Ball Milling Promoted N-Heterocycles Synthesis

In the last years, numerous protocols have been published using ball milling for organic synthesis. Compared to other methods such as microwave or ultrasound irradiation and ionic liquids, ball mill chemistry is an economical, and ecofriendly method in organic synthesis that is rather underrepresented in the knowledge of organic chemists. The aim of this review is to explore the advantages of the application of ball milling in synthesis of N-heterocyclic compounds.

Ball milling is a mechanical method broadly used to granulate minerals into very fine particles and the preparation or alteration of inorganic solids, although its use in organic synthesis is relatively uncommon [19][20][21][22].
The term mechanochemistry has been introduced in periodicals recently. According to IUPAC a mechanochemical reaction is defined as "a chemical reaction that is induced by the direct absorption of mechanical energy" [23]. However, the area is furthermore divided into: (i) mechanical activation of solids; (ii) mechanical alloying and (iii) the reactive milling of solids [24][25][26][27] (Figure 1). Very recently, ball milling has been used in synthesis of organic compounds. Several reviews describing the use of ball milling in the synthesis and reactions of organic compounds have been published [28][29][30][31][32]. This review is dedicated to the utilization of the ball-milling technique in the synthesis of heterocycles.

Pyrrole Synthesis
Zeng et al. [33] developed a mechanochemical and solvent free synthesis for preparing a series of 2,5-dimethylpyrrole-3,4-dicarboxylates and 3,4-diphenylpyrroles in moderate to excellent yields from various amines and acetoacetate or 2-phenylacetaldehyde, respectively, in the presence of Mn(OAc)3 as mediator (Scheme 1). Cascade mechanical milling reactions were reported for the first time by Kaupp et al. [34]. They investigated synthesis of pyrrole and indole products in quantitative yields by the reaction of trans-1,2 dibenzoylethene with primary, secondary enamine esters or enamine ketones in a ball mill (Scheme 2). The reactions took place through Michael addition of the enamine nitrogen followed by cyclization addition of the enamine double bond. The product is obtained by rearrangement to the enamine followed by elimination of water. Recently, ball milling reactions have not been limited to simple organic reactions like condensations but have become widely used in more complex reactions like: This review is dedicated to the utilization of the ball-milling technique in the synthesis of heterocycles.

Pyrrole Synthesis
Zeng et al. [33] developed a mechanochemical and solvent free synthesis for preparing a series of 2,5-dimethylpyrrole-3,4-dicarboxylates and 3,4-diphenylpyrroles in moderate to excellent yields from various amines and acetoacetate or 2-phenylacetaldehyde, respectively, in the presence of Mn(OAc) 3 as mediator (Scheme 1). This review is dedicated to the utilization of the ball-milling technique in the synthesis of heterocycles.

Pyrrole Synthesis
Zeng et al. [33] developed a mechanochemical and solvent free synthesis for preparing a series of 2,5-dimethylpyrrole-3,4-dicarboxylates and 3,4-diphenylpyrroles in moderate to excellent yields from various amines and acetoacetate or 2-phenylacetaldehyde, respectively, in the presence of Mn(OAc)3 as mediator (Scheme 1). Cascade mechanical milling reactions were reported for the first time by Kaupp et al. [34]. They investigated synthesis of pyrrole and indole products in quantitative yields by the reaction of trans-1,2 dibenzoylethene with primary, secondary enamine esters or enamine ketones in a ball mill (Scheme 2). The reactions took place through Michael addition of the enamine nitrogen followed by cyclization addition of the enamine double bond. The product is obtained by rearrangement to the enamine followed by elimination of water. Cascade mechanical milling reactions were reported for the first time by Kaupp et al. [34]. They investigated synthesis of pyrrole and indole products in quantitative yields by the reaction of trans-1,2 dibenzoylethene with primary, secondary enamine esters or enamine ketones in a ball mill (Scheme 2). The reactions took place through Michael addition of the enamine nitrogen followed by cyclization addition of the enamine double bond. The product is obtained by rearrangement to the enamine followed by elimination of water.
A solid-solid ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO4·H2O (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using Scheme 6. Synthesis of N-triazolylmethyloxindole.

Pyrazole Synthesis
Paveglio et al. [40] studied the mechanical parameters for the best conversion and selectivity for synthesis of 1H-pyrazole derivatives in a ball mill (Scheme 8.) The optimum conditions were 450 rpm, five balls (10 mm), and the use of 10% of para-toluenesulfonic acid (p-TSA) as catalyst for 3 min. A solid-solid ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO4·H2O (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using

Pyrazole Synthesis
Paveglio et al. [40] studied the mechanical parameters for the best conversion and selectivity for synthesis of 1H-pyrazole derivatives in a ball mill (Scheme 8.) The optimum conditions were 450 rpm, five balls (10 mm), and the use of 10% of para-toluenesulfonic acid (p-TSA) as catalyst for 3 min.

Pyrazole Synthesis
Paveglio et al. [40] studied the mechanical parameters for the best conversion and selectivity for synthesis of 1H-pyrazole derivatives in a ball mill (Scheme 8.) The optimum conditions were 450 rpm, five balls (10 mm), and the use of 10% of para-toluenesulfonic acid (p-TSA) as catalyst for 3 min. A solid-solid ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO4·H2O (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using A solid-solid ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO 4 ·H 2 O (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using a high-speed ball mill at 1290 rpm to give 1,3,5-triaryl-2-pyrazoline in good yields (up to 93%) (Scheme 9). The reaction was extended by using thiosemicarbazides and aliphatic enones to give 2-pyrazoline derivatives [28].
Molecules 2018, 23, x 5 of 21 a high-speed ball mill at 1290 rpm to give 1,3,5-triaryl-2-pyrazoline in good yields (up to 93%) (Scheme 9). The reaction was extended by using thiosemicarbazides and aliphatic enones to give 2-pyrazoline derivatives [28]. Ze et al. [42] developed a one-pot and solvent-free protocol for the synthesis in excellent yields of 3,5-diphenyl-1H-pyrazoles under mechanochemical ball-milling conditions using cheap sodium persulfate as the oxidant (Scheme 10) followed by a very simple work-up procedure. Twelve diflourinated pyrazolones were synthesized via a solventless one-pot, two-step mechanochemical reaction. The first step is the condensation between a β-ketoester and phenylhydrazine to give the corresponding pyrazoline, which is flourinated in the next step to afford the fluorinated pyrazolones [43] (Scheme 11). Scheme 11. Condensation of a β-ketoester and phenylhydrazine.
Bondock and coworkers [44], synthesized a series of pyrazolylthiosemicarbazones by reaction of thiosemicarbazide and appropriate aldehydes using sodium carbonate and 1 h ball milling. The reaction of phenacyl bromide with pyrazolylthiosemicarbazones afforded the corresponding 2-(arylidenehydrazino)-4-phenylthiazoles in high yield (up to 98%) (Scheme 12). Ze et al. [42] developed a one-pot and solvent-free protocol for the synthesis in excellent yields of 3,5-diphenyl-1H-pyrazoles under mechanochemical ball-milling conditions using cheap sodium persulfate as the oxidant (Scheme 10) followed by a very simple work-up procedure.
Molecules 2018, 23, x 5 of 21 a high-speed ball mill at 1290 rpm to give 1,3,5-triaryl-2-pyrazoline in good yields (up to 93%) (Scheme 9). The reaction was extended by using thiosemicarbazides and aliphatic enones to give 2-pyrazoline derivatives [28]. Ze et al. [42] developed a one-pot and solvent-free protocol for the synthesis in excellent yields of 3,5-diphenyl-1H-pyrazoles under mechanochemical ball-milling conditions using cheap sodium persulfate as the oxidant (Scheme 10) followed by a very simple work-up procedure. Twelve diflourinated pyrazolones were synthesized via a solventless one-pot, two-step mechanochemical reaction. The first step is the condensation between a β-ketoester and phenylhydrazine to give the corresponding pyrazoline, which is flourinated in the next step to afford the fluorinated pyrazolones [43] (Scheme 11). Scheme 11. Condensation of a β-ketoester and phenylhydrazine.
Bondock and coworkers [44], synthesized a series of pyrazolylthiosemicarbazones by reaction of thiosemicarbazide and appropriate aldehydes using sodium carbonate and 1 h ball milling. The reaction of phenacyl bromide with pyrazolylthiosemicarbazones afforded the corresponding 2-(arylidenehydrazino)-4-phenylthiazoles in high yield (up to 98%) (Scheme 12). Twelve diflourinated pyrazolones were synthesized via a solventless one-pot, two-step mechanochemical reaction. The first step is the condensation between a β-ketoester and phenylhydrazine to give the corresponding pyrazoline, which is flourinated in the next step to afford the fluorinated pyrazolones [43] (Scheme 11).
Molecules 2018, 23, x 5 of 21 a high-speed ball mill at 1290 rpm to give 1,3,5-triaryl-2-pyrazoline in good yields (up to 93%) (Scheme 9). The reaction was extended by using thiosemicarbazides and aliphatic enones to give 2-pyrazoline derivatives [28]. Ze et al. [42] developed a one-pot and solvent-free protocol for the synthesis in excellent yields of 3,5-diphenyl-1H-pyrazoles under mechanochemical ball-milling conditions using cheap sodium persulfate as the oxidant (Scheme 10) followed by a very simple work-up procedure. Twelve diflourinated pyrazolones were synthesized via a solventless one-pot, two-step mechanochemical reaction. The first step is the condensation between a β-ketoester and phenylhydrazine to give the corresponding pyrazoline, which is flourinated in the next step to afford the fluorinated pyrazolones [43] (Scheme 11). Scheme 11. Condensation of a β-ketoester and phenylhydrazine.
Bondock and coworkers [44], synthesized a series of pyrazolylthiosemicarbazones by reaction of thiosemicarbazide and appropriate aldehydes using sodium carbonate and 1 h ball milling. The reaction of phenacyl bromide with pyrazolylthiosemicarbazones afforded the corresponding 2-(arylidenehydrazino)-4-phenylthiazoles in high yield (up to 98%) (Scheme 12). Bondock and coworkers [44], synthesized a series of pyrazolylthiosemicarbazones by reaction of thiosemicarbazide and appropriate aldehydes using sodium carbonate and 1 h ball milling. The reaction of phenacyl bromide with pyrazolylthiosemicarbazones afforded the corresponding 2-(arylidenehydrazino)-4-phenylthiazoles in high yield (up to 98%) (Scheme 12).

Imidazole Synthesis
Lamaty et al. [45] investigated a solvent-free ball milling one-pot two-step synthesis of N-heterocyclic carbenes directly from anilines. This strategy allowed a significant improvement of the yields compared to conventional procedures. Synthesis of IPr Me ·HCl of was selected as a model reaction. The optimum reaction conditions were 2:1 molar equivalents of 2,6-diisopropylphenylamine:2,3-butanedione at 500 rpm for two hours. Variable carbon sources were used (formaldehyde, chloromethylethylether, 1,3,5-trioxane and paraformaldehyde), and the best results were obtained with paraformaldehyde and HCl (4M) in dioxane as a solvent to afford the product in 49% yield over the two steps. Under the optimium conditions, the scope of the reaction was studied for many products (IPr·HCl, IMes·HCl, Io-Tol·HCl and ICy·HCl), and the reaction proceeded effectively to afford NCH in high yield (up to 100%) for all substrates except a highly hindered 2,6-diphenylmethyl-4-methylphenyl substrate (Scheme 13).

Imidazole Synthesis
Lamaty et al. [45] investigated a solvent-free ball milling one-pot two-step synthesis of N-heterocyclic carbenes directly from anilines. This strategy allowed a significant improvement of the yields compared to conventional procedures. Synthesis of IPr Me ·HCl of was selected as a model reaction. The optimum reaction conditions were 2:1 molar equivalents of 2,6-diisopropylphenylamine:2,3-butanedione at 500 rpm for two hours. Variable carbon sources were used (formaldehyde, chloromethylethylether, 1,3,5-trioxane and paraformaldehyde), and the best results were obtained with paraformaldehyde and HCl (4M) in dioxane as a solvent to afford the product in 49% yield over the two steps. Under the optimium conditions, the scope of the reaction was studied for many products (IPr·HCl, IMes·HCl, Io-Tol·HCl and ICy·HCl), and the reaction proceeded effectively to afford NCH in high yield (up to 100%) for all substrates except a highly hindered 2,6-diphenylmethyl-4-methylphenyl substrate (Scheme 13).

Imidazole Synthesis
Lamaty et al. [45] investigated a solvent-free ball milling one-pot two-step synthesis of N-heterocyclic carbenes directly from anilines. This strategy allowed a significant improvement of the yields compared to conventional procedures. Synthesis of IPr Me ·HCl of was selected as a model reaction. The optimum reaction conditions were 2:1 molar equivalents of 2,6-diisopropylphenylamine:2,3-butanedione at 500 rpm for two hours. Variable carbon sources were used (formaldehyde, chloromethylethylether, 1,3,5-trioxane and paraformaldehyde), and the best results were obtained with paraformaldehyde and HCl (4M) in dioxane as a solvent to afford the product in 49% yield over the two steps. Under the optimium conditions, the scope of the reaction was studied for many products (IPr·HCl, IMes·HCl, Io-Tol·HCl and ICy·HCl), and the reaction proceeded effectively to afford NCH in high yield (up to 100%) for all substrates except a highly hindered 2,6-diphenylmethyl-4-methylphenyl substrate (Scheme 13). Scheme 13. Synthesis of N-heterocyclic carbenes directly from anilines. Scheme 13. Synthesis of N-heterocyclic carbenes directly from anilines.

Benzimidazole Synthesis
Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) were employed as a catalyst in the green synthesis of 1,2-disubstituted benzimidazoles derivatives by a ball milling technique which produced high yields with high selectivity [46] (Scheme 14).

Benzimidazole Synthesis
Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) were employed as a catalyst in the green synthesis of 1,2-disubstituted benzimidazoles derivatives by a ball milling technique which produced high yields with high selectivity [46] (Scheme 14). Recently, our research group [47] reported a high yielding ball milling synthetic method for a series of benzimidazol-2-ones or benzimidazol-2-thiones under solvent-free conditions by reaction of o-phenylenediamine and benzaldehydes or benzoic acids. Several reaction parameters were investigated such as milling ball weight, frequency and milling time. This method shows effectiveness for the reaction of different carboxylic acids, aldehydes, urea, ammonium thiocyanate or thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation of benzimidazolone or benzimidazolthione by ethyl chloroacetate was also studied (Scheme 18).

Benzimidazole Synthesis
Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) were employed as a catalyst in the green synthesis of 1,2-disubstituted benzimidazoles derivatives by a ball milling technique which produced high yields with high selectivity [46] (Scheme 14). Recently, our research group [47] reported a high yielding ball milling synthetic method for a series of benzimidazol-2-ones or benzimidazol-2-thiones under solvent-free conditions by reaction of o-phenylenediamine and benzaldehydes or benzoic acids. Several reaction parameters were investigated such as milling ball weight, frequency and milling time. This method shows effectiveness for the reaction of different carboxylic acids, aldehydes, urea, ammonium thiocyanate or thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation of benzimidazolone or benzimidazolthione by ethyl chloroacetate was also studied (Scheme 18). Recently, our research group [47] reported a high yielding ball milling synthetic method for a series of benzimidazol-2-ones or benzimidazol-2-thiones under solvent-free conditions by reaction of o-phenylenediamine and benzaldehydes or benzoic acids. Several reaction parameters were investigated such as milling ball weight, frequency and milling time. This method shows effectiveness for the reaction of different carboxylic acids, aldehydes, urea, ammonium thiocyanate or thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation of benzimidazolone or benzimidazolthione by ethyl chloroacetate was also studied (Scheme 18).

Benzimidazole Synthesis
Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) were employed as a catalyst in the green synthesis of 1,2-disubstituted benzimidazoles derivatives by a ball milling technique which produced high yields with high selectivity [46] (Scheme 14). Recently, our research group [47] reported a high yielding ball milling synthetic method for a series of benzimidazol-2-ones or benzimidazol-2-thiones under solvent-free conditions by reaction of o-phenylenediamine and benzaldehydes or benzoic acids. Several reaction parameters were investigated such as milling ball weight, frequency and milling time. This method shows effectiveness for the reaction of different carboxylic acids, aldehydes, urea, ammonium thiocyanate or thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation of benzimidazolone or benzimidazolthione by ethyl chloroacetate was also studied (Scheme 18). Reaction of anilines, CS2, and 2-aminophenol or thiophenol under solvent-free ball milling conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yields (Scheme 19) [48].  Reaction of anilines, CS2, and 2-aminophenol or thiophenol under solvent-free ball milling conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yields (Scheme 19) [48]. Reaction of anilines, CS 2 , and 2-aminophenol or thiophenol under solvent-free ball milling conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yields (Scheme 19) [48]. Reaction of anilines, CS2, and 2-aminophenol or thiophenol under solvent-free ball milling conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yields (Scheme 19) [48]. Reaction of anilines, CS2, and 2-aminophenol or thiophenol under solvent-free ball milling conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yields (Scheme 19) [48].

Scheme 21. Synthesis of 4-substituted-2-(arylidenehydrazino)thiazoles.
Nagarajaiah et al. [50] reported an efficient chlorination method to give α-chloroketones by the reaction of ketones with trichloroisocyanuric acid in the presence of p-TSA under ball-milling conditions. Then these α-chloroketones reacted with thiosemicarbazides and thiourea to afford 2-hydrazinylthiazoles and 2-aminothiazoles, respectively, in good yields (Scheme 22). Phung et al. [49] showed the importance of the ball milling technique in dry ice for regioselective conversion of an unactivated 2-aryl aziridine or 2-alkyl into an oxazolidinone (Scheme 23). Nagarajaiah et al. [50] reported an efficient chlorination method to give α-chloroketones by the reaction of ketones with trichloroisocyanuric acid in the presence of p-TSA under ball-milling conditions. Then these α-chloroketones reacted with thiosemicarbazides and thiourea to afford 2-hydrazinylthiazoles and 2-aminothiazoles, respectively, in good yields (Scheme 22).

Thiazole and Oxazole Synthesis
Solvent and catalyst-free reactions of α-haloketones with thiosemicarbazones to give the corresponding 4-substituted 2-(arylidenehydrazino)thiazoles in a ball milling reactor were reported by Abdel-Latif and coworkers [49] (Scheme 21). Nagarajaiah et al. [50] reported an efficient chlorination method to give α-chloroketones by the reaction of ketones with trichloroisocyanuric acid in the presence of p-TSA under ball-milling conditions. Then these α-chloroketones reacted with thiosemicarbazides and thiourea to afford 2-hydrazinylthiazoles and 2-aminothiazoles, respectively, in good yields (Scheme 22). Phung et al. [49] showed the importance of the ball milling technique in dry ice for regioselective conversion of an unactivated 2-aryl aziridine or 2-alkyl into an oxazolidinone (Scheme 23). Phung et al. [49] showed the importance of the ball milling technique in dry ice for regioselective conversion of an unactivated 2-aryl aziridine or 2-alkyl into an oxazolidinone (Scheme 23).

Scheme 21. Synthesis of 4-substituted-2-(arylidenehydrazino)thiazoles.
Nagarajaiah et al. [50] reported an efficient chlorination method to give α-chloroketones by the reaction of ketones with trichloroisocyanuric acid in the presence of p-TSA under ball-milling conditions. Then these α-chloroketones reacted with thiosemicarbazides and thiourea to afford 2-hydrazinylthiazoles and 2-aminothiazoles, respectively, in good yields (Scheme 22). Phung et al. [49] showed the importance of the ball milling technique in dry ice for regioselective conversion of an unactivated 2-aryl aziridine or 2-alkyl into an oxazolidinone (Scheme 23).

Scheme 25. Coupling of terminal alkynes, alkyl halides or aryl boronic acids and sodium azide.
Thorwirth and coworkers [51] have reported polymerization of 1,12-diazidododecane and bisethynyl compounds in a ball mill without destroying the polymer backbone (Scheme 26).

Pyridine Synthesis
Zhang et al. [53] reported an effective method for the synthesis of pyridyl isothiocyanates (ITCs) from the corresponding amines, where aqueous iron(III) chloride promotes desulfurization of a dithiocarbamate salt that is generated in situ from the amine and carbon disulfide in the presence of DABCO or sodium hydride under ball-milling conditions ( Scheme 28). Use of this protocol gives good yields.

Pyridine Synthesis
Zhang et al. [53] reported an effective method for the synthesis of pyridyl isothiocyanates (ITCs) from the corresponding amines, where aqueous iron(III) chloride promotes desulfurization of a dithiocarbamate salt that is generated in situ from the amine and carbon disulfide in the presence of DABCO or sodium hydride under ball-milling conditions ( Scheme 28). Use of this protocol gives good yields. Scheme 28. Synthesis of pyridyl isothiocyanates.

Quinoline Synthesis
Yu et al. [54] reported a high yield (up to 99%) synthetic method for quinoline derivatives by the reaction of N-formyldihydroquinoline on a solid base such as sodium hydroxide (NaOH) under high-speed ball milling conditions with a catalytic amount of polyethylene glycol 2000 (PEG 2000) as catalyst (Scheme 29).

Scheme 29. Deformylation of N-formyldihydroquinoline.
Under solvent-free high-speed ball milling styrene and N-aryl aldimines generated in situ are used for the synthesis of cis-2,4-diphenyltetrahydroquinolines in good yield via Diels-Alder cycloaddition reactions in presence of FeCl3 (Scheme 30). This method is a very efficient and green alternative to conventional methods for synthesis for these types of heterocyclic skeletons. The advantages of this method are a short reaction time, easy availability of the required reagents, solvent free conditions and a nontoxic catalyst [53].

Pyridine Synthesis
Zhang et al. [53] reported an effective method for the synthesis of pyridyl isothiocyanates (ITCs) from the corresponding amines, where aqueous iron(III) chloride promotes desulfurization of a dithiocarbamate salt that is generated in situ from the amine and carbon disulfide in the presence of DABCO or sodium hydride under ball-milling conditions ( Scheme 28). Use of this protocol gives good yields. Scheme 28. Synthesis of pyridyl isothiocyanates.

Quinoline Synthesis
Yu et al. [54] reported a high yield (up to 99%) synthetic method for quinoline derivatives by the reaction of N-formyldihydroquinoline on a solid base such as sodium hydroxide (NaOH) under high-speed ball milling conditions with a catalytic amount of polyethylene glycol 2000 (PEG 2000) as catalyst (Scheme 29).

Scheme 29. Deformylation of N-formyldihydroquinoline.
Under solvent-free high-speed ball milling styrene and N-aryl aldimines generated in situ are used for the synthesis of cis-2,4-diphenyltetrahydroquinolines in good yield via Diels-Alder cycloaddition reactions in presence of FeCl3 (Scheme 30). This method is a very efficient and green alternative to conventional methods for synthesis for these types of heterocyclic skeletons. The advantages of this method are a short reaction time, easy availability of the required reagents, solvent free conditions and a nontoxic catalyst [53].

Scheme 29. Deformylation of N-formyldihydroquinoline.
Under solvent-free high-speed ball milling styrene and N-aryl aldimines generated in situ are used for the synthesis of cis-2,4-diphenyltetrahydroquinolines in good yield via Diels-Alder cycloaddition reactions in presence of FeCl 3 (Scheme 30). This method is a very efficient and green alternative to conventional methods for synthesis for these types of heterocyclic skeletons. The advantages of this method are a short reaction time, easy availability of the required reagents, solvent free conditions and a nontoxic catalyst [53].

Pyrimidine Synthesis
Under mechanochemical solvent-free conditions, a multicomponent Biginelli reaction was reported to give dihydropyrimidones [58]. The starting aldehydes were prepared within the same reaction pot by Br+ catalyzed oxidation of their corresponding primary alcohols which results in formation of byproducts. The acid was used as catalyst in the cascade transformation leading to dihydropyrimidones (Scheme 34).

Pyrimidine Synthesis
Under mechanochemical solvent-free conditions, a multicomponent Biginelli reaction was reported to give dihydropyrimidones [58]. The starting aldehydes were prepared within the same reaction pot by Br+ catalyzed oxidation of their corresponding primary alcohols which results in formation of byproducts. The acid was used as catalyst in the cascade transformation leading to dihydropyrimidones (Scheme 34). Ould et al. [28] showed that the condensation reaction of an equimolar amount of an aldehyde, malononitrile and thiourea/urea by ball milling in 40 min gives 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (Scheme 36). The reactions proceed effectively without the aid of any catalyst or solvent to give the products in excellent yields (up to 98%). Scheme 36. Synthesis of 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles.

Pyrimidine Synthesis
Under mechanochemical solvent-free conditions, a multicomponent Biginelli reaction was reported to give dihydropyrimidones [58]. The starting aldehydes were prepared within the same reaction pot by Br+ catalyzed oxidation of their corresponding primary alcohols which results in formation of byproducts. The acid was used as catalyst in the cascade transformation leading to dihydropyrimidones (Scheme 34). Ould et al. [28] showed that the condensation reaction of an equimolar amount of an aldehyde, malononitrile and thiourea/urea by ball milling in 40 min gives 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (Scheme 36). The reactions proceed effectively without the aid of any catalyst or solvent to give the products in excellent yields (up to 98%). Scheme 36. Synthesis of 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles.

Pyrimidine Synthesis
Under mechanochemical solvent-free conditions, a multicomponent Biginelli reaction was reported to give dihydropyrimidones [58]. The starting aldehydes were prepared within the same reaction pot by Br+ catalyzed oxidation of their corresponding primary alcohols which results in formation of byproducts. The acid was used as catalyst in the cascade transformation leading to dihydropyrimidones (Scheme 34). Ould et al. [28] showed that the condensation reaction of an equimolar amount of an aldehyde, malononitrile and thiourea/urea by ball milling in 40 min gives 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (Scheme 36). The reactions proceed effectively without the aid of any catalyst or solvent to give the products in excellent yields (up to 98%).

Thiazine Synthesis
Sharifi et al. [65] reported that the use of KF-Al2O3 solid support in a solvent-free ball milling procedure involving the reaction of 2-aminothiophenols with 2-bromoalkanoates (Scheme 47) led to a green and efficient synthesis of a series of benzothiazinone in excellent yield.

Conclusions
Herein, we have reviewed the use of mechanochemical technique for synthesis of variety of N-heterocyles. As discussed, the ball milling technique is becoming a more promising green tool for the synthesis of various N-heterocycles, including condensation reactions, multicomponent cascade reactions, metal catalyzed synthesis, etc.