. Having a number of commercially available or easily accessible starting materials in hand, a large libraries of small organic molecules can be readily synthesized via MCRs. However, despite the obvious synthetic convenience and advantages of MCRs, and their availability for construction of a wide range of chemical structures, their wide applications have been overlooked over the years. Fortunately, during the last decade, the significance of MCRs, particularly those involving salicylaldehyde, for drug design has been well-recognized and substantial attempts have been made in this field, both in academia and industry. 4 M.Momahed Heravi. Ph.D. Professor in Organic Chemistry of the Department of Chemistry, Alzahra University. Telephone: +098(912)132 ± 9147, e-mail: mmheravi@alzahra.ac.ir, Mmh1331@yahoo.com Current research interests: heterocyclic chemistry, catalysis, organic methodology, green chemistry. V.Zadsirjan. Ph.D. in Organic Chemistry at the same University. Telephone: +098(218)804 ± 4040, e-mail: z_zadsirjan@yahoo.com Current research interests: heterocyclic chemistry, catalysis, organic methodology, green synthetic organic chemistry. M.Mollaiye. M.Sc. in Organic Chemistry at the same University. Telephone: +098(937)532 ± 9618, e-mail: malihe.mollaiye@yahoo.com Current research interests: heterocyclic chemistry, catalysis, organic methodology, green synthetic organic chemistry. Salicylaldehyde and its derivatives are commonly used as preservatives in essential oils, cosmetics and fragrances. 5 Salicylaldoximes containing branched alkyl chains are frequently used as extracting agents in the processes of separation and concentration in the copper recovery. 6 There are several different approaches to the preparation of salicylaldehyde. One of them comprises formylation of phenol with formaldehyde in the presence of Mg(OMe) 2 in anhydrous media. 7 Although salicylaldehyde is a simple molecule, it is an important and versatile precursor for a variety of useful compounds, particularly for complex heterocyclic systems. Salicylaldehyde and its derivatives can be effectively applied in MCRs, particularly, in (pseudo)-three and four-component reactions. There is a plethora of studies reporting the synthesis of various heterocycles via MCR involving salicylaldehyde as a suitable starting material. 8,9 However, a literature survey showed no comprehensive review covering these data.
In continuation of our interest in the chemistry of heterocyclic compounds 10 ± 14 and their synthesis via MCRs, 15 ± 23 in this review we will try to highlight the applications of salicylaldehyde as a privileged synthon for the synthesis of various heterocycles. Here, we decided to restrict our consideration to reactions involving both hydroxyl and aldehyde groups of salicylaldehydes in the MCRs.

Multi-component reactions of salicylaldehyde 2.1. Pseudo-three-component reactions
Pseudo-multicomponent reaction is a kind of MCRs wherein at least one of the reactants participates two or more times in the reaction, and the reaction product contains two or more molecules of this reactant.
It should be noted that a variety of catalysts such as NaOAc or KF, 50 56 and aluminium oxide 57 were also successfully applied in the aforementioned reaction.

Three-component reactions
Three-component reactions constitute the most numerous part of the MCRs of salycylaldehyde providing an access to functionalized chromene, coumarin, xanthene derivatives, etc., most of which relating to medicinally privileged scaffolds.
For example, 2-aminochromenes represent a very important class of chemical compounds as they are the main constituents of many natural products and also find a wide application as pigments, cosmetics, agrochemicals, etc. 58 However, their biological activities are of particular importance. 59 Three-component reactions between salicylaldehyde, malononitrile and various nucleophiles proved to be a powerfool tool to obtain these compounds.
In 2007, Shanthi and Perumal developed a facile and efficient approach to the synthesis of 2-amino-3-cyanochromene derivatives 17 via the reaction between substituted salicylaldehydes 1, malononitrile 15a and Hantzsch dihydropyridine ester 18 (Ref. 60) catalyzed by indium trichloride. 61 Using indoles 19 in place of ester 18, indolyl chromenes 20 were obtained (Scheme 6). Salicylaldehydes 1 bearing both electron-donating and electron-withdrawing substituents are suitable for this procedure, resulting in the formation of the corresponding chromenes 17, 20 in relatively short reaction times.
Indoles possessing a variety of important biological functions are considered to be a privileged scaffold in drug discovery, 63 therefore they are among the most popular starting materials in the MCRs.
Thus, Thakur et al. 64 reported the synthesis of 3-indolochromenes 27 using ethylenediammonium diformate (EDDF) as a catalyst and ethylene glycol acting both as a co-catalyst and a solvent (Scheme 10).
A probable mechanism demonstrating the role of ethylene glycol as a co-catalyst is shown in Scheme 11. EDDF is a salt and, therefore, it can be applied as an ambiphilic catalyst in which both the anion and cation act in combination as a nucleophile and electrophile. On the one hand, the acidic portion improved the electrophilicity of the carbonyl group of 1, while on the other hand, the immediately produced amine promotes an attack of the malonate ion 28. Following the protonation and elimination of the water molecule, the first Knoevenagel adduct 29 is generated undergoing cyclization to afford intermediate 2-iminochromene 23 via the Pinner reaction. 65 The diversity of catalysts for MCRs affording 3-indolopyrans is really impressive. In addition to an EDDF-ethylene glycol catalytic system, a plethora of heterogeneous and homogeneous catalytic systems have also been applied. Their examples include copper sulfonato salen, 66 Zn(salphen), 67 b-cyclodextrin, 68 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 69 tetrabutylammonium bromide (TBAB), 70 nanocomposite consisting of the reduced graphene oxide and zinc oxide nanoparticles (RGO/ZnO), 71 polystyrene-supported p-toluenesulfonic acid, 72 L-cysteine functionalized magnetic nanoparticles (LCMNP), 73
A new versatile tool for the synthesis of diversely substituted 4H-chromene scaffolds with a predefined arrangement of functional groups based on the electrocatalytic chain transformations of salicylaldehydes and CH-acids was proposed by Elinson et al. 78 Reactions were carried out in an individual cell in an alcohol medium using sodium bromide as an electrolyte.
Thus, electrochemically induced MCR between salicylaldehydes 1 and two different CH-acids (15 and 30) afforded functionalized 2-amino-4H-chromenes 31 in 65% ± 86% yields (Scheme 12). It should be noted that this is a rare example of a selective one-pot reaction with different CH-acids where a distinction is made according to their reactivity. Here, more acidic cyano derivative 15a serve as a source for the 2-amino-3-cyano-4H-chromene framework, while the less acidic CH-acid 30 contributes to the corresponding 4-substituent in 2-amino-4H-chromene 31.
With three moles of malononitrile 15a under the optimized conditions, the reaction led to the formation of chromeno[2,3-b]pyridine 32 with a fused dicyanomethylsubstituted 4H-chromene moiety. 79 As for salicylaldehydes 1, MCRs proceed smoothly with substrates containing both electron-withdrawing and electron-donating substituents. However, nitroalkanes gave only moderate yields in this reaction, probably due to the undesired oxidation on the cathode under the reaction conditions.
Electrocatalytic MCRs are very promising in view of the further development of 2-amino-4H-chromene chemistry as they allow the selective and one-step introduction of a wide range of medicinally significant functionalitites into the 2-amino-4H-chromene framework and also have obvious advantages over the traditional procedures as being simple, environmentally friendly and easy to scale-up.
Moreover, the same authors developed one more general approach to 4-functionalized 2-amino-4H-chromene derivatives 31 applying solvent-free or`on-solvent' strategies. 80 ± 84 According to these methods, MCRs between salicylaldehyde, malononitrile and a number of carbon nucleophiles 15, 33 ± 35 were performed either by grinding the starting materials substantially without any solvent or under`on-solvent' conditions, i.e. in a minimum amount of a solvent, using commercially available and inexpensive catalysts such as sodium acetate, potassium fluoride or sodium hydroxide (Scheme 13).
Depending on the nature of a carbon nucleophile, certain reaction parameters (catalyst, temperature, reaction time) were varied. Thus, the reaction with 3-methyl-2pyrazolin-5-one 33 proceeded in 10 min just upon grinding the reactants in a mortar (see Scheme 13). 80 It was shown that the desired products 36 were obtained even in the absence of any solvent, but only in satisfactory yields (55%). However, addition of 1 ml of water had a significant effect on the reaction rate, and the yields increased by more than 20%. For the reaction with 4-hydroxy-6-methyl-2Hpyran-2-one 34, two convenient procedures were proposed, one of them comprised stirring with NaOAc in EtOH for 30 minutes at room temperature (method A), and the second one involved grinding with NaOAc or KF under on-alcohol' conditions for 15 min at room temperature (method B) (see Scheme 13). 81 Both methods gave comparable yields of products 37. Cyanoacetates 15b,d reacted under similar`on-solvent' conditions in a (1 : 1) wateralcohol mixture, but it took these compounds about an hour to produce the corresponding products 38 in high yields. 82 At the same time, CH-acids such as cyanoacetamides 15c,e,f and nitroalkanes 35 required somewhat different reaction conditions. Thus, the reaction with nitroalkanes 35 proceeded under solvent-free conditions at 60 8C with both catalysts; however, KF proved to be more effective providing shorter reaction times (1 h vs 3 h with NaOAc) (see Scheme 13). 83 As it was mentioned above, application of nitroalkanes in the electrocatalytic method by Elinson et al. 78 was not especially successful because of the undesirable oxidation of the substrate. On the contrary, the proposed solvent-free procedure can be considered to be the most effective approach to 4-nitroalkyl-substituted 4H-chromenes 39 for the moment. As for cyanoacetamides 15c,e,f, a stronger base (NaOH) and higher temperatures were required for the reaction to be accomplished under on-water' conditions (see Scheme 13). 84 The probable mechanism for the reaction with cyanoacetamide is illustrated in Scheme 14.
First, sodium hydroxide deprotonates malononitrile 15a generating the anion 28, which undergoes the Knoevenagel condensation with salicylaldehyde 1 proceeding with the removal of the hydroxide anion to afford benzylidenemalononitrile 41. 85 In fact, the Knoevenagel adduct 41 can give rise to three reaction routes. The Michael addition of malononitrile to adduct 41 followed by an intramolecular cyclization yields (2-amino-3-cyano-4H-chromen-4-yl)malononitrile 42 (pathway a). Compound 42 was detected in the reaction mixture when the solvent-free reaction of salicylaldehyde 1, malononitrile 15a and cyanoacetamide 15c was performed in the presence of sodium hydroxide in shorter reaction times. (2-Amino-3-cyano-4H-chromen-4yl)malononitrile 42 could exist in equilibrium with 2-imino-2H-chromene-3-carbonitrile 23 and malononitrile 15a under certain reaction conditions. 55 If such an equilibrium takes place, the uptake of malononitrile from the equilibrium process by salicylaldehyde 1 could promote the base-stimulated addition of a weaker CH acid such as cyanoacetamide 15c to 2-imino-2H-chromene 42, resulting in the conversion of 42 into the corresponding 2-amino-4Hchromene 40 (see Scheme 14).
Despite the fact that every new substrate requires the tuning of the reaction conditions, the proposed solvent-free or`on-solvent' methods gave remarkable results and are characterized by high yields, operational simplicity and extremely simple isolation of the resulting functionalized 4H-chromene derivatives.
An alternative procedure for similar reactions with two different CH-acids was developed by Wang

Scheme 14
One more solvent-free procedure based on grinding the starting materials was developed to obtain fluorescent chromeno[2,3-d ]pyrimidines 25 (Scheme 15). 87 The reaction of substituted salicylaldehydes 1, malononitrile 15a and secondary amines 24 proceeded in the presence of a catalytic amount of ZnAl 2 O 4 nanoparticles at ambient temperature upon grinding in a mortar and was accomplished in two minutes, so it can be considered as the most rapid reaction to obtain the compounds of such type. Among other advantages, the chemical stability of the catalyst, its recyclability, environmentally benign and cost effectiveness are worth mentioning. As for the scope of the reaction, the substituents in salicylaldehyde 1 have no significant effect on the product yields. The amine component 24 is limited to only secondary amines; both cyclic and acyclic ones such as diethylamine reacted smoothly in high yields. However alkylarylamines were not reactive at all and could not be used in this reaction.

Scheme 15
The authors assumed that ZnAl 2 O 4 nanoparticles promoted both the Knoevenagel condensation of salicylaldehyde with malononitrile and nucleophilic attack of a secondary amine due to the presence of the acidic Zn 2+ and Al 3+ sites.

Scheme 16
A promising alternative to conventional harmful organic solvents in MRCs was found to be a choline chloride based deep eutectic solvent (DES, 44) used as a reaction medium in the reaction of salicylaldehyde 1, malononitrile 15a and a wide range of various nucleophiles to provide the corresponding 2-amino-3-cyano-4H-chromenes 43 (Scheme 17). 101 The required solvent 44 was obtained by the reaction of choline chloride and urea. 102 CHO OH + R 1 = H, 5-OMe, 5-OEt, 3-NO2, 3-Br, C4H4;

Scheme 17
Deep eutectic solvent is easily recovered from the reaction mixture and can be effectively reused at least three times without noticeable loss of activity. Remarkably, salicylaldehydes 1 bearing both electron-donating (e.g., MeO) and electron-withdrawing groups (e.g., Br) showed almost similar reactivity giving 4H-chromenes in 65% ± 98% yields. As for thiols, aromatic compounds like 2-naphthylthiol and a number of functionalized thiophenol derivatives produced the corresponding chromenes 43 in 80% ± 98% yields, while aliphatic ones (cyclohexylthiol and iso-butylthiol) were significantly less reactive (28% and 45%, respectively). At the same time, secondary amines 24a ± c provided benzopyrano[2,3-d ]pyrimidines 25 under similar conditions. It was shown that the scope of this reaction is limited to secondary amines, with cyclic ones such as piperidine 24b and morpholine 24c being much more reactive compared to acyclic dimethylamine 24a, whereas primary amines, e.g., benzylamine, did not react at all. Nevertheless, this method provides an easy access to a variety of chromenes 43 and benzopyrano[2,3-d ]pyrimidines 25 and is very attractive from the viewpoint of green chemistry since it requires mild conditions, no catalyst and recyclable non-toxic reaction medium.
A plausible mechanism for the synthesis of 2-amino-2chromenes 43 in DES 44 as exemplified by the reaction with thiophenol is shown in Scheme 18. First, the urea part of DES 44 assists the Knoevenagel condensation via hydrogen bonding between the urea hydrogen atom and the oxygen atom of the carbonyl group of salicylaldehyde 1. At the same time, urea 45a can activate deprotonation of malononitrile 15a using its Lewis basic sites, providing intermediate 46. thiophenol on the electrophilic carbon ± carbon double bond in 23 affords 2-amino-2-chromenes 43. 101 Mohammadzadeh et al. demonstrated that high surface area magnesium oxide in DMF represents a highly effective heterogeneous catalytic system for the reaction of salicylaldehyde 1, malononitrile 15a and aryl alcohols 48 ± 50 or ketones 51, 52 to produce chromeno[3,4-c]chromenes 53 ± 55 and chromeno [3,4-c]pyridines 56, 57, respectively (Scheme 19). 103 The reaction proceeds very rapidly and provides the corresponding heterocycles in high yields. The catalyst is easily prepared by dehydration of Mg(OH) 2 at about 450 8C for 2 hours. Unfortunately, the authors gave poor information about the scope of the reaction, but nevertheless, this method represents a very attractive approach to such polycyclic compounds.

Scheme 20
Using isonitriles 60 as nucleophiles in MCRs between salicylaldehyde and ortho-aminophenols 61 gives rise to 2-imino-1,4-benzoxazine derivatives 62 (Scheme 21). 105 Here, the hydroxy group of salicylaldehyde 1 is not involved in the reaction, whereas its presence in aminophenol 61 is of key importance for the formation of compounds 62.
A probable mechanism for the synthesis of compounds 62 is shown in Scheme 22. Initially, condensation of salicylaldehyde 1 and an appropriate aminophenol 61 gives Schiff base 63, which then reacts with isonitrile 60 to generate nitrilium intermediate 64. Nucleophilic attack by the oxygen of ortho-aminophenol 61 on the electrophilic carbon atom affords 2-imino-3,4-dihydroxybenzoxazine 65 undergoing successive oxidation to produce benzoxazine 62 (pathway a). An alternative cyclization pathway involving the salicylaldehyde hydroxyl group and subsequent oxidation that would result in the formation of imino-1-benzofuran 67 was not observed (pathway b). Probably, the NH precursor of 67 (66) is in equilibrium with 64, and the formation of 65 and 62 is thermodynamically favoured, driving the reaction to benzoxazine derivatives 62.
Apart from using carbon, nitrogen or sulfur nucleophiles in the three-component reactions of salicylaldehyde and cyanoacetic acid derivatives, application of phosphorus nucleophiles has also been reported. Thus, condensation of salicylaldehyde 1, malononitrile 15a and trialkyl phosphites 68 proceeds via the phospha-Michael addition and affords (2-amino-4H-chromen-4-yl)phosphonates 69. This reaction has attracted a special attention of researchers and was accomplished by a plenty of procedures using catalysts such as, e.g., K 3 PO 4 , 106 ethylene diaminediacetate, 107 iodine, 108 indium trichloride 109 and polyethylene glycol 400 110 (Scheme 23).
Metal complex catalysis, both hetero-and homogeneous, has also become an indispensable tool for MCRs involving salicylaldehydes as allowing the synthesis of a variety of useful heterocycles.
Copper(I)-catalyzed three-component reactions of salicylaldehyde, an alkyne and an amine (sometimes referred to as A 3 coupling reaction) provides a reliable approach to 2,3disubstituted benzo [

Scheme 21
silylalkynes, where only phenyl and hexyl substituents gave high yields, whereas the introduction of the methyl group decreased the yields to as low as 22% ± 28%. As for an amine component, the lowest yield was observed for diallylamine 24l (27% ± 30% yields). At the same time, for piperidine 24b, morpholine 24c or dibenzylamine 24m, the desired benzofurans 71 were formed in moderate to high yields (50% ± 99%), with the lowest yield (50%) obtained for a nitro-substituted compound.
A probable mechanism for the synthesis of benzofurans 71 is illustrated in Scheme 25. The authors assumed that the reaction proceeds through an intramolecular 5-exo-dig cyclization. Copper(I) chloride forms copper acetylide 72 with an alkynylsilane 70. 124 At the same time, copper(II) triflate plays a dual role: (a) it acts as a Lewis acid for the in situ generation of iminium intermediate 73 from aldehyde 1 and amine 24; and (b) activates the alkyne moiety to assist the intramolecular nucleophilic attack by a hydroxy group via 5-exo-dig cyclization in 74.
Later, Li et al. developed the CuI-catalyzed A 3 coupling reaction between salicylaldehydes 1, secondary amines 24, and arylacetylenes 75 followed by the base-assisted O-annulation reaction to obtain benzo[b]furan derivatives 76 (Scheme 26). 125 It was found that the final closure of the benzofuran ring requires the presence of a base, and the system K 2 CO 3 /Bu 4 NBr turned out to be optimal. Here, the yields of products 76 were influenced mainly by the structure of amine component 24 (the presence of at least one alkyl substituent decreased the yield by 19%), and the nature of a substituent in alkyne 75 (those substituted with electron-donating groups were more reactive).
It should be noted that the majority of other metal catalysts tested in the above-mentioned reaction, e.g., N,N H -ethylenebis(salicylideneiminato)copper(II), 126 Ni 2+ exchanged Y-zeolite, 127 133 A particular advantage of this procedure is that this catalytic system is easily recoverable and can be reused at least five times without loss in its efficiency. The amine component 24 is limited to aliphatic secondary amines 24 such as piperidine 24b, morpholine 24c and dibenzylamine 24m, whereas both secondary aralkyl amines (24o,p) and aromatic primary amines (PhNH 2 ) gave no desired benzo[b]furan products, probably due to the reduced nucleophilicity of the NH scaffold conjugated to the aromatic ring. Also, aromatic alkyne substrates 75 were found to be more reactive than aliphatic ones.

Scheme 29
Salicylaldehydes bearing both electron-withdrawing and electron-donating substituents reacted smoothly and in high yields in both types of reactions. In the synthesis of glycosylated iminocoumarins 81, the most reactive were propargyl glycosides (X = O, n = 1, reaction time 2 h), whereas for S-propynyl and sulfonyl glycoside derivatives it took 4 hours for the reaction to proceed.
The above-mentioned reaction between salicylaldehyde 1, sugar alkynes 83 and sulfonyl azides 79a,d,e was independently performed by Rajput et al. under the same conditions. 135 However, in this case the authors used only propargyl ethers of carbohydrates 83 as an alkyne component (Scheme 30). Glycosides 83 containing 6-deoxy, 2-deoxy-2-acetamido and disaccharide moieties as well as carbohydrates linked to other positions rather than anomeric afforded high yields of iminocoumarins 84. Also, sulfonylazides bearing different substituents showed virtually equal reactivity. Iminocoumarins 84 with deprotected acetoxy groups were subsequently tested as galectine antagonists and demonstrated high activity.
In 2013, Wu et al. 136 developed a straightforward procedure for the Pd-catalyzed carbonylation of salicylaldehydes 1 and substituted benzyl chlorides 85 to obtain chromenone derivatives 86 (Scheme 31). The scope of the reaction is rather wide; benzyl chlorides with both electrondonating and electron-withdrawing substituents were tolerated under the reaction conditions; however, the former substituents provided higher product yields (69% ± 99%) compared to the latter ones (71% ± 76%). As for salicylal-

Scheme 28
dehydes 1, substrates with different functionalities gave the desired product in moderate to high yields (44% ± 95%). The only one exception were nitro-substituted substrates, which proved to be unstable under reaction conditions and underwent the reduction of the nitro group to the amino one followed by self-polymerization.
A probable reaction mechanism is depicted in Scheme 32. The catalytic cycle is initiated by palladium(0) generated from palladium(II) by the action of the phosphine ligand. Then, the oxidative addition of benzyl chloride 85 to palladium(0) occurs to afford organopalladium species 87.
After the coordination and insertion of CO, the key intermediate acyl-palladium complex 88 is formed. Nucleophilic attack of the salicylaldehyde on complex 88 results in the elimination of 2-formylphenyl 2-phenylacetate affording final product 86 after the intramolecular condensation. 137 Palladium(0) can be regenerated by treatment with a base and used directly in the next catalytic cycle.

Scheme 32
Pd II -Catalyzed three-component coupling reaction between salicylaldehydes 1, alkynols 89 and anilines 90 or orthoesters 91 represents a straightforward diastereoselective synthetic route to chromane spiroacetals 92, 93, respectively (Scheme 33). 138 Previously, such compounds were obtained, e.g., by the hetero-Diels ± Alder reactions requiring tedious experimentation. 139 ± 141 In contrast, the proposed Pd II -catalyzed MCR is a convenient one-pot procedure performed under ambient temperature from easily available starting materials. In both cases, spiroacetals 92, 93 are produced stereospecifically and in high yields.
A plausible mechanism for the formation of spiroacetals 92 proposed by the authors is illustrated in Scheme 34.  152,153 Intramolecular nucleophilic addition of the hydroxy group to the oxonium ion affords 99, which undergoes a protodemetalation reaction to yield the desired product 92, thus terminating the second catalytic cycle.
Another general approach to densely substituted chromanes was elaborated by Taheri et al. by using diarylethylene 100 as the starting material in MCRs involving salicylaldehyde and carbon nucleophiles. 154 Three-component reaction of salicylaldehyde 1, 1,1-diphenylethylene 100 and indoles 19 or trimethoxybenzene 101 was accomplished in the presence of a sulfonyl-containing Brùensted acid ionic liquid 102 serving both as a catalyst and as a solvent at 80 8C to provide the desired chromanes 103, 104 in high yields (Scheme 35). The first reaction step comprises an intermolecular hydroalkoxylation of the carbon ± carbon double bond of 100. It was shown that the scope of the olefinic component is limited to 1,1-diphenylethylene 100 only, since other styrene derivatives such as methylstyrene have insufficient nucleophilicity to enter this reaction. Substituents in indoles 19 have almost no effect on the yield of chromanes 103. This method represents a convenient  approach to chromanes of such type and provides usual advantages of utilizing ionic liquids, namely, a simple reaction procedure, easy isolation of the desired compounds and possibility to reuse the ionic liquid several times with the same efficiency. In recent times, application of ultrasonic or microwave assistance in MCRs occupies a special place.
An unusual switchable three-component reaction between salicylaldehyde 1, 5-amino-3-methylisoxazole 105 and N-aryl-3-oxobutanamides 106 was reported in 2014 by Chebanov et al. 155 Applying either ultrasonication, or Lewis acid [Yb(OTf) 3 ] catalysis, or both, one can change the direction of the reaction and selectively obtain one of three kinds of heterocyclic scaffolds 107 ± 109 depending on the group in the N-aryl moiety (Scheme 36).
A plausible mechanism for such transformation is shown in Scheme 37. First, it should be mentioned that the formation of any of the products 107 ± 109 through intermediate 110 (pathway a) as for cyclic 1,3-diketones 156 was excluded as intermediate 110 did not react with amide 106 under any comparable conditions. Probably, the synthesis of chromane-3-carboxamide 107 proceeds via generation of imine 111 (pathway b) since ultrasonication of 111 and 106 at ambient temperature provided the desired compound 107 during the same reaction time. Expectedly, the Lewis acid activates the carbonyl group in salicylaldehyde 1. As a result, this active species can interact not only with the exocyclic NH 2 group but also with the 4-CH nucleophilic centre of aminoisoxazole 105. 157 When treated with carboxamide 106, adduct 112 (pathway c) generated from intermediate 113 can lose a water molecule via two different routes: either by elimination at ambient temperature resulting in the formation of dihydroisoxazolo[5,4-b]pyridine 108 or by nucleophilic substitution involving the phenolic OH group under ultrasonication providing oxygen-bridged compound 109. Presumably, in this case the main effect of ultrasound is the energy transfer to the reaction mixture required for the intramolecular heterocyclization, which cannot be provided by heating under conventional magnetic or even mechanical stirring. However, the possibility of the Lewis acid-mediated route cannot be completely excluded since it has been reported for the similar three-component reactions. 158,159 This route involves an initial attack of the exocyclic NH 2 moiety of aminoisoxazole on the acid-activated b-carbonyl substituent of acetoacetamide and subsequent reaction with salicylaldehyde.
The same tendency to form oxygen-bridged structures under MWI was also observed in the three-component reaction of salicylaldehyde 1, 5-amino-3-arylpyrazole 114 and pyruvic acid 115 (Scheme 38). 160 Refluxing the reaction mixture in acetic acid results in the formation of 3-aryl-6-(2hydroxyphenyl)pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives 116. The same result was also obtained by applying MWI at 150 8C, allowing one to gain a four-fold reduction in the reaction time due to the higher reaction temperature. Reaction of the starting materials in AcOH at ambient temperature by using ultrasonic irradiation produced oxygen-bridged 3-aryl-10,11-dihydro-4,10-methanopyrazolo[4,3-c] [1,5]benzoxazocine-4-carboxylic acid derivatives 117. Heterocycles 117 are rather stable and tolerated refluxing in a number of solvents (AcOH, MeOH, EtOH and BuOH). Also, treatment with NaOH in ethanol resulted in removal of the bridged moiety, oxidation, and transformation into compounds 116 in 90% yield.
A large group of MCRs involving salisylaldehyde comprises reactions with 1,3-dicarbonyl compounds. These reactions give rise to another very important privileged medicinal scaffold, namely, 2H-chromenes representing an ubiquitous structural motif in a variety of compounds displaying a wide range of biological activities. 163 Yang et al. pioneered to demonstrate that lipase can catalyze MCRs between salicylaldehyde, acetoacetone 124 and alcohols 125 to afford functionalized 2H-chromenes 126 in satisfactory yields (Scheme 41). 164 The scope of alcoholic substrates is limited to aliphatic alcohols, where the linear ones with a longer alkyl moiety are less reactive, and branched-chain alcohols do not react at all. The proposed procedure cannot be considered to be practically valuable; however, this study extends the utility of lipase in organic synthesis.
A more convenient approach to 2H-chromenes 126 comprises catalysis with L-proline (rt, 6 ± 8 h) providing higher yields of the products (52% ± 90%) for a wider range of alcohols. 165

Scheme 41
Petasis-borono-Mannich reaction represents an efficient synthetic route to 2H-chromenes proceeding without participation of 1,3-dicarbonyl compounds. Candeias et al. 166 and, independently, Petasis et al. 167 have shown that the reaction between salicylaldehyde 1, amine 24 and vinylboronic acids 127 can be successfully performed using water as a reaction medium to produce substituted 2H-chromenes 128 in high yields (Scheme 42).

Scheme 42
Changing one of the starting materials in this reaction results in changing the reaction pathway. For example, using phenylboronic acid 129 in the above-mentioned reaction led to the formation of alkylaminophenols 130 in yields up to 96%. At the same time, with an amino acid, e.g. L-phenylalanine 131, as an amino component, boron complex 132 was obtained in 85% yield with 99% de (Scheme 43).

Scheme 43
In all cases the resulting products required no laborious isolation or purification since they precipitated from the reaction mixture.
A convenient approach to 3-cinnamoylcoumarins 133 represents the three-component reaction between salicylaldehyde 1, b-keto esters 134 and aromatic aldehydes 135 catalyzed by bismuth(III) trifluoromethanesulfonate (Scheme 44). 168 Interestingly, addition of hydrazine turns this reaction into the four-component one, affording pyrazolyl-coumarins 136 in high yields under the same reaction conditions. This efficient and selective methodology characterized by using a`green' catalyst, low costs, short reaction times and an easy work-up procedure provides a useful approach to coumarin derivatives, a structural scaffold realized in a range of naturally occurring products and pharmaceuticals.

Scheme 45
A probable mechanism of this process is illustrated in Scheme  125a,e,f  170 The target compounds are probably formed through a reaction of in situ produced 3-acetyl-2Hchromen-2-one intermediates with isocyanides 60 via Michael addition/intramolecular cyclization/oxidation tandem reactions. Both strong electron-withdrawing and electron-donating substituents in salicylaldehydes 1 decrease the product yields (49% ± 59%), while the modest electronwithdrawing substituents have less pronounced effect. The highest yields were achieved with unsubstituted salicylaldehyde.

Scheme 47
Fluorescent 3-(2 H -benzothiazolyl)coumarins 142 were obtained by a convenient piperidine-mediated reaction between salicylaldehydes 1, ethyl cyanoacetate 15b and o-aminobenzenethiols 143 (Scheme 48). 171 This reaction proceeded smoothly for salicylaldehydes containing both electron-withdrawing and electron-donating substituents; however, the product yields in the latter case were higher, and the highest yield was obtained for the methoxy sub-stituent (80%). At the same time, the diethylamino substituent provided lower yield, probably due to a facile oxidation under reaction conditions. However, the scope of this reaction is limited to only one type of a substrate, namely, ethyl cyanoacetate 15b, since attempts to use malonic acid, malononitrile or diethyl malonate failed. Later, it was shown that this reaction can also be performed not only under basic catalysis conditions, but also under acidic ones (PhCO 2 H, BuOH, reflux, 8 ± 24 h). 172,173

Scheme 48
Alizadeh et al. demonstrated that the piperidine-iodine dual catalyst system showed excellent results in the synthesis of coumarins bearing a heterocyclic moiety. Reactions between salicylaldehyde 1, b-keto esters 134 and 1-(2aminophenyl)pyrrole 90j or isatoic anhydride 144 provided pyrrolo[1,2-a]quinoxaline-145 or quinazolinone-substituted coumarins 146 respectively (Scheme 49). 174,175 In the case of coumarin 146 the reaction requires the presence of ammonium acetate and thus is considered to be the fourcomponent process. 175 The highest yields of the heterocycles 145, 146 were attained with salicylaldehydes 1 having electron-withdrawing substituents (NO 2 , Cl), whereas the presence of electron-donating substituents (MeO) reduces the yields by on average 30%. The same tendency is observed with the elongation of the alkyl radical R 2 in  b-keto ester 134. Undoubtful advantages of this procedure are mild reaction conditions and easy isolation of the resulting compounds. A probable mechanism for the formation of 146 is illustrated in Scheme 50. First, isatoic anhydride 144 transforms into 2-aminobenzamide 147. Next, the piperidinecatalyzed Knoevenagel reaction and cyclization of salicylaldehyde 1 and b-keto ester 134a provides 3-acetylcoumarin 148. Then, I 2 -catalyzed condensation reaction of 2-aminobenzamide 147 and 3-acetylcoumarin 148 generates intermediate 149. Subsequently, an intramolecular nucleophilic attack of the amide NH 2 on the imine group in compound 149 provides the anticipated product 146. It appears that I 2 plays two essential roles in this reaction, a) the construction of imine 149, potentially via coordination to the carbonyl group, and b) activation of the imine group to promote its reaction with nucleophiles.
Among amine catalysts used in the MCRs involving salicylaldehyde and 1,3-dicarbonyl derivatives, amino acids occupy a special place.

Scheme 51
Application of N-acetylglycine as an inexpensive catalyst in the Biginelli reaction between salicylaldehyde, ethyl acetoacetate 134b and urea/thiourea 45a,b gave a surprising result. 177 It was found that salicylaldehyde reacts to form unexpected bicyclic oxygen-bridged pyrimidines 158a,b under refluxing in methanol in the presence of N-acetylglycine, whereas under traditional reaction conditions (MeOH, HCl) in the absence of the catalyst the expected dihydropyrimidine 159 was obtained (Scheme 52).
One more example of an unusual course of the Biginellilike MCRs was discovered by Gorobets et al. when studying the reaction between salicylaldehydes 1, 3-amino-1,2,4-triazole 153 and acetone 51b (Scheme 53). 178 The aldehyde component reacted with the exocyclic amino substituent rather than with the endocyclic nitrogen atom of triazole 153 resulting in the formation of tetrahydropyrimidine 160. Depending on the reaction conditions, condensation afforded various products. Thus, under refluxing in methanol with a catalytic amount of 4 N HCl, compound 160 was produced; however, the microwave irradiation (170 8C) of the reaction mixture led to the formation of oxygenbridged compound 161, in both cases in moderate yields.
A probable mechanism for the synthesis of 4H-chromenes 163 by the example of the reaction between salicylaldehyde 1, dimedone 2b and thiophenol 165a is depicted in Scheme 55. The process is induced by the formation of imine intermediate 166 by the reaction of salicylaldehyde 1 with L-proline. 246 ± 248 Next, 166 undergoes nucleophilic addition of thiophenol 165 (pathway a) or dimedone 2b (pathway b) to yield the corresponding Mannich-type intermediate 167 or 168, respectively, which are susceptible towards nucleophilic attack of the other nucleophile, providing the desired product 163 following an intramolecular dehydration. Although pathway a and pathway b are both able to generate 163, the authors believed that the reaction proceeds predominantly via the pathway b.
The authors proposed the reaction mechanism for the formation of 9-(1H-indol-3-yl)xanthen-1-(9H)-ones 173. LCMNP can probably activate salicylaldehyde 1 via formation of imine 175. Both carboxylic and amino moieties of the amino acid participate in activating the aldehyde for 162

Scheme 59
such as antipyrine 179, as well as indoles 19 and naphthol 50, are effectively catalyzed by an anhydrous FeCl 3 7PPh 3 catalytic system (Scheme 60). 258 It was shown that the addition of PPh 3 significantly improved the yields of products 180 ± 182, and such effect was not observed with any other metal catalyst tested. Here, triphenylphosphine acts as the hydrogen bond acceptor weakening the intramolecular H-bond in the dimedone moiety of an intermediate product, thus facilitating the interaction of the substrate with FeCl 3 and subsequent transformation to the final product of the reaction. The authors have found that the key feature of the process is the reversible alkylation of dimedone with salicylaldehyde allowing one to improve the selectivity of this three-component reaction with carbon-based nucleophiles.

Scheme 61
The plausible mechanism for the formation of 183 is shown in Scheme 62. Being treated with pyrrolidine 24e, salicylaldehyde 1 generates intermediate 185 that undergoes subsequently a nucleophilic attack by 184a forming inter-mediate 186. Then, compound 186 eliminates H 2 O to provide the corresponding product 183.
Multicomponent reactions between salicylaldehyde, barbituric acid 170a and pyrazolones 33 or isocyanides 60b,d give rise to chromeno [2,3-d ]pyrimidines 189,190. Soleimani et al. 261,262 demonstrated that these reactions are catalyzed by organic acids such as acetic and p-toluenesulfonic acids in water-ethanol media (Scheme 64). In both cases the scope of the reactions is limited to only barbituric acid, and attempts to replace it with, e.g., malononitrile, failed. Also, there are limitations concerning the substituents in the substrates Ð the presence of the 3-methoxy group in pyrazolone 33, as well as the nitro group in salicylaldehyde 1 in the case of reaction with isocyanides 60 reduces the yields up to 60%. Apart from these exceptions, both procedures provide excellent yields of the desired heterocycles. These procedures require rather prolonged heating; however, they have such undoubtful advantages as operational simplicity and using water as a component of the reaction medium.

Scheme 64
As noted above, in MCRs with salicylaldehyde and malononitrile, trialkylphosphites behave as usual nucleophiles, according to the typical reaction pattern. 107

Scheme 68
A probable mechanism for this reaction is presented in Scheme 69.
It should be noted that, to obtain similar benzopyrano [2,3-b]pyridines, different reaction conditions were also reported comprising the catalysis with piperidine, 267 triethylamine, 268 chitosan under solvent-free conditions 269 or SnO nanoparticles. 270 Here, the first two of the abovementioned methods provided lower yields compared to the procedure using ZrP 2 O 7 nanoparticles, and in the last one the procedure to prepare the heterogeneous catalyst is too laborious, while the method of applying the chitosan catalyst is very promising both in terms of high yields and simple experimentation.
A unique approach to construct a coumarin scaffold was proposed by Nandaluru et al. based on the inverse electron demand Diels-Alder reaction. 272

Scheme 69
including Knoevenagel condensation, transesterification, enamine formation, an inverse electron demand Diels-Alder reaction, 1,2-elimination and transfer hydrogenation (Scheme 71). Both dienophiles and dienes for the main inverse electron demand Diels-Alder step were produced in situ by a secondary amine-catalyzed strategy. The highest yields were achieved for 5-methoxy-and 5-methyl-substi-tuted salicylaldehyde, other substitution patterns gave similar results, whereas 6-methoxy-substituted salicylaldehyde did not enter the reaction at all. Generally, this MCR procedure allows the synthesis of a series of previously reported A-ring functionalized 6H-dibenzo[b,d ]pyran-6ones in superior yields (by up to 44%) compared to those obtained via a stepwise protocol. 273,274 An effective diastereoselective approach to C3-dihydrofuran-functionalized coumarins 200 via the four-component reaction between salicylaldehydes 1, substituted benzaldehydes 135, 6-methyl-4-hydroxy-2-pyranone 34 and pyridinium bromide 201 was developed by Sun et al. 275 The Et 3 N-catalyzed reaction proceeded smoothly under solvent-free conditions under MWI to provide coumarins 200 in 71% ± 89% yields (Scheme 72). Electronic effects both in

Scheme 73
salicylaldehydes and in the benzaldehyde components influence the product yields. Thus, the presence of electrondonating substituents in the positions 2 and 5 of salicylaldehydes 1 as well as in the para-position of benzaldehydes 135 renders these compounds more reactive and provides higher yields of coumarins 200 compared to those substituted with electron-withdrawing substituents.
A plausible mechanism for the synthesis of the corresponding product 200 is illustrated in Scheme 73. The first reaction step comprises the Knoevenagel condensation. At the same time, pyridinium ylide 202 generated by the reaction of pyridinium bromide 201 with Et 3 N undergoes the Michael addition with intermediate 203 to give enolate 204. The latter eliminates pyridine and cyclizes simultane-ously to afford dihydrofuran-functionalized coumarins 200. In total, one carbon7oxygen and two carbon7carbon bonds in dihydrofuran ring are generated in this MWassisted four-component domino reaction.
An elegant synthetic approach to a combinatorial library of biologically significant pyranopyrazoles and chromenopyrazoles 205 was developed based on application of nitroketene N,S-acetal 206, a unique versatile synthon bearing three functionalities on an ethene motif, in reaction between ethyl acetoacetate 134b, hydrazine hydrates 207 and salicylaldehyde 1 (Scheme 74). 276 This domino reaction sequence provides the formation of C7C, C7O, C7N, C = C, C = N bonds and one stereocentre in a single operation through condensation/Knoevenagel/Michael/ annulation reactions. The particular advantage of this procedure is that the target heterocycles are isolated by simple filtration.
A probable mechanism for the formation of chromenopyrazoles 205 is shown in Scheme 75. The initial step is condensation of ethyl acetoacetate 134b with hydrazine hydrate affording pyrazolone 33, which undergoes the Knoevenagel condensation with salicylaldehyde 1 to give Michael acceptor 208.   formed exclusively suggesting phenolic O-cyclization via pathway a to be more facile.

Conclusion
Salicylaldehydes, being commercially available and easily accessible starting materials, are efficiently utilized in a plethora of MCRs, mostly in (pseudo)three-as well as in four-component reactions. In this review, we focused our attention on the MCRs with the participation of at least one molecule of salicylaldehyde wherein both hydroxyl and aldehyde groups are involved in the reaction. We tried to cover applications of salicylaldehydes as privileged synthons for the synthesis of a wide range of various heterocylic systems such as chromenes, coumarins and xanthenes.