Ball Milling Promoted N-Heterocycles Synthesis

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Jun 4, 2018 - ball milling in the synthesis and reactions of organic compounds have been .... The first step is the condensation between a β-ketoester and.

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Ball Milling Promoted N-Heterocycles Synthesis Taghreed H. El-Sayed 1,2 , Asmaa Aboelnaga 1,2 , Mohamed A. El-Atawy 1,3 Mohamed Hagar 1,3, * 1

2 3

*

ID

and

Chemistry Department, Faculty of Science, Taibah University, Yanbu 46423 Saudi Arabia; [email protected] (T.H.E.-S.); [email protected] (A.A.); [email protected] (M.A.E.-A.) Chemistry Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Heliopolis, Cairo 11757, Egypt Chemistry Department, Faculty of Science, Alexandria University, P.O. 426 Ibrahemia, Alexandria 21321, Egypt Correspondence: [email protected] or [email protected]; Tel.: +966-545-527-958  

Received: 29 April 2018; Accepted: 2 June 2018; Published: 4 June 2018

Abstract: 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. Keywords: ball milling; green synthesis; mechanochemistry; N-heterocycles

1. Introduction The past decade has witnessed a sustainable and ever increasing interest in the reactivity of N-heterocycles due to their importance in Nature, medicinal chemistry, living matter, drug design, advanced materials, and natural product synthesis [1]. They constitute an important an important class of compounds found in many natural products [2] with anticancer [3], cytotoxic [4], anti-HIV [5], anti-malarial [6], anti-inflammatory [7], antimicrobial [8], anti-hyperglycemic and anti-dyslipidemic [9] activity, in addition to anti-neurodegenerative disorder drugs targeting Alzheimer’s, Parkinson disease, Huntington’s disease [10], and many more [11,12]. Many reviews involving the synthesis of N-heterocycles have been published, including cascade synthetic reactions [13], the synthesis of six membered rings [14], the synthesis of spiro hetrocycles [15], the microwave assisted synthesis of five-membered azaheterocyclic systems [16], synthesis of small N-hetrocycles [17] and metalation [18]. 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 [19–22]. 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 [24–27] (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 [28–32].

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Figure 1. Ball milling process. Figure Figure 1. 1. Ball Ball milling milling process. process.

Recently, milling reactions have not been simple organic reactions like reactions condensations Recently,ball ball milling reactions have notlimited been tolimited limited to simple simple organic like Recently, ball milling reactions have not been to organic reactions like but have become widely used in more complex reactions like: condensations but have become widely used in more complex reactions like: condensations but have become widely used in more complex reactions like:

• • • • • • •  •  •

Metal-catalyzed Metal-catalyzed organic reactions Metal-catalyzed organic organic reactions reactions nucleophilic reactions reactions nucleophilic reactions reactions cascade cascade reactions reactions reactions Diels–Alder reactions reactions Oxidation-reduction reactions Oxidation-reduction Oxidation-reduction reactions reactions Halogenation and aminohalogenation reactions Halogenation and aminohalogenation reactions Halogenation and aminohalogenation reactions Formation of calixarenes, rotaxanes and cage compounds Formation of of calixarenes, calixarenes, rotaxanes rotaxanes and and cage cage compounds compounds Formation Transformation of of biologically biologically active active compounds compounds Transformation Transformation of biologically active compounds Asymmetric synthesis Asymmetric synthesis synthesis Asymmetric This review review is dedicated dedicated to the the utilization of of the ball-milling ball-milling technique in in the the synthesis synthesis of of This This review is is dedicated to to the utilization utilization ofthe the ball-millingtechnique technique in the synthesis heterocycles. heterocycles. of heterocycles.

2. Five Membered Rings 2. Five Five Membered Membered Rings Rings 2. 2.1. Pyrrole Pyrrole Synthesis Synthesis 2.1. Zeng et et al. al. [33] [33]developed developedaaamechanochemical mechanochemicaland andsolvent solventfree free synthesis for preparing series Zeng et al. [33] developed mechanochemical and solvent free synthesis preparing aa series Zeng synthesis forfor preparing a series of of 2,5-dimethylpyrrole-3,4-dicarboxylates and 3,4-diphenylpyrroles in moderate to excellent yields of 2,5-dimethylpyrrole-3,4-dicarboxylates 3,4-diphenylpyrroles in moderate to excellent 2,5-dimethylpyrrole-3,4-dicarboxylates andand 3,4-diphenylpyrroles in moderate to excellent yieldsyields from from and or respectively, in from various various amines and acetoacetate acetoacetate or 2-phenylacetaldehyde, 2-phenylacetaldehyde, respectively, in the theofpresence presence of various aminesamines and acetoacetate or 2-phenylacetaldehyde, respectively, in the presence Mn(OAc)of 3 Mn(OAc) 3 as mediator (Scheme 1). Mn(OAc) 3 as mediator as mediator (Scheme 1).(Scheme 1).

O O RNH RNH22

R R11

R R22

Mn(OAc) Mn(OAc)33 Ball milling milling Ball solvent solvent free free

R R11

R R22

R R N N R R11

R R22

((R R11,, R R22))= =(( H, H, Ph Ph)) or or ((Me, Me, COOEt COOEt)) R R= = alkyl alkyl or or aryl aryl

Scheme 1. 1. Synthesis 2,5-dimethylpyrrole-3,4-dicarboxylates and and 3,4-diphenylpyrroles. 3,4-diphenylpyrroles. Synthesis of of 2,5-dimethylpyrrole-3,4-dicarboxylates 3,4-diphenylpyrroles. Scheme

Cascade mechanical milling reactions were reported for the first time by Kaupp et al. [34]. They Cascade mechanical mechanical milling milling reactions reactions were were reported reported for for the the first first time time by by Kaupp Kaupp et et al. al. [34]. [34]. They They Cascade investigated synthesis synthesis of of pyrrole pyrrole and and indole indole products products in in quantitative quantitative yields yields by by the the reaction reaction of of investigated investigated synthesis of pyrrole and indole products in quantitative yields by the reaction of trans-1,2 trans-1,2 dibenzoylethene with primary, secondary enamine esters or enamine ketones in a ball mill trans-1,2 dibenzoylethene withsecondary primary, secondary enamine esters or enamine a ball mill dibenzoylethene with primary, enamine esters or enamine ketones in aketones ball millin(Scheme 2). (Scheme 2). The reactions took place through Michael addition of the enamine nitrogen followed by (Scheme 2). The reactions took place through Michael addition of the enamine nitrogen followed by The reactions took place through Michael addition of the enamine nitrogen followed by cyclization cyclization addition addition of of the the enamine enamine double double bond. bond. The The product product is obtained obtained by by rearrangement rearrangement to to the the cyclization addition of the enamine double bond. The product is obtainedis by rearrangement to the enamine enamine followed by elimination of water. enamine followed by elimination followed by elimination of water. of water.

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Scheme of dibenzoylethene with secondary enamine esters enamine Scheme 2. Reaction Reaction of trans-1,2 dibenzoylethene with primary, secondary enamine or Scheme 2. 2. Reaction of trans-1,2 trans-1,2 dibenzoylethene with primary, primary, secondary enamine esters or oresters enamine Scheme 2. Reaction of trans-1,2 dibenzoylethene with primary, secondary enamine esters or enamine ketones. enamine ketones. ketones. Scheme 2. Reaction of trans-1,2 dibenzoylethene with primary, secondary enamine esters or enamine ketones. ketones.

2.2. Indole Synthesis. Synthesis. 2.2. 2.2. Indole 2.2. Indole Synthesis. 2.2. Indole Synthesis. Zille et al. [35] reported good Sonogashira reaction method under solvent free conditions Zille Zille et et al. al. [35] [35] reported reported aaa good good Sonogashira Sonogashira reaction reaction method method under under solvent solvent free free conditions conditions Zille et al. [35] reported a good Sonogashira reaction method under solvent free conditions involving the reaction of o-iodoaniline and terminal alkynes using ZnBr 2 as catalyst to afford afford involving theal.reaction of and alkynes using ZnBr to involving reaction of o-iodoaniline o-iodoaniline and terminal terminal alkynes usingunder ZnBr2solvent 2 as catalyst afford Zille et [35] reported a good Sonogashira reaction method free conditions involving the reaction of o-iodoaniline and terminal alkynes using 3). ZnBr2 as catalyst to afford 2-alkynylanilines in a planetary ball mill at 800 rpm for 30 min (Scheme 2-alkynylanilines in ball 800 rpm min 2-alkynylanilines in aa planetary planetary ball mill mill at atand 800terminal rpm for for 30 30 min (Scheme (Scheme 3). involving the reaction of o-iodoaniline alkynes using 3). ZnBr2 as catalyst to afford 2-alkynylanilines in a planetary ball mill at 800 rpm for 30 min (Scheme 3). 2-alkynylanilines in a planetary ball mill at 800 rpm for 30 min (Scheme 3).

Scheme 3. reaction synthesis Scheme 3. 3. Sonogashira Sonogashira reaction reaction for for synthesis synthesis of of indoles. indoles. Scheme Scheme 3.Sonogashira Sonogashira reactionfor for synthesisofofindoles. indoles. Scheme 3. Sonogashira reaction for synthesis of indoles.

Rhodium (III)-catalyzed (III)-catalyzed oxidative oxidative cyclization cyclization of of acetanilides acetanilides and and non-terminal non-terminal alkynes alkynes using using Rhodium Rhodium (III)-catalyzed oxidative cyclization ofofacetanilides and alkynes using Rhodium (III)-catalyzed oxidative cyclization acetanilides andnon-terminal non-terminal alkynes using dioxygen as a oxidant in the absence of a solvent, under mechanochemical conditions afforded 10 dioxygen as a oxidant in the absence a solvent, under mechanochemical conditions afforded 10 Rhodium (III)-catalyzed oxidativeofcyclization of acetanilides and non-terminal alkynes using dioxygen in of atosolvent, solvent, under mechanochemical conditionsafforded afforded10 dioxygenas asaaoxidant oxidantindole in the theinabsence absence under mechanochemical conditions differently substituted moderate good yields [36] (Scheme 4). differently substituted moderate good yields (Scheme 4). dioxygen as a oxidant indole in the in absence of ato solvent, under[36] mechanochemical conditions afforded 10 10differently differentlysubstituted substitutedindole indoleininmoderate moderatetotogood goodyields yields[36] [36](Scheme (Scheme4). 4). differently substituted indole in moderate to good yields [36] (Scheme 4).

Scheme Scheme 4. 4. Oxidative Oxidative cyclization cyclization of of acetanilides acetanilides and and non-terminal non-terminal alkynes. alkynes. Scheme4.4.Oxidative Oxidativecyclization cyclizationofofacetanilides acetanilidesand andnon-terminal non-terminalalkynes. alkynes. Scheme Scheme 4. Oxidative cyclization of acetanilides and non-terminal alkynes.

Under Under solvent-free solvent-free and and milling milling reaction reaction conditions, conditions, 2-carbonylindoles 2-carbonylindoles were were synthesized synthesized by by Under solvent-free and milling reaction conditions, 2-carbonylindoles were synthesized by cyclization of their corresponding enaminone using molecular iodine as a mediator for the Under solvent-free and milling reaction conditions, 2-carbonylindoles were synthesized by cyclization of their corresponding enaminone using molecular iodine as a mediator for the Under solvent-free and milling reaction conditions, 2-carbonylindoles were synthesized by cyclization of their corresponding enaminone using molecular iodine as a mediator for the annulation The enaminone precursors prepared by mechanochemical of cyclization corresponding enaminone usingwere molecular iodine a mediator the reaction annulation annulation process. The enaminone precursors were prepared byas mechanochemical reaction of cyclizationofprocess. oftheir their corresponding enaminone using molecular iodine as a for mediator for the annulation process. The enaminone precursors were prepared by mechanochemical reaction of aniline derivatives with alpha-haloketone to afford arylaminomethylenecarbonyl derivative then by process. The process. enaminone were prepared by mechanochemical reaction of aniline derivatives aniline derivatives with alpha-haloketone to afford arylaminomethylenecarbonyl derivative then by annulation Theprecursors enaminone precursors were prepared by mechanochemical reaction of aniline derivatives with alpha-haloketone to afford arylaminomethylenecarbonyl derivative then by subsequent thermal condensation with dimethyl acetal [37] (Scheme 5). with alpha-haloketone toalpha-haloketone afford arylaminomethylenecarbonyl derivative then by subsequent thermal subsequent thermalwith condensation with N,N′-dimethylformamide N,N′-dimethylformamide dimethyl acetal [37] (Scheme 5). by aniline derivatives to afford arylaminomethylenecarbonyl derivative then subsequent thermal condensation with N,N′-dimethylformamide dimethyl acetal [37] (Scheme 5). 0 condensation with N,N -dimethylformamide dimethyl acetal [37] (Scheme subsequent thermal condensation with N,N′-dimethylformamide dimethyl5). acetal [37] (Scheme 5).

Scheme Scheme 5. 5. Cyclization Cyclization of of enaminone enaminone for for synthesis synthesis of of 2-carbonylindoles. 2-carbonylindoles. Scheme 5. Cyclization of enaminone for synthesis of 2-carbonylindoles. Scheme 5. Cyclization of enaminone for synthesis of 2-carbonylindoles. Scheme 5. Cyclization of enaminone for synthesis of 2-carbonylindoles.

Recently, Recently, Vadivelu Vadivelu et et al. al. reported reported solvent-free solvent-free ball ball milling milling of of three three components—malimide, components—malimide, Recently, Vadivelu et al. reported solvent-free ball milling of three components—malimide, N-propargyl isatin and an an alkyl or aryl arylsolvent-free azide—along with DABCO and components—malimide, CuO nanoparticles as as aa N-propargyl and alkyl or azide—along with DABCO and CuO nanoparticles Recently,isatin Vadivelu et al. reported ball milling of three Recently, Vadivelu et al. reported solvent-free ball milling of three components—malimide, N-propargyl isatin and an alkyl or aryl azide—along with DABCO and CuO nanoparticles as a recyclable heterogeneous catalyst to afford N-triazolylmethyloxindole [38] (Scheme 6). recyclable heterogeneous catalyst N-triazolylmethyloxindole 6). N-propargyl isatin and an alkyl to or afford aryl azide—along with DABCO [38] and(Scheme CuO nanoparticles as a N-propargyl isatin and an alkyl or aryl azide—along with DABCO and CuO nanoparticles as a recyclable heterogeneous catalyst to afford N-triazolylmethyloxindole [38] (Scheme 6). recyclable heterogeneous catalyst to afford N-triazolylmethyloxindole [38] (Scheme 6). recyclable heterogeneous catalyst to afford N-triazolylmethyloxindole [38] (Scheme 6).

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Scheme 6. Synthesis Synthesis of N-triazolylmethyloxindole. N-triazolylmethyloxindole. Scheme Scheme 6. 6. Synthesis of of N-triazolylmethyloxindole. Scheme 6. Synthesis of N-triazolylmethyloxindole.

2.3. Indeno[1,2-b]pyrrole Synthesis Synthesis 2.3. 2.3. Indeno[1,2-b]pyrrole Indeno[1,2-b]pyrrole Synthesis 2.3. Indeno[1,2-b]pyrrole Synthesis Synthesis of N-heterocyclic N-heterocyclic compounds with with α-hydroxyketone and and N=O-semiaminal Synthesis Synthesis of of N-heterocyclic compounds compounds with α-hydroxyketone α-hydroxyketone and N=O-semiaminal N=O-semiaminal functionalities had been reported by Kaupp et al. [39]. The reaction proceeded a three-cascade Synthesis of been N-heterocyclicbycompounds with The α-hydroxyketone and via N=O-semiaminal functionalities functionalities had had been reported reported by Kaupp Kaupp et et al. al. [39]. [39]. The reaction reaction proceeded proceeded via via aa three-cascade three-cascade reactions vinylogous vinylogous substitution, cyclization, and 1,3-hydrogen shiftproceeded by reaction reaction ofaninhydrin ninhydrin and functionalities had been reported by Kaupp etand al. [39]. The reaction via three-cascade reactions substitution, cyclization, 1,3-hydrogen shift by of reactions vinylogous substitution, cyclization, and 1,3-hydrogen shift by reaction of ninhydrin and and enamino ester (Scheme 7). reactions vinylogous substitution, cyclization, and 1,3-hydrogen shift by reaction of ninhydrin and enamino enamino ester ester (Scheme (Scheme 7). 7). enamino ester (Scheme 7).

Scheme 7. Synthesis of indeno[1,2-b]pyrrole. Scheme 7. Synthesis Synthesis of of indeno[1,2-b]pyrrole. indeno[1,2-b]pyrrole. Scheme Scheme 7. 7. Synthesis of indeno[1,2-b]pyrrole.

2.4. Pyrazole Synthesis 2.4. Pyrazole Synthesis 2.4. Pyrazole Synthesis Paveglio et al. [40] studied the mechanical parameters for the best conversion and selectivity for Paveglio et al. [40] studied the mechanical parameters for the best conversion and selectivity for Paveglio et al. [40] studied the mechanical for8.) synthesis of 1H-pyrazole derivatives in a ball parameters mill (Scheme conditions were 450 theThe bestoptimum conversion and selectivity for synthesis of 1H-pyrazole derivatives in a ball mill (Scheme 8.) The optimum conditions were 450 synthesis of 1H-pyrazole derivatives in a ball mill (Scheme 8.) The optimum conditions were 450 rpm, rpm, five balls (10 mm), and the use ofin10% of para-toluenesulfonic acid (p-TSA) conditions as catalyst for 3 min. of 1H-pyrazole derivatives a ball mill (Scheme 8.) The optimum were 450 rpm, five balls (10 mm), and the use of 10% of para-toluenesulfonic acid (p-TSA) as catalyst for 3 min. five mm), and the use 10% para-toluenesulfonic acid (p-TSA) as catalyst for 3 min. rpm,balls five (10 balls (10 mm), and theofuse ofof 10% of para-toluenesulfonic acid (p-TSA) as catalyst for 3 min.

Scheme 8. Synthesis of 1H-pyrazole derivatives. Scheme 8. Synthesis of 1H-pyrazole derivatives. Scheme 8. Synthesis of 1H-pyrazole 1H-pyrazole derivatives. derivatives. Scheme 8. Synthesis of

A solid-solid ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO4·H2O A solid-solid ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO4·H2O (0.5 equivalents) by Zhu of and coworkers The reaction proceeded effectively A solid-solidwas ballreported milling reaction chalcone and[41]. phenylhydrazine catalyzed by NaHSO4using ·H2O (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using

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5 ofO21 ball milling reaction of chalcone and phenylhydrazine catalyzed by NaHSO4 ·H 2 21 5 of 5 of 21 (0.5 equivalents) was reported by Zhu and coworkers [41]. The reaction proceeded effectively using a a high-speed ball mill at 1290 rpm to give 1,3,5-triaryl-2-pyrazoline in good yields (up to 93%) ahigh-speed high-speed ball mill 1290to rpm give1,3,5-triaryl-2-pyrazoline 1,3,5-triaryl-2-pyrazoline ingood good yields (up 93%) ballball millmill at 1290 rpm givetoto 1,3,5-triaryl-2-pyrazoline in good yields (upyields to 93%) (Scheme 9). ahigh-speed atat1290 rpm give (up tototo93%) (Scheme 9). The reaction was extended by using thiosemicarbazides in and aliphatic enones give (Scheme 9). The reaction was extended by using thiosemicarbazides and aliphatic enones to give The reaction was extended by using thiosemicarbazides and aliphatic enones to give 2-pyrazoline (Scheme 9). The reaction [28]. was extended by using thiosemicarbazides and aliphatic enones to give 2-pyrazoline derivatives 2-pyrazoline derivatives [28]. derivatives [28]. 2-pyrazoline derivatives [28].

Scheme 9. Synthesis of 1,3,5-triaryl-2-pyrazoline. Scheme 9. Synthesis of 1,3,5-triaryl-2-pyrazoline. Scheme9.9.Synthesis Synthesisofof1,3,5-triaryl-2-pyrazoline. 1,3,5-triaryl-2-pyrazoline. Scheme

Ze Zeetetal. al.[42] [42]developed developedaaone-pot one-potand andsolvent-free solvent-freeprotocol protocolfor forthe thesynthesis synthesisininexcellent excellentyields yields Zeetetal. al.[42] [42]developed developedaaone-pot one-potand andsolvent-free solvent-freeprotocol protocolfor forthe thesynthesis synthesisininexcellent excellentyields yields Ze ofof3,5-diphenyl-1H-pyrazoles 3,5-diphenyl-1H-pyrazolesunder undermechanochemical mechanochemicalball-milling ball-millingconditions conditionsusing usingcheap cheapsodium sodium 3,5-diphenyl-1H-pyrazolesunder undermechanochemical mechanochemicalball-milling ball-millingconditions conditionsusing using cheap sodium ofof 3,5-diphenyl-1H-pyrazoles persulfate asasthe persulfate theoxidant oxidant(Scheme (Scheme10) 10)followed followedby bya avery verysimple simplework-up work-upprocedure. procedure. cheap sodium persulfateasasthe theoxidant oxidant(Scheme (Scheme10) 10)followed followedby byaavery verysimple simplework-up work-upprocedure. procedure. persulfate

Scheme 10. Synthesis of 3,5-diphenyl-1H-pyrazoles. Scheme 10. Synthesis ofof3,5-diphenyl-1H-pyrazoles. Scheme10. 10.Synthesis Synthesisof 3,5-diphenyl-1H-pyrazoles. Scheme 3,5-diphenyl-1H-pyrazoles.

Twelve diflourinated pyrazolones were synthesized via a solventless one-pot, two-step Twelve diflourinated diflourinated pyrazolones pyrazolones were synthesized synthesized via via a a solventless solventless one-pot, one-pot, two-step two-step Twelve solventless mechanochemical reaction. The first were step is the condensation between a β-ketoester and mechanochemical reaction. reaction. The The first step is the the condensation condensation between between aaa β-ketoester β-ketoester and and mechanochemical The first step is the condensation between mechanochemical first step is β-ketoester phenylhydrazine to give the corresponding pyrazoline, which is flourinated in the next step to phenylhydrazineto give the corresponding pyrazoline, which flourinated thestep next step phenylhydrazine the corresponding pyrazoline, is flourinated in theinin next tostep afford totogive give the corresponding pyrazoline, which isisflourinated the next toto afford the fluorinated pyrazolones [43] (Scheme 11). which afford the fluorinated pyrazolones [43] (Scheme 11). the fluorinated pyrazolones [43] (Scheme 11). 11). afford the fluorinated pyrazolones [43] (Scheme

Scheme 11. Condensation of a β-ketoester and phenylhydrazine. Scheme11. 11.Condensation Condensation ofaaβ-ketoester β-ketoester andphenylhydrazine. phenylhydrazine. Scheme Scheme 11. Condensation of of a β-ketoester and and phenylhydrazine.

Bondock and coworkers [44], synthesized a series of pyrazolylthiosemicarbazones by reaction Bondockand andcoworkers coworkers[44], [44],synthesized synthesizedaaseries seriesofofpyrazolylthiosemicarbazones pyrazolylthiosemicarbazonesby byreaction reaction Bondock of thiosemicarbazide and appropriate aldehydes usingofsodium carbonate and 1 h ball by milling. The Bondock and coworkers [44], synthesized a series pyrazolylthiosemicarbazones reaction of thiosemicarbazide and appropriate aldehydes using sodium carbonate and 1 h ball milling. The ofreaction thiosemicarbazide andbromide appropriate aldehydes using sodium carbonate and 1 hthe ballcorresponding milling. The of phenacyl with pyrazolylthiosemicarbazones afforded ofreaction thiosemicarbazide appropriate aldehydes using sodium carbonate andthe 1 hcorresponding ball milling. phenacyland bromide with pyrazolylthiosemicarbazones pyrazolylthiosemicarbazones afforded reaction ofof phenacyl bromide with afforded corresponding 2-(arylidenehydrazino)-4-phenylthiazoles in high yield (up to 98%) (Scheme 12).the The reaction of phenacyl bromide with pyrazolylthiosemicarbazones afforded the corresponding 2-(arylidenehydrazino)-4-phenylthiazolesininhigh highyield yield(up (uptoto98%) 98%)(Scheme (Scheme12). 12). 2-(arylidenehydrazino)-4-phenylthiazoles 2-(arylidenehydrazino)-4-phenylthiazoles in high yield (up to 98%) (Scheme 12).

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Scheme 12. 12. Synthesized Synthesized of 2-(arylidenehydrazino)-4-phenylthiazoles. Synthesized of of 2-(arylidenehydrazino)-4-phenylthiazoles. Scheme

2.5. Imidazole Imidazole Synthesis Imidazole Synthesis 2.5. Lamaty et et al. al. [45] [45] investigated investigated aa solvent-free solvent-free ball ball milling milling one-pot one-pot two-step two-step synthesis synthesis of of Lamaty Lamaty N-heterocyclic carbenes carbenes directly from anilines. This strategy allowed significant improvement of N-heterocyclic carbenes directly directlyfrom fromanilines. anilines.This This strategy allowed a significant improvement N-heterocyclic strategy allowed aa significant improvement of Me·HCl of was selected as a model the yields compared to conventional procedures. Synthesis of IPr Me Me the yields compared to conventional procedures. Synthesis of IProf ·IPr HCl of wasofselected as a model of the yields compared to conventional procedures. Synthesis was selected as a ·HCl reaction. The optimum optimum reaction conditions werewere 2:1 2:1 molar equivalents ofof 2,6-diisopropyl2,6-diisopropylreaction. The reaction conditions were 2:1 molar model reaction. The optimum reaction conditions molarequivalents equivalentsof 2,6-diisopropylphenylamine:2,3-butanedione at at 500 rpm rpm for for two two hours. hours. Variable Variable carbon sources were used used phenylamine:2,3-butanedione two hours. phenylamine:2,3-butanedione at 500 Variable carbon carbon sources sources were (formaldehyde, chloromethylethylether, 1,3,5-trioxane and paraformaldehyde), and the best results (formaldehyde, (formaldehyde, chloromethylethylether, chloromethylethylether, 1,3,5-trioxane 1,3,5-trioxane and and paraformaldehyde), paraformaldehyde), and and the the best results were obtained with paraformaldehyde and HCl (4M) in dioxane as a solvent to afford thethe product in were obtained a solvent to to afford the product in obtained with with paraformaldehyde paraformaldehydeand andHCl HCl(4M) (4M)inindioxane dioxaneasas a solvent afford product 49% yield over the two steps. Under the optimium conditions, the scope of the reaction was studied 49% yield overover the two steps. UnderUnder the optimium conditions, the scope the reaction was studied in 49% yield the two steps. the optimium conditions, theof scope of the reaction was for many many products (IPr·HCl, HCl, IMes·IMes HCl,·HCl, Io-Tol· HCl·HCl andand ICy· HCl), and the reaction proceeded for (IPr· HCl, Io-Tol· HCl and ICy· HCl), and the studied forproducts many products (IPr·IMes· HCl, Io-Tol ICy ·HCl), and thereaction reaction proceeded proceeded effectively to to afford afford NCH NCH in in high high yield yield (up (up to to 100%) 100%) for for all all substrates substrates except except aa highly highly hindered hindered effectively effectively 2,6-diphenylmethyl-4-methylphenyl substrate (Scheme 13). 2,6-diphenylmethyl-4-methylphenyl substrate (Scheme 13).

Scheme 13. 13. Synthesis of of N-heterocyclic carbenes carbenes directly from from anilines. Scheme Scheme 13. Synthesis Synthesis of N-heterocyclic N-heterocyclic carbenes directly directly from anilines. anilines.

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2.6. Benzimidazole Synthesis Molecules 2018, 23, x 7 of 21 2.6. Benzimidazole Recyclable ionicSynthesis liquid-coated ZnO-nanoparticles (ZnO-NPs, 5) were wereemployed employed Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst catalyst 5) as as a a catalyst in the green synthesis of 1,2-disubstituted benzimidazoles derivatives by a ball milling in the green synthesis of 1,2-disubstituted (ZnO-NPs, benzimidazoles derivatives by a ball milling Recyclable ionic liquid-coated ZnO-nanoparticles catalyst 5) were employed as a 2.6.catalyst Benzimidazole Synthesis technique which produced high yields withwith highhigh selectivity [46] (Scheme 14). technique which produced high selectivity [46] (Scheme 14). by a ball milling catalyst in the green synthesis of yields 1,2-disubstituted benzimidazoles derivatives Recyclable ionic liquid-coated ZnO-nanoparticles (ZnO-NPs, catalyst 5) were employed as a technique which produced high yields with high selectivity [46] (Scheme 14). 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).

Scheme 14. Synthesis of 1,2-disubstituted benzimidazoles. Scheme 14. Synthesis of 1,2-disubstituted benzimidazoles. Scheme 14. Synthesis of 1,2-disubstituted benzimidazoles.

At room temperature, 1 h ball milling afforded 100% yield of substituted Scheme Synthesis of 1,2-disubstituted benzimidazoles. At (anilino-thiocarbonyl)-benzimidazolidine-2-thiones room 1 h ball14.milling afforded 100%by yield of substituted reaction of aniline At temperature, room temperature, 1 h ball milling afforded 100% yield(anilino-thiocarbonyl)ofderivatives substitutedand benzimidazolidine-2-thiones by reaction of aniline derivatives and o-phenylenediisothiocyanate o-phenylenediisothiocyanate (Scheme 15) [44]. (anilino-thiocarbonyl)-benzimidazolidine-2-thiones by reaction of aniline derivatives and At room temperature, 1 h ball milling afforded 100% yield of substituted (Scheme 15) [44]. o-phenylenediisothiocyanate (Scheme 15) [44]. (anilino-thiocarbonyl)-benzimidazolidine-2-thiones by reaction of aniline derivatives and o-phenylenediisothiocyanate (Scheme 15) [44].

Scheme 15. Synthesis of (anilino-thiocarbonyl)-benzimidazolidine-2-thiones. Scheme 15. Synthesis of (anilino-thiocarbonyl)-benzimidazolidine-2-thiones.

Scheme 15. Synthesis of (anilino-thiocarbonyl)-benzimidazolidine-2-thiones. Recently, our research group [47] reported a high yielding ball milling synthetic method for a Scheme 15. Synthesis of (anilino-thiocarbonyl)-benzimidazolidine-2-thiones. series of benzimidazol-2-ones benzimidazol-2-thiones under conditions by reaction Recently, our research groupor[47] reported a high yielding ballsolvent-free milling synthetic method for a Recently, our research group [47] reportedor abenzoic highunder yielding ball milling synthetic method of o-phenylenediamine andorbenzaldehydes acids. Several reaction parameters were series of benzimidazol-2-ones benzimidazol-2-thiones solvent-free conditions by reaction Recently, our research group [47] reported a high yielding ball milling synthetic method for a for aofseries of benzimidazol-2-ones or benzimidazol-2-thiones underreaction solvent-free conditions investigated such asand milling ball weight, frequency and Several milling time. This method showsby o-phenylenediamine benzaldehydes or benzoic acids. parameters were series of benzimidazol-2-ones or benzimidazol-2-thiones under solvent-free conditions by reaction reaction of o-phenylenediamine benzaldehydes oracids, benzoic acids.time. Several reaction parameters effectiveness for the reactionand of different urea, ammonium investigated such as milling ball weight,carboxylic frequency andaldehydes, milling This methodthiocyanate shows of o-phenylenediamine and benzaldehydes or benzoic acids. Several reaction parameters were or thiourea with o-phenylenediamine (Schemes 16and and 17). Moreover; alkylationshows of forsuch the reaction of different carboxylic acids, aldehydes, urea,time. ammonium thiocyanate were effectiveness investigated as milling ball weight, frequency milling This method investigated such as milling ball weight, frequency and milling time. This method shows benzimidazolone or benzimidazolthione by ethyl chloroacetate was also studied (Scheme 18). or thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation of effectiveness for the of different carboxylic acids, ammoniumthiocyanate thiocyanate or effectiveness for reaction the reaction of different carboxylic acids,aldehydes, aldehydes, urea, urea, ammonium benzimidazolone or benzimidazolthione by ethyl chloroacetate was also studied of (Scheme 18). thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation benzimidazolone or thiourea with o-phenylenediamine (Schemes 16 and 17). Moreover; alkylation of or benzimidazolthione chloroacetateby was also studied (Scheme 18). benzimidazoloneby or ethyl benzimidazolthione ethyl chloroacetate was also studied (Scheme 18).

Scheme 16. Synthesis of benzimidazoles from carboxylic acids or aldehydes. Scheme 16. Synthesis of benzimidazoles from carboxylic acids or aldehydes. Scheme 16. Synthesis of benzimidazoles from carboxylic acids or aldehydes.

Scheme 16. Synthesis of benzimidazoles from carboxylic acids or aldehydes.

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Scheme17. 17.Synthesis Synthesisof of benzimidazol-2-ones benzimidazol-2-ones Scheme or benzimidazol-2-thione. Scheme 17. Synthesis of benzimidazol-2-onesor orbenzimidazol-2-thione. benzimidazol-2-thione. Scheme 17. Synthesis of benzimidazol-2-ones or benzimidazol-2-thione. Scheme 17. Synthesis of benzimidazol-2-ones or benzimidazol-2-thione.

Scheme 18. Alkylation of benzimidazolone or benzimidazolthione. Scheme18. 18. Alkylation Alkylation of of benzimidazolone benzimidazoloneor orbenzimidazolthione. benzimidazolthione. Scheme Scheme 18. Alkylation of benzimidazolone or benzimidazolthione. Reaction of anilines, CS2, and 2-aminophenol or thiophenol under solvent-free ball milling Scheme 18. Alkylation of benzimidazolone or benzimidazolthione.

Reactionleads of anilines, CS and 2-aminophenol or or thiazoles, thiophenol under solvent-free ball milling conditions to a series of2, 2-anilinobenzoxazoles respectively, in good toball excellent Reaction or thiophenol thiophenol undersolvent-free solvent-free milling Reactionofofanilines, anilines,CS CS2 2,, and and 2-aminophenol 2-aminophenol or under ball milling conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yieldsReaction (Scheme 19)anilines, [48]. of ofto 2, and 2-aminophenol or under solvent-free ball milling conditions leads orthiophenol thiazoles,respectively, respectively, good excellent conditions leads toa aseries seriesCS of2-anilinobenzoxazoles 2-anilinobenzoxazoles or thiazoles, iningood to to excellent yields (Scheme 19) [48]. conditions leads to a series of 2-anilinobenzoxazoles or thiazoles, respectively, in good to excellent yields (Scheme 19) [48]. yields (Scheme 19) [48]. yields (Scheme 19) [48].

Scheme 19. Synthesis of 2-anilinobenzoxazoles or 2-anilinobenzothiazoles.

Scheme 2-anilinobenzoxazolesoror2-anilinobenzothiazoles. 2-anilinobenzothiazoles. Scheme19. 19.Synthesis Synthesis of 2-anilinobenzoxazoles Scheme 19. Synthesis of 2-anilinobenzoxazoles or 2-anilinobenzothiazoles.

Scheme 19.Synthesis Synthesis of 2-anilinobenzoxazoles or 2-anilinobenzothiazoles. 2.7. Indeno[2,1-d]imidazole

Kaupp et al. reported a good reaction of ninhydrin with ureas/thioureas to afford heterocyclic 2.7. Indeno[2,1-d]imidazole Synthesis 2.7. Indeno[2,1-d]imidazole Synthesis 2.7.2.7. Indeno[2,1-d]imidazole Synthesis Indeno[2,1-d]imidazole Synthesis and addition cascade reactions under ball milling technique bis-semi acetals by substitution Kauppetetal. al.reported reported aa good good reaction reaction of to to afford heterocyclic Kaupp of ninhydrin ninhydrinwith withureas/thioureas ureas/thioureas afford heterocyclic conditions [39] (Scheme 20). Kaupp et al.al. reported a agood of with ureas/thioureas afford heterocyclic Kaupp et reported goodreaction reaction ofninhydrin ninhydrin with ureas/thioureas totoafford heterocyclic bis-semi acetals by substitution and addition cascade reactions under ball milling technique bis-semi acetals by substitution and addition cascade reactions under ball milling technique bis-semi bybysubstitution and reactions under underball ballmilling millingtechnique technique bis-semiacetals acetals substitution and addition addition cascade cascade reactions conditions [39](Scheme (Scheme 20). conditions [39] 20). conditions [39] (Scheme conditions [39] (Scheme20). 20).

Scheme 20. Reaction of ninhydrin with ureas/thioureas. Scheme 20. Reaction of ninhydrin with ureas/thioureas. Scheme20. 20.Reaction Reactionof of ninhydrin Scheme 20. Reaction ofninhydrin ninhydrinwith withureas/thioureas. ureas/thioureas. Scheme with ureas/thioureas.

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Solvent andand catalyst-free reactions of α-haloketones with thiosemicarbazones to give the Solventand catalyst-free reactions of α-haloketones with thiosemicarbazones to give the 2.8. Thiazole Thiazole and Oxazole Oxazole Synthesis 2.8. Synthesis corresponding 4-substituted 2-(arylidenehydrazino)thiazoles millingreactor reactorwere werereported reported by corresponding 4-substituted 2-(arylidenehydrazino)thiazoles in in aa ball ball milling Solvent and catalyst-free reactions of α-haloketones with thiosemicarbazones to give the Solvent and catalyst-free reactions of α-haloketones with thiosemicarbazones to give the Abdel-Latif and coworkers [49] (Scheme 21). 21). by Abdel-Latif and coworkers [49] (Scheme corresponding 4-substituted 4-substituted 2-(arylidenehydrazino)thiazoles 2-(arylidenehydrazino)thiazoles in in aa ball ball milling milling reactor reactor were were reported reported corresponding by Abdel-Latif Abdel-Latif and and coworkers coworkers [49] [49] (Scheme (Scheme 21). 21). by

Scheme 21. Synthesis of 4-substituted-2-(arylidenehydrazino)thiazoles. Scheme 21. Synthesis of 4-substituted-2-(arylidenehydrazino)thiazoles. Scheme 21. Synthesis of 4-substituted-2-(arylidenehydrazino)thiazoles.

Scheme Synthesisan ofefficient 4-substituted-2-(arylidenehydrazino)thiazoles. Nagarajaiah et al. [50]21.reported chlorination method to give α-chloroketones by the Nagarajaiah et al. [50] reported an efficient chlorination method to give α-chloroketones reaction of ketones with trichloroisocyanuric acid in the presence of p-TSA under ball-milling by Nagarajaiah et et al. al. [50] [50] reported reported an an efficient efficient chlorination chlorination method method to to give give α-chloroketones α-chloroketones by by the the Nagarajaiah conditions. Then these α-chloroketones reacted with thiourea afford the reaction of ketones with trichloroisocyanuric acid thiosemicarbazides in the presence of and p-TSA undertoball-milling reaction of ketones with trichloroisocyanuric acid in the presence of p-TSA under ball-milling reaction Then of ketones with trichloroisocyanuric acid in the presence of (Scheme p-TSAand under ball-milling 2-hydrazinylthiazoles and 2-aminothiazoles, respectively, in good yields 22).thiourea conditions. these α-chloroketones with thiosemicarbazides to afford conditions. Then Then these α-chloroketones reacted reacted with with thiosemicarbazides and thiourea thiourea to afford afford conditions. these α-chloroketones reacted thiosemicarbazides and to 2-hydrazinylthiazoles andand 2-aminothiazoles, in good goodyields yields(Scheme (Scheme 2-hydrazinylthiazoles 2-aminothiazoles,respectively, respectively, in in 22).22). 2-hydrazinylthiazoles and 2-aminothiazoles, respectively, good yields (Scheme 22).

Scheme 22. Synthesis of 2-hydrazinylthiazoles and 2-aminothiazoles. Scheme 22. Synthesis of 2-hydrazinylthiazoles and 2-aminothiazoles.

22. Synthesis of2-hydrazinylthiazoles 2-hydrazinylthiazoles and 2-aminothiazoles. Phung et Scheme al. Scheme [49] 22. showed the ofimportance of the ball milling technique in dry ice for Synthesis and 2-aminothiazoles. regioselective conversion of an unactivated 2-aryl aziridine or 2-alkyl into an oxazolidinone (Scheme Phung et al. [49] showed the importance of the ball milling technique in dry ice for 23). Phung et al. [49] showed the importance of the ball milling technique in dry ice for Phung et al. [49] showedof importance of theaziridine ball milling technique dry ice for regioselective regioselective conversion ofthe an unactivated unactivated 2-aryl 2-aryl aziridine or 2-alkyl 2-alkyl into an anin oxazolidinone (Scheme regioselective conversion an or into oxazolidinone (Scheme 23). conversion of an unactivated 2-aryl aziridine or 2-alkyl into an oxazolidinone (Scheme 23). 23).

Scheme 23. Conversion of aziridine into an oxazolidinone. Scheme 23. Conversion of aziridine into an oxazolidinone.

Scheme Conversionof of aziridine aziridine into Scheme 23.23. Conversion intoan anoxazolidinone. oxazolidinone.

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2.9.series Triazole A of Synthesis 1,4-substituted-1H-1,2,3-triazoles were synthesized in high yields (up to 99%) by A series of 1,4-substituted-1H-1,2,3-triazoles were synthesized in high yields (up to 99%) by 2.9. Triazole Triazole Synthesis 2.9. Synthesis 1,3-dipolar cycloaddition of alkynes with and catalytic amount of (up Cu(OAc) a A series of 1,4-substituted-1H-1,2,3-triazoles were synthesized in high yields to 99%) using by 1,3-dipolar cycloaddition of alkynes withdecylazide decylazide and a acatalytic amount of Cu(OAc) 2 using2 a A series of 1,4-substituted-1H-1,2,3-triazoles were synthesized in high yields (up to 99%) by 1,3-dipolar cycloaddition of alkynes with decylazide and a catalytic amount of Cu(OAc) 2 using a ball-millball-mill at rpm speed (13.3 Hz) min [51] (Scheme A 800 series of rotation 1,4-substituted-1H-1,2,3-triazoles synthesized in24). high yields (up to 99%) by at 800 rpm rotation speed (13.3 Hz)for for10 10 were min [51] (Scheme 24). 1,3-dipolar cycloaddition of speed alkynes with decylazide and catalytic24). amount of of Cu(OAc) Cu(OAc)22 using using aa ball-mill at 800 rpm rotation (13.3 Hz) for 10 minand [51]aa(Scheme 1,3-dipolar cycloaddition of alkynes with decylazide catalytic amount ball-mill at 800 rpm rotation speed (13.3 Hz) for 10 min [51] (Scheme 24). ball-mill at 800 rpm rotation speed (13.3 Hz) for 10 min [51] (Scheme 24).

Scheme 24. 1,3-Dipolar cycloaddition of alkynes with decylazide.

Scheme 24. 1,3-Dipolar cycloaddition of alkynes with decylazide.

Scheme 24. 1,3-Dipolar cycloaddition of alkynes with decylazide. Under mechanical milling, synthesis of 1,2,3-triazole derivatives occurred by a coupling of Scheme 24. 1,3-Dipolar cycloaddition of alkynes with decylazide. Scheme 24. 1,3-Dipolar cycloaddition of alkynes with decylazide. Under mechanical milling, synthesis of derivatives occurred asulfate coupling terminal alkynes, alkyl halides or aryl boronic acids and derivatives sodium azide over copper(II) Under mechanical milling, synthesis of 1,2,3-triazole 1,2,3-triazole occurred by by a coupling of of supported on alumina (Cu/Al 2 O 3 ) in the absence of any solvent (Scheme 25) [52]. terminal alkynes, alkyl alkyl halides or aryl acids and azide over copper(II) supported Under mechanical milling, synthesis of 1,2,3-triazole occurred by asulfate coupling of terminal alkynes, halides orboronic aryl boronic acidssodium andderivatives sodium azide over copper(II) sulfate

Under mechanical milling, synthesis of 1,2,3-triazole derivatives occurred by a coupling of

terminal alkynes, halides orin aryl aryl boronic acids and sodium sodium azide over copper(II) copper(II) sulfate sulfate on alumina (Cu/Al ) in(Cu/Al the absence of any solvent (Scheme 25) [52]. supported on alumina 2O3)or the absence ofacids any solvent (Scheme 25) [52]. 2 Oalkyl 3alkyl terminal alkynes, halides boronic and azide over supported on on alumina alumina (Cu/Al (Cu/Al22O O33)) in in the the absence absence of of any any solvent solvent (Scheme (Scheme 25) 25) [52]. [52]. supported

Scheme 25. Coupling of terminal alkynes, alkyl halides or aryl boronic acids and sodium azide.

Thorwirth and coworkers [51] have reported polymerization of acids 1,12-diazidododecane and Scheme 25. Coupling of terminal alkynes, alkyl halides halides or andand sodium azide. Scheme 25. Coupling of terminal alkynes, alkyl oraryl arylboronic boronic acids sodium azide. Scheme 25. Coupling of terminal alkynes, alkyl halides or polymer aryl boronic acids and sodium azide. bisethynyl inof a ball mill alkynes, without destroying backbone (Scheme Schemecompounds 25. Coupling terminal alkyl halidesthe or aryl boronic acids and sodium26). azide.

Thorwirth and coworkers [51] have reported polymerization of 1,12-diazidododecane and

Thorwirth andand coworkers polymerization 1,12-diazidododecane Thorwirth coworkers [51]have havereported reported polymerization ofof1,12-diazidododecane 1,12-diazidododecane and and bisethynyl compounds in a ball[51] mill without destroying the polymer backbone (Scheme 26). Thorwirth and coworkers [51] have reported polymerization of and bisethynyl compounds in a ball mill without destroying the polymer backbone (Scheme 26). bisethynyl compounds compounds in in aa ball ball mill mill without without destroying destroying the the polymer polymer backbone backbone (Scheme (Scheme 26). 26). bisethynyl

Scheme 26. Polymerization of 1,12-diazidododecane and bisethynyl.

Ranu et al. [52] reported Cu/Al2O3 as a catalyst for the synthesis of Scheme 26. Polymerization of 1,12-diazidododecane bisethynyl. 1,4-disubstituted-1,2,3-triazoles by the reaction of terminal alkynes,and alkyl halide/aryl boronic acid Scheme 26. Polymerization of 1,12-diazidododecane and bisethynyl. Scheme 26. Polymerization of 1,12-diazidododecane and bisethynyl. Scheme 26. Polymerization of 1,12-diazidododecane and bisethynyl. and sodium azide under solvent free and ball milling conditions. This method averts the use of Ranu et al. [52] reported Cu/Al2O3 as a catalyst for the synthesis of hazardous organo- azides to afford arylalkyl- and arylaryl-substituted 1,2,3-triazoles in excellent Ranu et et al. al. [52] reported reported Cu/Al22O O as aa alkynes, catalystalkylfor forhalide/aryl the synthesis synthesis of 1,4-disubstituted-1,2,3-triazoles by the reaction of33 terminal boronic acid Ranu Cu/Al as catalyst the of yield 27). [52]Cu/Al Ranu et (Scheme al. [52] reported O as a catalyst for the synthesis of 1,4-disubstituted-1,2,3-triazoles 2 free 3 and 1,4-disubstituted-1,2,3-triazoles by the reaction of terminal alkynes,This alkylmethod halide/aryl boronic acid and sodium azide under solvent ball of milling conditions. averts the use of 1,4-disubstituted-1,2,3-triazoles by the reaction terminal alkynes, alkyl halide/aryl boronic acid

by theand reaction of terminal alkynes, alkyl halide/aryl boronic acid andThis sodium azide under solvent sodium azide under solvent freearylalkyland ball ball and milling conditions. method averts the use of of free hazardous organoazides to afford arylaryl-substituted inthe excellent and sodium azide under solvent free and milling conditions. This 1,2,3-triazoles method averts use hazardous organoazides to afford arylalkyland arylaryl-substituted 1,2,3-triazoles in excellent and ball milling conditions. This method averts the use of hazardous organoazides to afford arylalkylyield (Scheme 27). azides to afford arylalkyl- and arylaryl-substituted 1,2,3-triazoles in excellent hazardous organoyield (Scheme (Scheme 27). 27). and arylaryl-substituted 1,2,3-triazoles in excellent yield (Scheme 27). yield

Scheme 27. Synthesis of 1,4-disubstituted-1,2,3-triazoles from aryl boronic acid.

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Scheme 27. Synthesis of 1,4-disubstituted-1,2,3-triazoles from aryl boronic acid. Scheme 27. Synthesis of 1,4-disubstituted-1,2,3-triazoles from aryl boronic acid.

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3. Six Membered Rings 3. Six Membered Rings 3.1. Pyridine Synthesis 3.1. Pyridine Synthesis synthesis of pyridyl pyridyl isothiocyanates isothiocyanates (ITCs) (ITCs) Zhang et al. [53] reported an effective method for the 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 from the corresponding amines, where aqueous iron(III) promotes desulfurization of of a dithiocarbamate salt that is generated in situ from the aminechloride and carbon disulfide in the presence 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 DABCO or sodium hydride under ball-milling conditions ( Scheme 28). Use of this protocol gives good yields. good yields.

Scheme 28. Synthesis Scheme 28. Synthesis of of pyridyl pyridyl isothiocyanates. isothiocyanates. Scheme 28. Synthesis of pyridyl isothiocyanates.

3.2. Quinoline Synthesis 3.2. Quinoline Synthesis Synthesis 3.2. Quinoline Yu et al. [54] reported a high yield (up to 99%) synthetic method for quinoline derivatives by the Yu et al. al. [54] [54] reported reportedaahigh highyield yield(up (uptoto 99%) synthetic method quinoline derivatives by 99%) synthetic method forfor quinoline derivatives by the reaction of N-formyldihydroquinoline on a solid base such as sodium hydroxide (NaOH) under the reaction of N-formyldihydroquinoline a solid basesuch suchasassodium sodiumhydroxide hydroxide (NaOH) (NaOH) under reaction of N-formyldihydroquinoline on on a solid base high-speed ball milling conditions with a catalytic amount of polyethylene glycol 2000 (PEG 2000) as high-speed ball milling conditions with a catalytic amount of polyethylene glycol 2000 (PEG 2000) as catalyst (Scheme 29). catalyst (Scheme 29).

Scheme 29. Deformylation of N-formyldihydroquinoline. Scheme 29. Deformylation Scheme 29. Deformylation of of N-formyldihydroquinoline. N-formyldihydroquinoline.

Under solvent-free high-speed ball milling styrene and N-aryl aldimines generated in situ are Under solvent-free high-speed ball milling styrene and N-aryl aldimines generated in situ are usedUnder for the synthesishigh-speed of cis-2,4-diphenyltetrahydroquinolines in goodgenerated yield via Diels–Alder solvent-free ball milling styrene and N-aryl aldimines in situ are used used for the synthesis of cis-2,4-diphenyltetrahydroquinolines in good yield via Diels–Alder cycloaddition reactions in presence of FeCl3 (Scheme 30)in. This is Diels–Alder a very efficient and green for the synthesis of cis-2,4-diphenyltetrahydroquinolines goodmethod yield via cycloaddition cycloaddition reactions in presence of FeCl3 (Scheme 30). This method is a very efficient and green alternativeinto conventional for synthesis for these types of heterocyclic skeletons. The reactions presence of FeClmethods (Scheme 30). This method is a very efficient and green alternative to 3 alternative to conventional methods for synthesis for these types of heterocyclic skeletons. The advantages ofmethods this method are a short reaction easy availability of the reagents, conventional for synthesis for these typestime, of heterocyclic skeletons. The required advantages of this advantages of this method are a short reaction time, easy availability of the required reagents, solvent free and time, a nontoxic catalyst [53]. method are aconditions short reaction easy availability of the required reagents, solvent free conditions and solvent free conditions and a nontoxic catalyst [53]. a nontoxic catalyst [53].

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Scheme Diels–Aldersynthesis synthesis of of cis-2,4-diphenyltetrahydroquinolines. cis-2,4-diphenyltetrahydroquinolines. Scheme 30. 30. Diels–Alder Scheme 30. Diels–Alder synthesis of cis-2,4-diphenyltetrahydroquinolines.

3.3. Imidazo[1,2-a]pyridine Synthesis

3.3. Imidazo[1,2-a]pyridine SchemeSynthesis 30. Diels–Alder synthesis of cis-2,4-diphenyltetrahydroquinolines.

3.3. Imidazo[1,2-a]pyridine Synthesis reactions between 2-amioazines, aldehydes and isonitriles were One pot Ugi-multicomponent

Scheme 30. Diels–Alder synthesis of cis-2,4-diphenyltetrahydroquinolines. One pot Ugi-multicomponent between 2-amioazines, aldehydes and isonitriles were conducted under solvent-free mechanochemical ball-milling conditions to afford 3.3. Imidazo[1,2-a]pyridine Synthesisreactions One pot Ugi-multicomponent reactions between 2-amioazines, aldehydes and isonitriles were conducted under solvent-free mechanochemical ball-milling conditions to afford 3-aminoimidazo 3-aminoimidazo[1,2-a]pyridine derivatives in good to excellent yields at room temperature The conducted under solvent-free mechanochemical ball-milling conditions to [55]. afford 3.3. Imidazo[1,2-a]pyridine Synthesis One pot Ugi-multicomponent reactions between 2-amioazines, aldehydes and isonitriles were [1,2-a]pyridine to excellent yieldsto atexcellent room temperature [55]. The reaction has been reaction hasderivatives been shownintogood display good functional group tolerance (Scheme 31). 3-aminoimidazo[1,2-a]pyridine derivatives in good yields at room temperature [55]. The conducted solvent-free reactions mechanochemical ball-milling conditions to afford pot under Ugi-multicomponent between 2-amioazines, aldehydes and isonitriles were shown to One display good functional group tolerance (Scheme 31). reaction has been shown to display good functional group tolerance (Scheme 31).

3-aminoimidazo[1,2-a]pyridine derivatives in good to excellent yields at room temperature The conducted under solvent-free mechanochemical ball-milling conditions to [55]. afford reaction has been shown to display good functional group tolerance (Scheme 31). 3-aminoimidazo[1,2-a]pyridine derivatives in good to excellent yields at room temperature [55]. The reaction has been shown to display good functional group tolerance (Scheme 31). Scheme 31. Ugi-multi-component reaction.

Scheme 31. Ugi-multi-component reaction. Scheme 31. Ugi-multi-component A series of 2,3-substituted imidazo[1,2-a]pyridines werereaction. obtained by reaction of 2-aminoScheme 31. Ugi-multi-component reaction. pyridines with methyl ketones or 1,3-dicarbonyl compounds by I2-enhanced A series of 2,3-substituted imidazo[1,2-a]pyridines were obtained by reactioncondensation/ of 2-aminoScheme 31. Ugi-multi-component reaction. A series of 2,3-substituted imidazo[1,2-a]pyridines were obtained by reaction 2-aminocyclization via ball milling under solvent-free conditions. This method gives good functionalofgroup pyridines with ketones imidazo[1,2-a]pyridines or 1,3-dicarbonyl compounds by I2-enhanced A series of methyl 2,3-substituted were obtained by reactioncondensation/ of 2-aminoand broad molecular diversity with good product yields [56] (Scheme 32). pyridines with methyl ketones or 1,3-dicarbonyl compounds by I -enhanced condensation/ cyclization cyclization via ball millingketones under solvent-free conditions. This method good functional group 2 pyridines with or 1,3-dicarbonyl compounds by gives I2-enhanced A series of methyl 2,3-substituted imidazo[1,2-a]pyridines were obtained by reactioncondensation/ of 2-aminoand broad molecular diversity with good product yields [56] (Scheme 32). via ball milling under solvent-free conditions. This method gives good functional group group and broad cyclization millingketones under solvent-free conditions. This method good functional pyridines via withball methyl or 1,3-dicarbonyl compounds by gives I2-enhanced condensation/ molecular diversity with good product yields [56] (Scheme 32). and broad molecular diversity with good product yields [56] (Scheme cyclization via ball milling under solvent-free conditions. This method32). gives good functional group

and broad molecular diversity with good product yields [56] (Scheme 32).

Scheme 32. Synthesis of 2,3-substituted imidazo[1,2-a]pyridines. Scheme 32. Synthesis of 2,3-substituted imidazo[1,2-a]pyridines.

3.4. Chromeno[3,4-b]pyridine Synthesis Scheme 32. Synthesis of 2,3-substituted imidazo[1,2-a]pyridines. Scheme 32. Synthesis of 2,3-substituted imidazo[1,2-a]pyridines. 3.4. Chromeno[3,4-b]pyridine Recently, Kausar et al.Synthesis described a synthesis of sixteen different pyridocoumarins in excellent Scheme 32. Synthesis of 2,3-substituted imidazo[1,2-a]pyridines. yield by solvent free ball of 3-aminocoumarin, aldehydes andpyridocoumarins phenylacetylenein along with 3.4. Chromeno[3,4-b]pyridine Synthesis Recently, Kausar et al.milling described a synthesis of sixteen different excellent 3.4. Chromeno[3,4-b]pyridine Synthesis 2)-H of 3-aminocoumarin [57] CuI-Zn(OAc) 2 as free a catalyst for activation and functionalization of C(sp yield by solvent ball milling of 3-aminocoumarin, aldehydes and phenylacetylene along with 3.4. Chromeno[3,4-b]pyridine Recently, Kausar et al. Synthesis described a synthesis of sixteen different pyridocoumarins in excellent 2)-H of 3-aminocoumarin [57] (Scheme 33). CuI-Zn(OAc) 2 as a catalyst for activation and functionalization of C(sp Recently, Kausar et ball al. described a synthesis of sixteen different pyridocoumarins in with excellent yieldRecently, by solvent free milling of 3-aminocoumarin, aldehydes andpyridocoumarins phenylacetylene along Kausar et al. described a synthesis of sixteen different in excellent (Scheme 33). 2)-Hphenylacetylene yieldCuI-Zn(OAc) by solvent free milling of 3-aminocoumarin, aldehydes and along 2 as aball catalyst for activation and functionalization of C(sp of 3-aminocoumarin [57] with yield by solvent free ball milling of 3-aminocoumarin, aldehydes and phenylacetylene along with 2 )-H of 3-aminocoumarin [57] (Scheme 33). CuI-Zn(OAc) as a catalyst for activation and functionalization of C(sp 2 CuI-Zn(OAc) 2 as a catalyst for activation and functionalization of C(sp2)-H of 3-aminocoumarin [57] (Scheme 33). 33). (Scheme

Scheme 33. Synthesis of pyridocoumarins. Scheme 33. Synthesis of pyridocoumarins. Scheme 33. Synthesis of pyridocoumarins. Scheme 33. Synthesis of pyridocoumarins.

Scheme 33. Synthesis of pyridocoumarins.

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13 13 of of 21 21 13 of 21 13 of 21

3.5. Pyrimidine Synthesis 3.5. Pyrimidine Synthesis 3.5.3.5. Pyrimidine Synthesis Pyrimidine Synthesis Under mechanochemical solvent-free conditions, a multicomponent Biginelli reaction was Under mechanochemical solvent-free conditions, a multicomponent Biginelli reaction was Under mechanochemical solvent-free conditions, a multicomponent multicomponent Biginelli reaction was reported to give dihydropyrimidones [58]. The starting aaldehydes were prepared within thewas same Under mechanochemical solvent-free conditions, Biginelli reaction reported to give dihydropyrimidones [58]. The starting aldehydes were prepared within the same 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 reported to give dihydropyrimidones [58]. The starting aldehydes were prepared within the same in reaction pot by Br+ catalyzed oxidation of their corresponding primary alcohols which results in reaction pot by Br+ of corresponding primaryalcohols alcoholswhich which results in formation of byproducts. The oxidation acid was used as catalyst in the primary cascade transformation leading reaction pot by Br+catalyzed catalyzed oxidation of their their corresponding results in to formation of byproducts. The acid was used as catalyst in the cascade transformation leading to formation ofof byproducts. The acid in the the cascade cascadetransformation transformationleading leading formation byproducts. The acid was was used used as catalyst catalyst in to to dihydropyrimidones (Scheme 34). dihydropyrimidones (Scheme 34). dihydropyrimidones (Scheme34). 34). dihydropyrimidones (Scheme R R

R Oxone, KBr, TEMPO

O

30 min ball mill

R'

H+

HO

O

O

R = Me, Br, Cl, NO2, OMe R' = OEt or Me R'' = H or Me X = O or S

NH2

R' O

R''HN

NH

3h Ball-milling

N R''

X

X

Scheme 34. Multicomponent Biginellireaction. reaction. Scheme34. 34.Multicomponent Multicomponent Biginelli Scheme 34. Multicomponent Biginelli reaction. reaction. Scheme Biginelli

On thetheother hands, Sachdeva etet al. reported the formation ofdihydropyrimidones dihydropyrimidones using a otherhands, hands,Sachdeva Sachdevaet al. reported reported the the formation a a OnOn al. formation of of dihydropyrimidones dihydropyrimidonesusing using the other al. reported mechanochemical Biginelli reaction in presence of SnCl 4 ·5H 2 O as a catalyst instead of the free acid mechanochemical Biginellireaction reactionin presence of SnCl44··5H 2O as a catalyst instead of the free acid mechanochemical Biginelli presence SnCl 5H a catalyst instead of the mechanochemical Biginelli reaction in in presence of of SnCl asas a catalyst instead of the free free acidacid [59] 4 ·5H 2 O2O [59][59] (Scheme 35). (Scheme 35). [59] (Scheme (Scheme 35). 35).

R

R

O

O

NH2

EtO H2N

O

O

SnCl4.5H2O Grinding

EtO

NH N H

O

O

Scheme 35. Synthesis of dihydropyrimidones by Biginelli reaction.

Scheme 35. Synthesis of dihydropyrimidones by Biginelli reaction. Scheme Scheme 35. 35. Synthesis Synthesis of of dihydropyrimidones dihydropyrimidones by by Biginelli Biginelli reaction. reaction.

Ould et al. [28] showed that the condensation reaction of an equimolar amount of an aldehyde, Ould et al. [28] showed that the condensation reaction of an equimolar amount of an aldehyde, malononitrile and thiourea/urea by ball reaction milling ofinan equimolar 40 min amount gives of 2-thioxo or Ould et al. [28] showed that the condensation an aldehyde, Ould et al.and [28] showed that the reaction equimolar malononitrile thiourea/urea bycondensation ball milling in of 40 anmin gives amount 2-thioxoof an or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (Scheme reactions proceed or malononitrile and thiourea/urea by ball derivatives milling in 40 36). min Thegives 2-thioxo aldehyde, malononitrile and thiourea/urea by ball milling in 40 min gives 2-thioxo or 2-oxo-1,2,3,42-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 products36). in excellent yields (up to 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile derivatives (Scheme The reactions proceed tetrahydropyrimidine-5-carbonitrile derivatives (Scheme effectively effectively without the aid of any catalyst or solvent to 36). giveThe thereactions productsproceed in excellent yieldswithout (up to 98%). effectively without the aid of any catalyst or solvent to give the products in excellent yields (up to the aid of any catalyst or solvent to give the products in excellent yields (up to 98%). 98%). 98%).

+

RCHO + CN

CN

X

CN H2N

Ball milling NH2

R = p-CH3-O-C6H4, p-OH-C6H4, p-Cl-C6H4, Ph

Solvent free Catalyst free

R

NH2

HN

NH X

Scheme 36. Synthesis of 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles.

Scheme Scheme 36. 36. Synthesis Synthesis of of 2-thioxo 2-thioxo or or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles. 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles.

Scheme 36. Synthesis of 2-thioxo or 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carbonitriles. 3.6. Pyrano[2,3-d]pyrimidine Synthesis

3.6. Pyrano[2,3-d]pyrimidine Synthesis Mashkouri et al. [22] Synthesis used aromatic aldehydes, malononitrile, and barbituric acid (Scheme 37) 3.6. Pyrano[2,3-d]pyrimidine Pyrano[2,3-d]pyrimidine Synthesis 3.6. to Mashkouri synthesize pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones in good yield (up to 94%) under a ball37) et al. [22] [22]used used aromaticaldehydes, aldehydes,malononitrile, malononitrile, andbarbituric barbituric acid (Scheme Mashkouri et and acid (Scheme 37)37) to Mashkouri et al. al. [22] usedaromatic aromatic aldehydes, malononitrile, and barbituric acid (Scheme milling technique in circulating warm water to heat the reaction for 55 min milling. to synthesize pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones in good yield (up tounder 94%) aunder a ball synthesize pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones in good yield (up to 94%) ball milling to synthesize pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones in good yield (up to 94%) under a ball milling technique in circulating warm water to heat the reaction for 55 min milling. technique in circulating warm water heat the reaction for 55 min milling technique in circulating warmtowater to heat the reaction formilling. 55 min milling.

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14 of 21 14 of of 21 21 14

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14 of 21

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Scheme 37. 37. Synthesize Synthesize pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones. pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones. Scheme Scheme 37. Synthesize pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones.

2.7. Diazine Synthesis 3.7. Diazine and and Diazepine Diazepine Synthesis 2.7. Diazine and Diazepine Synthesis Kaupp et et al. al. [39] the condensation of with various Kaupp [39] studied studied theSynthesize condensation of o-phenylene o-phenylene diamines diamines with various 1,2-dicarbonyl 1,2-dicarbonyl Scheme 37. the pyrano[2,3-d]pyrimidine-2,4(1H,3H)-diones. Kaupp et al.ball [39] studied condensation of o-phenylene diamines with variousThe 1,2-dicarbonyl compounds under milling conditions to afford a series of heterocycles. condensation compounds under ball milling conditions to afford a series of heterocycles. The condensation compounds under ball milling conditions toand afford a series ofquinoxaline heterocycles.derivatives The condensation reaction of substituted o-phenylenediamines benzil gave h reaction of substituted o-phenylenediamines and benzil gave quinoxaline derivatives within within 11 h 2.7. Diazine Diazepine Synthesis reaction of and substituted o-phenylenediamines and benzil gave quinoxaline derivatives within 1 h (Scheme 38). 38). Moreover, was benzo[a]phenazin-5-ol obtained by condensation reaction reaction between between (Scheme Moreover, was benzo[a]phenazin-5-ol obtaineddiamines bya aacondensation condensation (Scheme 38). was benzo[a]phenazin-5-ol obtained by reaction between Kaupp etMoreover, al. [39] studied the condensation of o-phenylene with various 1,2-dicarbonyl ◦ 2-hydroxy1,4-naphthoquinone and o-phenylenediamine within 15 min at 70 °C. 2-hydroxy1,4-naphthoquinone and o-phenylenediamine within 15 min at 70 C. 2-hydroxy1,4-naphthoquinone o-phenylenediamine at 70 °C. The condensation compounds under ball millingand conditions to afford a within series 15 of min heterocycles. reaction of substituted o-phenylenediamines and benzil gave quinoxaline derivatives within 1 h (Scheme 38). Moreover, was benzo[a]phenazin-5-ol obtained by a condensation reaction between 2-hydroxy1,4-naphthoquinone and o-phenylenediamine within 15 min at 70 °C.

Scheme 38. Condensationofofo-phenylenediamines o-phenylenediamines and benzil to quinoxaline. Scheme Condensation Scheme 38. 38. Condensation Condensation of o-phenylenediamines o-phenylenediamines and and benzil benzil to to quinoxaline. quinoxaline. Scheme 38. of and benzil to quinoxaline.

Substituted benzo[a]phenazin-5-ols were produced in 100% yield by milling of 2-hydroxy-

Substituted benzo[a]phenazin-5-ols were for produced ina100% 100%cascade yield by by milling milling of 2-hydroxybenzo[a]phenazin-5-ols were produced in yield 2-hydroxy1,4-naphthoquinone and 15 min via reaction (twoof additions Scheme 38.o-phenylenediamines Condensation of o-phenylenediamines andfour benzil to quinoxaline. 1,4-naphthoquinone and o-phenylenediamines for 15 min via a four cascade reaction (two additions two and eliminations, Scheme 39). two and eliminations, Scheme 39). Substituted benzo[a]phenazin-5-ols were produced in 100% yield by milling of 2-hydroxy1,4-naphthoquinone and o-phenylenediamines for 15 min via a four cascade reaction (two additions two and eliminations, Scheme 39).

Scheme 39. Cascade synthesis of benzo[a]phenazin-5-ols.

Scheme were 39. Cascade Cascade synthesis of benzo[a]phenazin-5-ols. benzo[a]phenazin-5-ols. Ball milling conditions successfully wasof in the condensation reactions between Scheme 39. synthesis Scheme 39. Cascade synthesis ofused benzo[a]phenazin-5-ols. o-diaminoarenes with 1,2-dicarbonyl compounds afford a variety of differently substituted Scheme 39. Cascade synthesis oftobenzo[a]phenazin-5-ols. quinoxalines pyrido[2,3-b]pyrazines [60,61] (Scheme 40). in the condensation reactions between Ball milling orconditions were successfully was used Ball milling conditions were successfully was used in the condensation reactions between Ball milling conditions were successfully wasto used in the reactions between o-diaminoarenes with 1,2-dicarbonyl compounds afford a condensation variety of differently substituted o-diaminoarenes with 1,2-dicarbonyl compounds to afford afforda avariety variety of differently substituted o-diaminoarenes with 1,2-dicarbonyl compounds to of differently substituted quinoxalines or pyrido[2,3-b]pyrazines [60,61] (Scheme 40). quinoxalines or pyrido[2,3-b]pyrazines 40). quinoxalines or pyrido[2,3-b]pyrazines[60,61] [60,61](Scheme (Scheme 40).

Scheme 40. Synthesis of quinoxalines or pyrido[2,3-b]pyrazines.

3-Oxo-3,4-dihydroquinoxaline was produced in 90% yield by milling of 2-oxoglutaric acid and o-phenylenediamine for 10 min (Scheme 41). Four-cascade reactions consisting of substitution, Scheme Synthesis quinoxalines or Scheme 40.40. Synthesis ofofquinoxalines quinoxalines orpyrido[2,3-b]pyrazines. pyrido[2,3-b]pyrazines. Synthesis of Scheme 40. or pyrido[2,3-b]pyrazines. elimination, cyclization and ring opening of o-phenylenediamines with alloxane hydrate and 3-oxo-3,4-dihydroquinoxaline-2-carbonylureas produced 3-oxo-3,4-dihydroquinoxaline-2-carbonyl3-Oxo-3,4-dihydroquinoxalinewas wasproduced produced in milling of 2-oxoglutaric acid acid and and 3-Oxo-3,4-dihydroquinoxaline in 90% 90%yield yieldbyby milling of 2-oxoglutaric 3-Oxo-3,4-dihydroquinoxaline was produced in 90% yield by milling of 2-oxoglutaric acid and ureas [39] (Scheme 42). o-phenylenediamine for 10 min (Scheme 41). Four-cascade reactions consisting of substitution, o-phenylenediamine for 10 min min (Scheme (Scheme 41). 41). Four-cascade consisting of o-phenylenediamine for 10 Four-cascade reactions reactions of substitution, substitution, elimination, cyclization and ring opening of o-phenylenediamines withconsisting alloxane hydrate and elimination, cyclization and ring opening of o-phenylenediamines with alloxane hydrate and 3-oxo-3,4-dihydroquinoxaline-2-carbonylureas 3-oxo-3,4-dihydroquinoxaline-2-carbonylelimination, cyclization and ring opening of produced o-phenylenediamines with alloxane hydrate and 3-oxo-3,4-dihydroquinoxaline-2-carbonylureas produced 3-oxo-3,4-dihydroquinoxaline-2-carbonylureas [39] (Scheme 42).

ureas [39] (Scheme 42).

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3-oxo-3,4-dihydroquinoxaline-2-carbonylureas produced 3-oxo-3,4-dihydroquinoxaline-2-carbonylureas [39] (Scheme 42). Molecules 2018, 23, x 15 of 21 Molecules 2018, 23, x

15 of 21

Molecules 2018, 23, x

15 of 21

Scheme 41. Synthesis of 3-oxo-3,4-dihydroquinoxaline.

Scheme 41. Synthesis of 3-oxo-3,4-dihydroquinoxaline. Scheme 41. Synthesis of 3-oxo-3,4-dihydroquinoxaline. Scheme 41. Synthesis of 3-oxo-3,4-dihydroquinoxaline.

Scheme 42. Synthesis of 3-oxo-3,4-dihydroquinoxaline-2-carbonyl-ureas.

Scheme 42. Synthesisofof3-oxo-3,4-dihydroquinoxaline-2-carbonyl-ureas. 3-oxo-3,4-dihydroquinoxaline-2-carbonyl-ureas. Synthesis Kaupp Scheme et al. [62]42.described cascade mechanochemical reactions of solid-state ninhydrin and Scheme 42. Synthesis of 3-oxo-3,4-dihydroquinoxaline-2-carbonyl-ureas. o-phenylenediamines, o-mercaptoaniline, urea/thiourea and methyl 3-aminocrotonate in a ball mill Kaupp et al. [62] described cascade mechanochemical reactions of solid-state ninhydrin and at 20–25 Hz to give indenoquinoxaline ketones (Scheme 43). reactions of solid-state ninhydrin and Kaupp et al. [62] described cascade mechanochemical o-phenylenediamines, o-mercaptoaniline, urea/thiourea and methyl 3-aminocrotonate in a ball mill Kaupp et al. [62] described cascade mechanochemical reactions of solid-state ninhydrin and o-phenylenediamines, urea/thiourea at 20–25 Hz to giveo-mercaptoaniline, indenoquinoxaline ketones (Scheme and 43). methyl 3-aminocrotonate in a ball mill at o-phenylenediamines, o-mercaptoaniline, urea/thiourea and methyl 3-aminocrotonate in a ball mill 20–25 Hz to give indenoquinoxaline ketones (Scheme 43). at 20–25 Hz to give indenoquinoxaline ketones (Scheme 43).

Scheme 43. Synthesis of indenoquinoxaline ketones.

Scheme 43. Synthesis of indenoquinoxaline ketones. Scheme 43. Synthesis of indenoquinoxaline ketones.

Scheme 43. Synthesis of indenoquinoxaline ketones.

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16 of 21 16 of 21 16 of 21 16 of 21

Nagarajaiah Nagarajaiah et al. [50] [50] reported reported an an efficient efficient ball-milling ball-milling reaction reaction of of α-chloroketones α-chloroketones with with Nagarajaiah et al. [50] reported an efficient ball-milling reaction of α-chloroketones with Nagarajaiah et to al.give [50]quinoxalines reported an(Scheme efficient ball-milling reaction of α-chloroketones with o-phenylenediamine 44). o-phenylenediamine to give quinoxalines (Scheme 44). o-phenylenediamine to give quinoxalines (Scheme 44). o-phenylenediamine to give quinoxalines (Scheme 44).

Scheme 44. 44. Reaction Reaction of of α-chloroketones α-chloroketones with with o-phenylenediamine o-phenylenediamine to to quinoxalines. quinoxalines. Scheme Scheme 44. Reaction of α-chloroketones with o-phenylenediamine to quinoxalines. Scheme 44. Reaction of α-chloroketones with o-phenylenediamine to quinoxalines.

Carlier et al. [63] described catalyst- and solvent-free mechanochemical reactions of diamines Carlier et al. [63] described catalyst- and solvent-free mechanochemical reactions of diamines Carlier et al. [63] described catalystand solvent-free reactions derivatives, of diamines and 1,2or 1,3-dicarbonyls to give dibenzophenazines andmechanochemical dibenzopyridoquinoxaline derivatives, and 1,2- or 1,3-dicarbonyls to give dibenzophenazines dibenzophenazines and dibenzopyridoquinoxaline dibenzopyridoquinoxaline derivatives, and 1,2- or 1,3-dicarbonyls to give 45). dibenzophenazines and dibenzopyridoquinoxaline derivatives, respectively, in good yield (Scheme respectively, in respectively, in good good yield yield (Scheme (Scheme 45). 45). respectively, in good yield (Scheme 45).

Scheme 45. Synthesis of dibenzophenazines and dibenzopyridoquinoxaline. Scheme 45. Synthesis of dibenzophenazines and dibenzopyridoquinoxaline. Scheme 45. Synthesis of dibenzophenazines and dibenzopyridoquinoxaline.

Etman, et al. [64] reported an efficient reaction without the aid of any catalyst or solvent, of Etman, et al. [64] reported an efficient reaction without the aid of any catalyst or solvent, of Etman,with et al. al.o-phenylenediamine [64] reported reported an an efficient efficient reaction withoutconditions the aid aid of of any any catalyst or solvent, solvent,the of Etman, et [64] reaction without the catalyst or of ninhydrin under ball milling (Scheme 46). Using ninhydrin with o-phenylenediamine under ball milling conditions (Scheme 46). Using the ninhydrinwith with o-phenylenediamine under conditions (Scheme 46).conventional Usingwith the ninhydrin o-phenylenediamine under ball milling conditions (Scheme 46). Using conventional method gave only 60% yields ofball the milling same product by heating of the ninhydrin conventional method gave only 60% yields of the same product by heating of ninhydrin with conventional method gave only yields of the same product by heating of ninhydrin with method gave only 60% of the60% same product by heating of ninhydrin with o-phenylenediamine o-phenylenediamine inyields EtOH/AcOH (7:3). o-phenylenediamine in EtOH/AcOH (7:3). o-phenylenediamine in EtOH/AcOH (7:3).in EtOH/AcOH (7:3).

Scheme 46. Reaction of ninhydrin with o-phenylenediamine. Scheme 46. Reaction of ninhydrin with o-phenylenediamine. Scheme46. 46. Reaction Reaction of of ninhydrin ninhydrinwith witho-phenylenediamine. o-phenylenediamine. Scheme

3.8. Thiazine Synthesis 3.8. Thiazine Synthesis 3.8. Thiazine Synthesis 3.8. Thiazine Synthesis Sharifi et al. [65] reported that the use of KF–Al2O3 solid support in a solvent-free ball milling Sharifi et al. [65] reported that the use of KF–Al2O3 solid support in a solvent-free ball milling Sharifiinvolving et al. [65]the reported that the use of KF–Al2O3 with solid2-bromoalkanoates support in a solvent-free ball procedure reaction of 2-aminothiophenols (Scheme 47)milling led to Sharifiinvolving et al. [65]the reported that use of KF–Al2 O3 with solid2-bromoalkanoates support in a solvent-free ball procedure reaction of the 2-aminothiophenols (Scheme 47)milling led to the reaction 2-aminothiophenols within2-bromoalkanoates (Scheme 47) led to aprocedure green andinvolving efficient synthesis of aofseries of benzothiazinone excellent yield. procedure reaction 2-aminothiophenols with in 2-bromoalkanoates a green andinvolving efficient the synthesis of of a series of benzothiazinone excellent yield. (Scheme 47) led to a a green and efficient synthesis of a series of benzothiazinone in excellent yield. green and efficient synthesis of a series of benzothiazinone in excellent yield.

Scheme 47. Synthesis of benzothiazinone. Scheme 47. Synthesis of benzothiazinone. Scheme 47. Synthesis of benzothiazinone.

Scheme 46. Reaction of ninhydrin with o-phenylenediamine.

3.8. Thiazine Synthesis Sharifi et al. [65] reported that the use of KF–Al2O3 solid support in a solvent-free ball milling procedure the reaction of 2-aminothiophenols with 2-bromoalkanoates (Scheme 47)17led to Molecules 2018,involving 23, 1348 of 21 a green and efficient synthesis of a series of benzothiazinone in excellent yield.

Molecules 2018, 23, x Molecules 2018, 23, x

Scheme47. 47. Synthesis Synthesis of of benzothiazinone. benzothiazinone. Scheme

17 of 21 17 of 21

Moreover, hydroxyindeno[2,1-b]benzo[1,4]thiazine was produced by the reaction of ninhydrin Moreover, hydroxyindeno[2,1-b]benzo[1,4]thiazine was produced by the reaction of ninhydrin with o-mercaptoaniline hydrochloride in a in three-reaction three-reaction cascade cascade (substitution, (substitution, cyclization and with o-mercaptoaniline hydrochloride in a in three-reaction cascade (substitution, cyclization and elimination, Scheme 48). elimination, Scheme 48).

Scheme 48. Synthesis Scheme 48. Synthesis of of hydroxyindeno[2,1-b]benzo[1,4]thiazine. hydroxyindeno[2,1-b]benzo[1,4]thiazine. Scheme 48. Synthesis of hydroxyindeno[2,1-b]benzo[1,4]thiazine.

3.9. Azaborinine Synthesis 3.9. Azaborinine Synthesis The six membered heterocyclic diazaborinine and O, B, N six-membered heteroborinone could The six NN six-membered heteroborinone could be six membered memberedheterocyclic heterocyclicdiazaborinine diazaborinineand andO,O,B,B, six-membered heteroborinone could be obtained by mixing of 1,8-diaminonaphthalene or anthranilic acid and phenylboronic acid in a obtained by mixing of 1,8-diaminonaphthalene or anthranilic acidacid andand phenylboronic acidacid in a in balla be obtained by mixing of 1,8-diaminonaphthalene or anthranilic phenylboronic ball mill without solvent for 1 h followed by heating in a vacuum [30] (Scheme 49). mill without solvent for 1for h followed by heating in a vacuum [30] (Scheme 49). 49). ball mill without solvent 1 h followed by heating in a vacuum [30] (Scheme

Scheme 49. Synthesis of azaborinines. Scheme 49. Synthesis of azaborinines.

4. Higher Membered Heterocycles 4. Higher Heterocycles 4. Higher Membered Membered Heterocycles Kaupp et al. [66] studied the transformation of N-arylmethyleneiminium salts to Tröger’s bases Kaupp et et al. [66]studied studied thetransformation transformationofofN-arylmethyleneiminium N-arylmethyleneiminium salts Tröger’s bases to to Tröger’s in in theKaupp presenceal.of[66] water vaporthe or MgSO4·7H2O.after milling for 5–10 min. Thesalts products were bases formed in the presence of water vapor or MgSO 4·7H2O.after milling for 5–10 min. The products were formed the presence of water vapor or MgSO · 7H O. after milling for 5–10 min. The products were formed 4 2 via a three-reaction cascade involving a double arylaminomethylation and methylenation of the via a three-reaction cascade involving a double arylaminomethylation and methylenation of the tetrahydro-1,5-diazocine intermediate (Scheme 50). tetrahydro-1,5-diazocine intermediate (Scheme 50).

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via a three-reaction cascade involving a double arylaminomethylation and methylenation of the tetrahydro-1,5-diazocine intermediate (Scheme 50). Molecules 2018, 23, x 18 of 21

Scheme Scheme 50. 50. Synthesis Synthesis of of 1,5-diazocine. 1,5-diazocine.

5. 5. Conclusions Conclusions Herein, mechanochemical technique Herein, we we have have reviewed reviewed the the use use of of mechanochemical technique for for synthesis synthesis of of variety variety of of N-heterocyles. As discussed, the ball milling technique is becoming a more promising green tool for N-heterocyles. As discussed, the ball milling technique is becoming a more promising green tool for the N-heterocycles, including the synthesis synthesis of of various various N-heterocycles, including condensation condensation reactions, reactions, multicomponent multicomponent cascade cascade reactions, metal catalyzed synthesis, etc. reactions, metal catalyzed synthesis, etc. Author Author Contributions: Contributions: All All authors authors equally. equally. Conflicts of Interest: The authors declare no conflict conflict of of interest. interest.

Reference References 1. 2. 3. 4. 5. 5. 6. 6.

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