Recent Advances in Mechanochemical Organic Synthesis

*Davor Margetić and Vjekoslav Štrukil*

## **Abstract**

In this review, the recent advances in mechanochemical organic synthesis are presented. These include variety of chemical reactions, organic functional group transformations, organic catalytic processes, and photochemical reactions which were not carried in mechanochemical conditions before.

**Keywords:** mechanochemistry, organic synthesis, green chemistry, ball milling, methodology and technique developments

## **1. Introduction**

The use of mechanical energy to promote chemical reactions has become a fastgrowing area of green chemistry research in the last decade. With the realization of its practical potentials by chemists and researchers in academia and industry, in recent years, the number of published accounts on mechanosynthesis in various research fields is increasing, ranging from inorganic, metal-organic to organic reactions. Mechanochemistry also become widely exploited for synthesis of drug solid forms [1]. The topic of mechanochemistry was the subject of several review articles [2–9] and books [10, 11]. In this review, the most recent accounts on the mechanochemical organic synthesis are covered.

## **2. Synthesis**

Multi-step synthesis is applicable to ball milling solid-state conditions, which is documented by the increasing number of one-pot, multi-step reactions. In the initial milling process, compatible second reagents were added, and milling was continued. Among them are one-pot two-step Negishi C▬C cross-coupling which applies different physical forms of zinc to generate organozinc reagent which was coupled with aryl halide and palladium catalyst in the second milling step. This reaction was also carried out as one-pot one-step reaction [12]. Further examples are one-pot two-step synthesis of thioureas from amines employing thiocarbamoyl benzotriazoles [13], one-pot two-step synthesis of pyrazolones [14], two-step synthesis of paracetamol and procainamide [15], and three-step, two-pot Gabriel synthesis of amines [16]. For illustration, reductive cyclization of fullerene was carried out by three consecutive ball milling reactions (**Figure 1**) [17]. This

solvent-free Michael reaction of fullerene anion to enones (chalkones) was carried out in a two-step, one-pot procedure, starting by zinc reduction of fullerene to carbanion, with water additive used to protonate generated carbanions. The mechanochemical conditions led to the formation of C60-substituted cyclopentanol **3** and hydrofullerene derivative **4**. This mixture was transformed to **3** by short milling with Et3N. Dehydration to C60-fused cyclopentenes **5** was achieved by milling of **3** with trifluoromethanesulfonic acid.

One-pot, three-step synthesis of pyrroles from amines, alkyne esters, and chalkones saves time and increases the practicality of synthesis (**Figure 2**) [18]. The first step is reaction of amines with alkyne esters which affords β-enaminoesters **7**. Without separation, chalkone, I2, and Phi(OAc)2 were added to vessel for subsequent milling, which produced dihydropyrroles **9** via Michael reaction. Dehydrogenative oxidation with DDQ led to formation of substituted pyrroles **10**.

Some novel variants and reagents were recently applied for reactions which were previously carried out in ball mill such as the formation of peptide bond and imines; Michael, Mannich, and Wittig reactions; porphyrin metalation; halogenations; and various multicomponent reactions. For instance, amide bond formation by one-pot two-step procedure, followed by polymerization in mill [19], application of PhI(OAc)2 cross dehydrogenative coupling for the amidation of aldehydes via C▬H activation [20], formation of phosphinecarboxamides [21], Rh catalyzed amidation [22] or via Ritter reaction [23] and amination to prepare sulfonamides employing Ir catalyst [24] were reported. In addition, a mechanistic study for amide bond formation is published [25].

Some of the traditional transition metal catalysts used in solution reactions can be replaced with elementary metals as catalysts under mechanochemical conditions. For this purpose, different materials for balls and milling vessels were used by Mack, including silver, copper [26], and nickel, even aluminum jars and balls for amorphization [27] and silicon nitride for Scholl reaction [28]. An exemplary reaction is cyclopropenation of alkynes with diazoacetates carried out in ball mill using various materials for vial and balls. Silver foil was found to be a recyclable metal catalyst which does not loose activity and diastereoselectivity after several reaction cycles [29]. The optimal results of [2+1] cycloadditions for internal alkynes were achieved with stainless steel vials and balls, with the addition of silver foil (**Figure 3**), whereas copper foil showed much better performance in cyclopropanations of terminal alkynes [30]. Silver foil in conjunction with PdCl2(PPh3)2 catalyst

**Figure 1.**

*Reductive cyclization of C60 with enones by three-step milling.*

**29**

**Figure 4.**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

coupling of aliphatic alkynes with aryl iodides.

recyclable.

rins [37, 38].

**Figure 3.**

*Cyclopropenation of alkenes and alkynes with diazoacetates.*

*Nickel-catalyzed [2+2+2+2] cycloaddition of alkynes.*

alkynes, and ketones [33].

was also employed as the effective co-catalyst for mechanochemical Sonogashira

On the other hand, catalysis of [2+2+2+2] cycloaddition of alkynes to cyclooctatetraenes (**Figure 4**) with Nickel foil was ineffective (SS vial/ball) and with Tungsten carbide balls was moderate, whereas with nickel powder (SS vial/ball), it was moderately active, and pellets were used to obtain high conversion. Nickel vial in combination with nickel balls provided low conversion [31]. Nickel powder generated in situ is responsible for the catalytic activity and, by using the neodymium magnet to separate nickel pellets from crude reaction mixture, makes the catalyst

Metal catalyst additives such as Pd foil, Cr, and Ni powder showed the activity in alkyne hydrogenation using water as hydrogen source. Efficient mechanochemical hydrogenation method employs SUS304 stainless steel which contains zero-valent Cr and Ni constituents for balls and vial [32]. Alkene and alkyne bonds and nitro, azido, and keto groups were reduced in 62–100% yield by in situ hydrogen generation (**Figure 5**). Furthermore with SUS304 steel vials as catalyst, alkanes and Et2O were used as hydrogen sources for hydrogenation of aromatic compounds, alkenes,

Novel mechanochemical C▬C bond forming reactions include Friedel-Crafts acylation [34] and alkylation which was also employed in polymer synthesis [35]. Porphyrin synthesis in which mechanochemical procedure was reported earlier was extended to bulkier aromatics [36] and the solventless metalation of porphy-

Mack has shown that different products could be obtained in enolate addition reactions, when solution procedure was replaced by solvent-free conditions (**Figure 6**)

[39]. Whereas in solution 3-hydroxy-1,3-diphenylbutan-1-one and dypnone were formed by base-catalyzed aldol condensation of acetophenone, in ball mill

**Figure 2.** *Three-step synthesis of substituted pyrroles.*

#### *Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

*Organic Synthesis - A Nascent Relook*

**3** with trifluoromethanesulfonic acid.

bond formation is published [25].

*Reductive cyclization of C60 with enones by three-step milling.*

*Three-step synthesis of substituted pyrroles.*

solvent-free Michael reaction of fullerene anion to enones (chalkones) was carried out in a two-step, one-pot procedure, starting by zinc reduction of fullerene to carbanion, with water additive used to protonate generated carbanions. The mechanochemical conditions led to the formation of C60-substituted cyclopentanol **3** and hydrofullerene derivative **4**. This mixture was transformed to **3** by short milling with Et3N. Dehydration to C60-fused cyclopentenes **5** was achieved by milling of

One-pot, three-step synthesis of pyrroles from amines, alkyne esters, and chalkones saves time and increases the practicality of synthesis (**Figure 2**) [18]. The first step is reaction of amines with alkyne esters which affords β-enaminoesters **7**. Without separation, chalkone, I2, and Phi(OAc)2 were added to vessel for subsequent milling, which produced dihydropyrroles **9** via Michael reaction. Dehydrogenative oxidation with DDQ led to formation of substituted pyrroles **10**. Some novel variants and reagents were recently applied for reactions which were previously carried out in ball mill such as the formation of peptide bond and imines; Michael, Mannich, and Wittig reactions; porphyrin metalation; halogenations; and various multicomponent reactions. For instance, amide bond formation by one-pot two-step procedure, followed by polymerization in mill [19], application of PhI(OAc)2 cross dehydrogenative coupling for the amidation of aldehydes via C▬H activation [20], formation of phosphinecarboxamides [21], Rh catalyzed amidation [22] or via Ritter reaction [23] and amination to prepare sulfonamides employing Ir catalyst [24] were reported. In addition, a mechanistic study for amide

Some of the traditional transition metal catalysts used in solution reactions can be replaced with elementary metals as catalysts under mechanochemical conditions. For this purpose, different materials for balls and milling vessels were used by Mack, including silver, copper [26], and nickel, even aluminum jars and balls for amorphization [27] and silicon nitride for Scholl reaction [28]. An exemplary reaction is cyclopropenation of alkynes with diazoacetates carried out in ball mill using various materials for vial and balls. Silver foil was found to be a recyclable metal catalyst which does not loose activity and diastereoselectivity after several reaction cycles [29]. The optimal results of [2+1] cycloadditions for internal alkynes were achieved with stainless steel vials and balls, with the addition of silver foil (**Figure 3**), whereas copper foil showed much better performance in cyclopropanations of terminal alkynes [30]. Silver foil in conjunction with PdCl2(PPh3)2 catalyst

**28**

**Figure 2.**

**Figure 1.**

was also employed as the effective co-catalyst for mechanochemical Sonogashira coupling of aliphatic alkynes with aryl iodides.

On the other hand, catalysis of [2+2+2+2] cycloaddition of alkynes to cyclooctatetraenes (**Figure 4**) with Nickel foil was ineffective (SS vial/ball) and with Tungsten carbide balls was moderate, whereas with nickel powder (SS vial/ball), it was moderately active, and pellets were used to obtain high conversion. Nickel vial in combination with nickel balls provided low conversion [31]. Nickel powder generated in situ is responsible for the catalytic activity and, by using the neodymium magnet to separate nickel pellets from crude reaction mixture, makes the catalyst recyclable.

Metal catalyst additives such as Pd foil, Cr, and Ni powder showed the activity in alkyne hydrogenation using water as hydrogen source. Efficient mechanochemical hydrogenation method employs SUS304 stainless steel which contains zero-valent Cr and Ni constituents for balls and vial [32]. Alkene and alkyne bonds and nitro, azido, and keto groups were reduced in 62–100% yield by in situ hydrogen generation (**Figure 5**). Furthermore with SUS304 steel vials as catalyst, alkanes and Et2O were used as hydrogen sources for hydrogenation of aromatic compounds, alkenes, alkynes, and ketones [33].

Novel mechanochemical C▬C bond forming reactions include Friedel-Crafts acylation [34] and alkylation which was also employed in polymer synthesis [35]. Porphyrin synthesis in which mechanochemical procedure was reported earlier was extended to bulkier aromatics [36] and the solventless metalation of porphyrins [37, 38].

Mack has shown that different products could be obtained in enolate addition reactions, when solution procedure was replaced by solvent-free conditions (**Figure 6**) [39]. Whereas in solution 3-hydroxy-1,3-diphenylbutan-1-one and dypnone were formed by base-catalyzed aldol condensation of acetophenone, in ball mill

**Figure 3.** *Cyclopropenation of alkenes and alkynes with diazoacetates.*

**Figure 4.**

**Figure 5.** *Nickel-catalyzed hydrogenation reactions.*

**Figure 6.** *Aldol condensation of acetophenone.*

1,5-pentadione **21** was obtained as the major product. This product was formed by an initial aldol reaction followed by the Michael addition. In addition, products **22** and **23** arising from the 1,2-addition of the enolate with initial Michael adducts were obtained.

Dehydrogenative C▬H/C▬H arylation of oximes and anilides as directing groups was carried out by Xu (**Figure 7**) [40]. The mechanochemical process is fast (1 h, 6 × (10 min + 1 min break)) and mild, with less amount of arenes, and highly para-selective. A variety of functional groups could be tolerated in LAG (DMF) conditions with TfOH as an additive in conjunction with Pd catalyst and oxidant. Optimal reaction conditions were also applied to olefinic C▬H arylation with simple arenes. Kinetic isotope effects of experiments using deuterated substrates showed KIE data which are consistent with those reported in the similar transformation using arenes as solvents. Slightly different mechanochemical conditions were employed by Su in oxidative C▬H dehydrogenative homocoupling of *N*-arylcarbamates (**24**, R1 = NHCO2R): Pd(OAc)2 catalyst in conjunction with Cu(OTf)2 as an oxidant and HFIP additive and silica gel as grinding auxiliary [41].

The synthesis of benzo[b]furans by electrophilic cyclization of 2-alkynylanisoles **27** was accomplished by milling with equimolar amount of iodine (**Figure 8**) [42]. The formation of C▬O bond is achieved in moderate to high yields (30–83%). This is an example of reaction where the optimization of conditions indicated that lower milling speed (15 Hz) and shorter milling time provided better yields. The increase of milling frequency, extension of the reaction time, or use of an iodine excess caused the formation of side products, diiodinated *E*-alkenes.

C▬N bond forming reactions were paid larger attention to. Mechanochemical nitration reactions of aromatics are extended to various reagents: NaNO3 in conjunction with MoO3 as an additive [43], BiNO3 with MgSO4 [44], as well as BiNO3 alone was applied for nitration of fullerene C60 [45]. Amine guanylation with *N,N*′-Di-Boc-1H-pyrazole-1-carboxamidine [46] and facile Boc deprotection was achieved with TsOH [47]. Another mechanochemical nitrogen deprotection (*N*-demethylation) by modified Polonovski reaction of various alkaloid *N*-oxide hydrochlorides (of biologically interesting molecules, dextromethorphan, atropine, noscapine, and benzoyltropine) was carried out using iron dust and LAG (**Figure 9**) [48]. Toxic and expensive reagents are replaced by iron dust.

Strecker reaction of benzaldehyde with benzylamine and KCN in simple reaction conditions using unusual material (stones as ball bearings) provided a mixture of α-aminonitrile **34** and imine **35** (**Figure 10**) [49]. A favorable formation of **34** was achieved by silica gel additive with its ability to adsorb moisture (instead of the common Brønsted and Lewis acid catalysts), and α-aminonitrile **34** was produced almost exclusively. The replacement of ZrO2/stone material with agate

**31**

gas outlet [50].

**Figure 7.**

**Figure 8.**

**Figure 9.**

**Figure 10.** *Strecker reaction.*

*Dehydrogenative C*▬*H/C*▬*H arylation.*

*Synthesis of benzo[b]furans by electrophilic cyclization.*

*Demethylation of alkaloid* N*-oxide hydrochlorides.*

amines **41** in high yield [53].

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

worked equally well, and a variety of α-aminonitrile products was synthetized in high yields. Lignin additives as Brønsted acid also provided high yields, with α-aminonitrile/imine ratio less specific. The formation of gaseous HCN in Strecker reactions using K3[Fe(CN)6] was detected by trapping in modified milling jar with

Palladium-catalyzed Buchwald-Hartwig amination of aryl chlorides in ball mill has provided moderate to high yields of diarylamine products **38** (**Figure 11**) [51]. A sodium sulfate grinding auxiliary was necessary to improve mixing. Noteworthy, these reactions did not require inert gas protection. Under air, Browne used KO<sup>t</sup>

and Pd-PEPPSI-iPENT catalyst for Buchwald-Hartwig amination [52]. Ito has found that olefin additives can act as efficient molecular dispersants for catalysts in a solid-state Buchwald-Hartwig amination reaction (where aggregation is suppressed through olefin coordination with Pd catalyst). For instance, 1,4-cyclooctadiene facilitates the reaction of aryl halides **39** with diarylamines **40** to obtain triaryl-

Efficient spiroimidazoline synthesis by the reaction of 2-substituted 1H-indene-

1,3-(2H)-diones **42** and barbituric acid-derived alkenes **45** with amidines promoted by *N*-iodosuccinimide (NIS) was reported by Wang (**Figure 12**) [54]. The

Bu

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

#### **Figure 7.**

*Organic Synthesis - A Nascent Relook*

*Nickel-catalyzed hydrogenation reactions.*

*Aldol condensation of acetophenone.*

**Figure 5.**

**Figure 6.**

homocoupling of *N*-arylcarbamates (**24**, R1

grinding auxiliary [41].

1,5-pentadione **21** was obtained as the major product. This product was formed by an initial aldol reaction followed by the Michael addition. In addition, products **22** and **23** arising from the 1,2-addition of the enolate with initial Michael adducts were obtained. Dehydrogenative C▬H/C▬H arylation of oximes and anilides as directing groups was carried out by Xu (**Figure 7**) [40]. The mechanochemical process is fast (1 h, 6 × (10 min + 1 min break)) and mild, with less amount of arenes, and highly para-selective. A variety of functional groups could be tolerated in LAG (DMF) conditions with TfOH as an additive in conjunction with Pd catalyst and oxidant. Optimal reaction conditions were also applied to olefinic C▬H arylation with simple arenes. Kinetic isotope effects of experiments using deuterated substrates showed KIE data which are consistent with those reported in the similar transformation using arenes as solvents. Slightly different mechanochemical conditions were employed by Su in oxidative C▬H dehydrogenative

conjunction with Cu(OTf)2 as an oxidant and HFIP additive and silica gel as

excess caused the formation of side products, diiodinated *E*-alkenes.

nitration reactions of aromatics are extended to various reagents: NaNO3 in conjunction with MoO3 as an additive [43], BiNO3 with MgSO4 [44], as well as BiNO3 alone was applied for nitration of fullerene C60 [45]. Amine guanylation with *N,N*′-Di-Boc-1H-pyrazole-1-carboxamidine [46] and facile Boc deprotection was achieved with TsOH [47]. Another mechanochemical nitrogen deprotection (*N*-demethylation) by modified Polonovski reaction of various alkaloid *N*-oxide hydrochlorides (of biologically interesting molecules, dextromethorphan, atropine, noscapine, and benzoyltropine) was carried out using iron dust and LAG

(**Figure 9**) [48]. Toxic and expensive reagents are replaced by iron dust.

The synthesis of benzo[b]furans by electrophilic cyclization of 2-alkynylanisoles **27** was accomplished by milling with equimolar amount of iodine (**Figure 8**) [42]. The formation of C▬O bond is achieved in moderate to high yields (30–83%). This is an example of reaction where the optimization of conditions indicated that lower milling speed (15 Hz) and shorter milling time provided better yields. The increase of milling frequency, extension of the reaction time, or use of an iodine

C▬N bond forming reactions were paid larger attention to. Mechanochemical

Strecker reaction of benzaldehyde with benzylamine and KCN in simple reaction conditions using unusual material (stones as ball bearings) provided a mixture of α-aminonitrile **34** and imine **35** (**Figure 10**) [49]. A favorable formation of **34** was achieved by silica gel additive with its ability to adsorb moisture (instead of the common Brønsted and Lewis acid catalysts), and α-aminonitrile **34** was produced almost exclusively. The replacement of ZrO2/stone material with agate

= NHCO2R): Pd(OAc)2 catalyst in

**30**

*Dehydrogenative C*▬*H/C*▬*H arylation.*

#### **Figure 8.**

*Synthesis of benzo[b]furans by electrophilic cyclization.*

#### **Figure 9.**

*Demethylation of alkaloid* N*-oxide hydrochlorides.*

**Figure 10.** *Strecker reaction.*

worked equally well, and a variety of α-aminonitrile products was synthetized in high yields. Lignin additives as Brønsted acid also provided high yields, with α-aminonitrile/imine ratio less specific. The formation of gaseous HCN in Strecker reactions using K3[Fe(CN)6] was detected by trapping in modified milling jar with gas outlet [50].

Palladium-catalyzed Buchwald-Hartwig amination of aryl chlorides in ball mill has provided moderate to high yields of diarylamine products **38** (**Figure 11**) [51]. A sodium sulfate grinding auxiliary was necessary to improve mixing. Noteworthy, these reactions did not require inert gas protection. Under air, Browne used KO<sup>t</sup> Bu and Pd-PEPPSI-iPENT catalyst for Buchwald-Hartwig amination [52]. Ito has found that olefin additives can act as efficient molecular dispersants for catalysts in a solid-state Buchwald-Hartwig amination reaction (where aggregation is suppressed through olefin coordination with Pd catalyst). For instance, 1,4-cyclooctadiene facilitates the reaction of aryl halides **39** with diarylamines **40** to obtain triarylamines **41** in high yield [53].

Efficient spiroimidazoline synthesis by the reaction of 2-substituted 1H-indene-1,3-(2H)-diones **42** and barbituric acid-derived alkenes **45** with amidines promoted by *N*-iodosuccinimide (NIS) was reported by Wang (**Figure 12**) [54]. The

formation of two new C-N bonds in the process was achieved in a very short time by the reaction which started with aza-Michael addition to alkenes.

Another user and environmentally friendly protocol than isocyanide synthesis via Ugi reaction was the development of solid-state Hofmann reaction (synthesis of isocyanides from amines) (**Figure 13**) [55]. The implementation of the reaction in mechanochemical conditions significantly reduces the amounts of chloroform, from bulk solvent to 2.1 equivalents. Milling in two 15-minute steps, where chloroform was added each time, afforded better yields than one 30-min milling with all chloroform added at once. The addition of NBu3 was beneficial for sterically more hindered substrates.

Enzymes can tolerate ball milling conditions, and enzymatic reactions were successfully carried out for several transformations: esterification of primary alcohols [56], peptide bond formation [57], ester hydrolysis [58], and cleavage of cellulose [59]. An enzymatic kinetic resolution of racemic secondary alcohols *rac*-**50** was performed by acylation with isopropenyl acetate catalyzed by lipase B from *Candida antarctica* lipase B (CALB) (**Figure 14**) [60]. Milling of *rac*-**50** in ZrO2 vessel showed that biocatalyst is stable in reaction conditions and a partial highly enantioselective hydrolysis provided acetates (*R*)-**52** and the remaining alcohols (*S*)-**50**. High enantioselectivity was also obtained with immobilized lipase PS-IM. Acylative kinetic resolution could be coupled with ketone reduction in one-pot sequential process starting from acetophenone **49**.

Similar methodology was applied by Juaristi for the mechanoenzymatic resolution of racemic chiral amines. CALB was applied in the combination of isopropyl acetate as acylating agent and dioxane additive (in agate jars), and amide products were obtained with excellent enantiopurity (ee 66–>99%). Enantiopure chiral amines were used in the synthesis of (*R*)- and (*S*)-Rasagiline [61].

Besides hydrogenation reaction facilitated in SUS304 ss and Strecker reaction, gaseous reagents were also in situ generated in transfer hydrogenation of carbonyls with polymethylhydrosiloxane as hydrogen source [62], reduction of NO2 group by catalytic transfer hydrogenation employing Pd and ammonium formate [15], and synthesis of thioureas by generation of ammonia from NH4Cl and Na2CO3 [13].

Among the reactions for the formation of other types of bonds which were not previously carried in ball milling conditions are C▬P bond by phosphonylation with MnOAc [63], O▬P phosphate nucleoside bond using CDI [64], S▬P bond via Arbuzov reaction [65], C▬B bond by borylation using Ir catalyst [66], and P▬S and P▬Se bond formation by milling of phosphines with S and Se [67].

*Buchwald-Hartwig amination.*

**33**

**Figure 15.**

**Figure 13.**

**Figure 14.**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

esters **56** were obtained in moderate to high yields and ees.

catalyzed reaction with cyclodextrins as additives [76].

4*H*-pyrans which started with Knoevenagel reaction [78].

obtained from glucose-based polysaccharides [80].

*Hofmann reaction of amines with chloroform.*

*Acylative kinetic resolution of secondary alcohols.*

*Enantioselective fluorination of β-keto esters.*

A recent example of mechanochemical enantioselective reactions is the fluorination of aliphatic cyclic and acyclic β-keto esters using *N*-fluorobenzenesulfonimide with the aid of chiral oxazoline copper catalysts (**Figure 15**) [68]. Fluorinated keto

The epimerization of (3R,6′R,3′R)-lutein to 3′-epilutein was successfully carried out in a stainless steel jar MET-A (composition 84.5% Fe, 13% Cr) in conjunction with acidic cation-exchange resin [69]. This transformation was accompanied with the formation of anhydrolutein, and the best *dr* ratio after optimization was 37:63. Some cycloaddition reactions were carried out in ball mill for the first time. A mechanistic study of Diels-Alder reactions of selected anthracenes by Arrhenius kinetics was reported by Andersen and Mack [70]. The array of 1,3-dipolar cycloaddition reactions is recently extended with nitrones [71] and nitrile oxides [72]. Among the recent examples of oxidation/reduction reactions are Cannizzaro disproportionation of furfural [73] and benzylic oxidation of lignin by oxone and TEMPO [74]. Nitro group was reduced by Ni2B-NaBH4 system [75] and by AuNPs-

Ionic liquids as novel promoter/additive which could be regenerated were employed for the synthesis of imines [77] and in multicomponent synthesis of

Solvent-free mechanochemical conditions were also used in synthesis of reactive species. Synthesis of naphthalenediimide radical ions was achieved by milling of naphthalenediimides with trialkyl and triarylphosphines and Et3N base [79]. The ArSN reaction provides bistrialkyl(aryl)phosphonium naphthalenediimide radical anions which were isolated, and automated ball milling procedure was superior to manual grinding and sonication conditions. The formation of free radicals was also

**Figure 12.** *Synthesis of spiroimidazolines.*

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

A recent example of mechanochemical enantioselective reactions is the fluorination of aliphatic cyclic and acyclic β-keto esters using *N*-fluorobenzenesulfonimide with the aid of chiral oxazoline copper catalysts (**Figure 15**) [68]. Fluorinated keto esters **56** were obtained in moderate to high yields and ees.

The epimerization of (3R,6′R,3′R)-lutein to 3′-epilutein was successfully carried out in a stainless steel jar MET-A (composition 84.5% Fe, 13% Cr) in conjunction with acidic cation-exchange resin [69]. This transformation was accompanied with the formation of anhydrolutein, and the best *dr* ratio after optimization was 37:63.

Some cycloaddition reactions were carried out in ball mill for the first time. A mechanistic study of Diels-Alder reactions of selected anthracenes by Arrhenius kinetics was reported by Andersen and Mack [70]. The array of 1,3-dipolar cycloaddition reactions is recently extended with nitrones [71] and nitrile oxides [72].

Among the recent examples of oxidation/reduction reactions are Cannizzaro disproportionation of furfural [73] and benzylic oxidation of lignin by oxone and TEMPO [74]. Nitro group was reduced by Ni2B-NaBH4 system [75] and by AuNPscatalyzed reaction with cyclodextrins as additives [76].

Ionic liquids as novel promoter/additive which could be regenerated were employed for the synthesis of imines [77] and in multicomponent synthesis of 4*H*-pyrans which started with Knoevenagel reaction [78].

Solvent-free mechanochemical conditions were also used in synthesis of reactive species. Synthesis of naphthalenediimide radical ions was achieved by milling of naphthalenediimides with trialkyl and triarylphosphines and Et3N base [79]. The ArSN reaction provides bistrialkyl(aryl)phosphonium naphthalenediimide radical anions which were isolated, and automated ball milling procedure was superior to manual grinding and sonication conditions. The formation of free radicals was also obtained from glucose-based polysaccharides [80].

$$\begin{array}{ccccc} \mathsf{R}^{\mathsf{I}} & \stackrel{\sim}{\longrightarrow}^{\sim} & \mathsf{N}\mathsf{H}\_{\mathsf{I}} \\ \mathsf{R}^{\mathsf{I}} & \stackrel{\sim}{\longrightarrow}^{\sim} & \mathsf{C}\mathsf{H}\mathsf{Cl}\_{3} & \stackrel{\text{ball wall}}{\longrightarrow} & \mathsf{R}^{\mathsf{I}} \stackrel{\sim}{\longrightarrow}^{\sim} \\ \mathsf{A}\mathsf{T} & \mathsf{N}\mathsf{A}\mathsf{T}\mathsf{A} & \mathsf{N}\mathsf{A}\mathsf{O}\mathsf{T} \\ & & \mathsf{N}\mathsf{A}\mathsf{T}\mathsf{S}\mathsf{A} & \mathsf{A}\mathsf{B} \\ \mathsf{S}\mathsf{T}\mathsf{A}\mathsf{T}\mathsf{A} & \mathsf{N}\mathsf{A}\mathsf{T}\mathsf{A} & \mathsf{N}\mathsf{A} \\ \end{array} \\ \begin{array}{ccccc} \mathsf{T}\mathsf{C} & \mathsf{N}\mathsf{C} \\ \mathsf{T}\mathsf{A}\mathsf{T}\mathsf{B}\mathsf{T} & \mathsf{N}\mathsf{A} \\ \mathsf{T}\mathsf{A}\mathsf{T}\mathsf{B}\mathsf{T} & \mathsf{N}\mathsf{A} \\ \mathsf{T}\mathsf{B}\mathsf{T}\mathsf{A} & \mathsf{N}\mathsf{A} \end{array} \\ \begin{array}{ccccc} \mathsf{T}\mathsf{C} & \mathsf{N}\mathsf{A} \\ \mathsf{T}\mathsf{B}\mathsf{T}\mathsf{A} & \mathsf{N}\mathsf{A} \\ \mathsf{T}\mathsf{B}\mathsf{T}\mathsf{B}\mathsf{T} & \mathsf{N}\mathsf{A} \\ \end{array} \\ \end{array}$$

**Figure 13.**

*Organic Synthesis - A Nascent Relook*

hindered substrates.

process starting from acetophenone **49**.

formation of two new C-N bonds in the process was achieved in a very short time by

Another user and environmentally friendly protocol than isocyanide synthesis via Ugi reaction was the development of solid-state Hofmann reaction (synthesis of isocyanides from amines) (**Figure 13**) [55]. The implementation of the reaction in mechanochemical conditions significantly reduces the amounts of chloroform, from bulk solvent to 2.1 equivalents. Milling in two 15-minute steps, where chloroform was added each time, afforded better yields than one 30-min milling with all chloroform added at once. The addition of NBu3 was beneficial for sterically more

Enzymes can tolerate ball milling conditions, and enzymatic reactions were successfully carried out for several transformations: esterification of primary alcohols [56], peptide bond formation [57], ester hydrolysis [58], and cleavage of cellulose [59]. An enzymatic kinetic resolution of racemic secondary alcohols *rac*-**50** was performed by acylation with isopropenyl acetate catalyzed by lipase B from *Candida antarctica* lipase B (CALB) (**Figure 14**) [60]. Milling of *rac*-**50** in ZrO2 vessel showed that biocatalyst is stable in reaction conditions and a partial highly enantioselective hydrolysis provided acetates (*R*)-**52** and the remaining alcohols (*S*)-**50**. High enantioselectivity was also obtained with immobilized lipase PS-IM. Acylative kinetic resolution could be coupled with ketone reduction in one-pot sequential

Similar methodology was applied by Juaristi for the mechanoenzymatic resolution of racemic chiral amines. CALB was applied in the combination of isopropyl acetate as acylating agent and dioxane additive (in agate jars), and amide products were obtained with excellent enantiopurity (ee 66–>99%). Enantiopure chiral

Besides hydrogenation reaction facilitated in SUS304 ss and Strecker reaction, gaseous reagents were also in situ generated in transfer hydrogenation of carbonyls with polymethylhydrosiloxane as hydrogen source [62], reduction of NO2 group by catalytic transfer hydrogenation employing Pd and ammonium formate [15], and synthesis of thioureas by generation of ammonia from NH4Cl and Na2CO3 [13]. Among the reactions for the formation of other types of bonds which were not previously carried in ball milling conditions are C▬P bond by phosphonylation with MnOAc [63], O▬P phosphate nucleoside bond using CDI [64], S▬P bond via Arbuzov reaction [65], C▬B bond by borylation using Ir catalyst [66], and P▬S

amines were used in the synthesis of (*R*)- and (*S*)-Rasagiline [61].

and P▬Se bond formation by milling of phosphines with S and Se [67].

the reaction which started with aza-Michael addition to alkenes.

**32**

**Figure 12.**

**Figure 11.**

*Buchwald-Hartwig amination.*

*Synthesis of spiroimidazolines.*

*Hofmann reaction of amines with chloroform.*

**Figure 14.**

*Acylative kinetic resolution of secondary alcohols.*

**Figure 15.** *Enantioselective fluorination of β-keto esters.*

Several examples of advantageous application of mechanochemistry in supramolecular chemistry are given in recent literature. The encapsulation of fullerene C60 in mechanochemical conditions was extended from γ-cyclodextrin, cucurbit [15], uril and sulfocalix [16], arene hosts to molecular cages [81]. Other molecular guests were encapsulated by ball milling in calixarene (fluorene) [82], cyclodextrins (steroids) [83], as well as daidzein and genistein [84]. Synthesis of metal-organic framework in the presence of guest was used for the entrapment of boron dipyrromethene dyes in MOF. This complex could not be obtained by direct milling of MOF with BODIPY dyes [85]. Furthermore, the size of mechanochemically prepared hemicucurbituril macrocycles was effectively controlled by anion templating [86]. Pseudorotaxanes which were prepared in solution were transformed into diamide rotaxanes [2] by solvent-free reaction of amine and acyl chloride terminus forming amide stoppers [87]. On the other hand, for the synthesis of rotaxanes [2], a one-pot, two-step mechanochemical protocol was used. It involves the preparation of pseudorotaxane and stoppering by 1,3-dipolar alkyne-azide cycloaddition in the second step.

## **3. Methodology and technique developments**

## **3.1 Mechanochemistry meets photochemistry**

While the photochemical activation of molecules in solution is a well-known phenomenon, its integration with milling mechanochemistry has largely remained unexplored. The first step in this direction was made by MacGillivray who described the photochemical [2+2] dimerization of 4,4′-di(pyridyl)ethylene molecules, pre-assembled in a cocrystal by template-directed solid-state cocrystallization, into a cyclobutane product [88]. The milling, achieved by shaking a glass vial in a vortex machine, was required for the cocrystallization step, while the broadband UV lamp from a laboratory photoreactor was used to affect the dimerization in the solid state. This approach, named "vortex grinding," requires the vortex shaker to be placed inside the photoreactor chamber and is not compatible with standard milling equipment. Recently, visible light photoredox catalysis has grown into an exciting and very productive research field, but the challenge of combining it with solidstate milling remained. Further investigations by König showed that solvent-free visible light-induced photocatalytic reactions could be realized in thin liquid films by means of a rod mill, consisting of a test tube containing the reaction mixture and a glass rod attached to a stirrer [89] or by a "rotating film reactor" where a glass vial is rotated at 1200 rpm to form a film exposed to blue light [90]. In this way, alcohol oxidations using riboflavin tetraacetate photocatalyst and coupling of aryl halides with pyrroles and phosphites in the presence of rhodamine 6G were accomplished (**Figure 16a**).

In 2017, our group reported on the first successful implementation of mechanochemical ball milling in a commercial shaker mill with visible light photocatalysis, named the "mechanochemically-assisted solid-state photocatalysis" or "MASSPC" [91]. The major obstacle in employing photochemical activation in mechanochemical reactions is the nontransparency of milling jars typically made of stainless steel, tungsten carbide, or Teflon. To overcome this issue, custom-made Duran glass jars completely translucent to visible light were designed. Plastic jars made of polymethylmethacrylate (PMMA), extensively used in real-time in situ monitoring of mechanochemical reactions [92], were found to be inadequate for this purpose due to the insufficient transparency caused by the wear of the plastic material during milling. In parallel, a photochemical reactor that would enable simultaneous

**35**

formation of 1

**Figure 16.**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

high-speed vibrational milling and irradiation of the milled sample was constructed. While the initial experiments with LED strips wrapped around the glass jars showed promise as the simplest solution, prolonged exposure to high-frequency vibrations led to breakage of the strip, and this approach was eventually abandoned. Instead, an LED reactor that would fit around the oscillating glass jar was devised and successfully used in the aerobic thiophenol-promoted photocatalytic oxidation

*(a) Rod mill and rotating film reactors for solvent-free photocatalysis. (b) MASSPC reactor for simultaneous ball milling and LED irradiation. (c) A multiposition jar adapter for planetary ball milling and the lunar motion of vials in the adapter. (d) Resonant acoustic mixing device and the effect of acceleration on the* 

transformation of an alkyne into the diketone product, while the gas chromatographic analysis allowed reaction quantification and the detection of intermediate isomeric vinyl sulfides as the photoactive species that react with singlet oxygen. The

approach by synthesizing anthracene-9,10-*endo*-peroxide from anthracene in the presence of eosin Y photocatalyst. The plastic PMMA jars and LED strips were next reported in the photochemical borylation of aromatic diazonium salts using eosin Y as the photocatalyst under milling conditions and green light irradiation [93]. All these results demonstrate the promising potential of merging mechanochemistry with photochemistry into a novel research area of solvent-free organic synthesis.

One practical limitation of using conventional ball mills for synthetic purposes is their low throughput, i.e., the inability to process more than a few samples simultaneously. To address this problem, Cravotto and Colacino resorted to modification of a standard jar for planetary ball milling by transforming it to a multiposition jar

O2 under these conditions was also demonstrated by the MASSPC

O2) was involved in the

of diphenylacetylene to a diketone benzil (**Figure 16b**). The obtained results suggested that singlet oxygen (1

*cocrystallization of carbamazepine and nicotinamide.*

**3.2 High-throughput mechanochemistry**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

**Figure 16.**

*Organic Synthesis - A Nascent Relook*

the second step.

**3. Methodology and technique developments**

**3.1 Mechanochemistry meets photochemistry**

Several examples of advantageous application of mechanochemistry in supramolecular chemistry are given in recent literature. The encapsulation of fullerene C60 in mechanochemical conditions was extended from γ-cyclodextrin, cucurbit [15], uril and sulfocalix [16], arene hosts to molecular cages [81]. Other molecular guests were encapsulated by ball milling in calixarene (fluorene) [82], cyclodextrins (steroids) [83], as well as daidzein and genistein [84]. Synthesis of metal-organic framework in the presence of guest was used for the entrapment of boron dipyrromethene dyes in MOF. This complex could not be obtained by direct milling of MOF with BODIPY dyes [85]. Furthermore, the size of mechanochemically prepared hemicucurbituril macrocycles was effectively controlled by anion templating [86]. Pseudorotaxanes which were prepared in solution were transformed into diamide rotaxanes [2] by solvent-free reaction of amine and acyl chloride terminus forming amide stoppers [87]. On the other hand, for the synthesis of rotaxanes [2], a one-pot, two-step mechanochemical protocol was used. It involves the preparation of pseudorotaxane and stoppering by 1,3-dipolar alkyne-azide cycloaddition in

While the photochemical activation of molecules in solution is a well-known phenomenon, its integration with milling mechanochemistry has largely remained unexplored. The first step in this direction was made by MacGillivray who described the photochemical [2+2] dimerization of 4,4′-di(pyridyl)ethylene molecules, pre-assembled in a cocrystal by template-directed solid-state cocrystallization, into a cyclobutane product [88]. The milling, achieved by shaking a glass vial in a vortex machine, was required for the cocrystallization step, while the broadband UV lamp from a laboratory photoreactor was used to affect the dimerization in the solid state. This approach, named "vortex grinding," requires the vortex shaker to be placed inside the photoreactor chamber and is not compatible with standard milling equipment. Recently, visible light photoredox catalysis has grown into an exciting and very productive research field, but the challenge of combining it with solidstate milling remained. Further investigations by König showed that solvent-free visible light-induced photocatalytic reactions could be realized in thin liquid films by means of a rod mill, consisting of a test tube containing the reaction mixture and a glass rod attached to a stirrer [89] or by a "rotating film reactor" where a glass vial is rotated at 1200 rpm to form a film exposed to blue light [90]. In this way, alcohol oxidations using riboflavin tetraacetate photocatalyst and coupling of aryl halides with pyrroles and phosphites in the presence of rhodamine 6G were accomplished

In 2017, our group reported on the first successful implementation of mechanochemical ball milling in a commercial shaker mill with visible light photocatalysis, named the "mechanochemically-assisted solid-state photocatalysis" or "MASSPC" [91]. The major obstacle in employing photochemical activation in mechanochemical reactions is the nontransparency of milling jars typically made of stainless steel, tungsten carbide, or Teflon. To overcome this issue, custom-made Duran glass jars completely translucent to visible light were designed. Plastic jars made of polymethylmethacrylate (PMMA), extensively used in real-time in situ monitoring of mechanochemical reactions [92], were found to be inadequate for this purpose due to the insufficient transparency caused by the wear of the plastic material during milling. In parallel, a photochemical reactor that would enable simultaneous

**34**

(**Figure 16a**).

*(a) Rod mill and rotating film reactors for solvent-free photocatalysis. (b) MASSPC reactor for simultaneous ball milling and LED irradiation. (c) A multiposition jar adapter for planetary ball milling and the lunar motion of vials in the adapter. (d) Resonant acoustic mixing device and the effect of acceleration on the cocrystallization of carbamazepine and nicotinamide.*

high-speed vibrational milling and irradiation of the milled sample was constructed. While the initial experiments with LED strips wrapped around the glass jars showed promise as the simplest solution, prolonged exposure to high-frequency vibrations led to breakage of the strip, and this approach was eventually abandoned. Instead, an LED reactor that would fit around the oscillating glass jar was devised and successfully used in the aerobic thiophenol-promoted photocatalytic oxidation of diphenylacetylene to a diketone benzil (**Figure 16b**).

The obtained results suggested that singlet oxygen (1 O2) was involved in the transformation of an alkyne into the diketone product, while the gas chromatographic analysis allowed reaction quantification and the detection of intermediate isomeric vinyl sulfides as the photoactive species that react with singlet oxygen. The formation of 1 O2 under these conditions was also demonstrated by the MASSPC approach by synthesizing anthracene-9,10-*endo*-peroxide from anthracene in the presence of eosin Y photocatalyst. The plastic PMMA jars and LED strips were next reported in the photochemical borylation of aromatic diazonium salts using eosin Y as the photocatalyst under milling conditions and green light irradiation [93]. All these results demonstrate the promising potential of merging mechanochemistry with photochemistry into a novel research area of solvent-free organic synthesis.

## **3.2 High-throughput mechanochemistry**

One practical limitation of using conventional ball mills for synthetic purposes is their low throughput, i.e., the inability to process more than a few samples simultaneously. To address this problem, Cravotto and Colacino resorted to modification of a standard jar for planetary ball milling by transforming it to a multiposition jar

adapter capable of processing up to 12 samples at the same time [94]. The adapter can be made in different sizes to accommodate 4 vials of 100 mL, 8 vials of 20 mL, or 12 vials of 2 mL volume. In the case of a planetary ball mill equipped with four milling stations, this technical modification enables fast screening and optimization for up to 48 different reaction conditions. Besides high-throughput operation mode and time- and cost-effectiveness, "mechanochemical parallel synthesis" (1) avoids cleaning and cross contamination as the reaction mixtures can be stored or analyzed directly in the vial, (2) it allows reactions on a milligram scale (ca. 10 mg), (3) aluminum adapters serve as heat sinks and prevent reaction mixtures from overheating, and (4) the vials can be periodically loaded/unloaded to enable processing a large number of samples. Vials loaded into a multiposition adapter/ jar experience the so-called *lunar motion* due to the existence of a separate rotation axis in addition to the adapter/jar axis and the principal "sun" wheel axis characteristic for planetary ball milling. This results in a motion different in conventional planetary ball mills with a nonconstant force exerted on the vials and their content. When the vials are closer to the principal axis, this force becomes less intense, while in the opposite position on the outer rim of the adapter, the force is as strong as in conventional milling (**Figure 16c**).

The development of mechanochemical parallel synthesis was successfully employed in the synthesis of a library of 3,4-dihydro-2H-benzo[e][1, 3] oxazines by a one-pot three-component reaction between a phenol, a paraformaldehyde, and a primary amine. More than 60 experiments per week were performed, as opposed to expected 6–8 weeks required for the same output using conventional milling. A typical experiment in a 2 mL vial was done on 0.53 mmol scale using 60 stainless steel balls (1 mm diameter), while 20 mL vials were charged with 3.19 mmol of a phenol/amine along with 60 glass beads (3 mm diameter). The reaction mixtures were milled at 550 rpm for 4 h affording yields comparable to solution synthesis.

#### **3.3 Ball-free milling: resonant acoustic mixing**

The traditional paradigm of mechanochemistry is the use of milling balls to introduce mechanical and thermal energy into a system through mechanisms such as impact, shear, or their combination, depending on the milling mode. The number, mass, size, or material the balls are made of, as well as their relation to the volume of a milling jar, are all important variables in determining the outcome of a mechanochemical ball milling reaction. However, in a technique called the "resonant acoustic mixing" or RAM, solid-state reactions can be performed in the absence of milling bodies [95]. Unlike conventional ball milling, where the introduced energy causes physical damage to particles, generates defects, and often leads to aggregation of particulates, compaction, the so-called "snow balling," or even complete amorphization, RAM is a much softer technique for mixing solids with minimal damage to particles. It is therefore particularly convenient in cases where mixing of impact-sensitive materials such as explosives and propellants is required. In a resonant acoustic mixer device, effective mixing is accomplished by transferring the mechanical energy of a vibrating plate connected to a bed of springs to a sample container placed on top of the plate. The plate and the container are set into an oscillating motion at a fixed resonance frequency, resulting in local zones of intense mixing (**Figure 16d**). Since the frequency of plate vibration is fixed (ca. 61 Hz), the intensity of mixing is simply adjusted by changing the amplitude of the oscillation; hence the acceleration or the "G-force" exerted on a powder sample in the container can be controlled.

In 2018, Michalchuk and Boldyreva reported the first in situ study of a RAMinduced cocrystallization of nicotinamide (**NIC**) and carbamazepine (**CBZ**) in

**37**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

transferred by means other than impact or shear.

Since the introduction of real-time in situ techniques for monitoring mechanochemical reactions [92], based on synchrotron PXRD, Raman spectroscopy, and their combination, mechanistic details for a number of organic transformations, metalorganic framework (MOF) systems, and solid-state cocrystallizations have been studied and revealed [96]. These in situ studies also allow for kinetic considerations of solid-state milling reactions under LAG conditions [97], as well as investigations of the effect of milling parameters such as frequency [98], number of milling balls [99], or the ball to reactant ratio on the course of mechanochemical reactions [100]. On a technical side, such investigations go hand in hand with the development of equipment necessary to conduct them. In this respect, accessories such as milling jars for in situ studies deserve special attention. Filinchuk et al. have employed a 3D printer as a low-cost and rapid way to fabricate several types of plastic jars made of PMMA or polylactic acid (PLA) transparent to X-rays and showed how different geometries and material of the jars can reduce background (due to scattering) and minimize absorption, as well as improve the angular resolution during PXRD measurements [101]. In comparison with standard jars used in most experiments (type 0 and its modification type 1), jars with thinner walls (type 2) and added grooves (type 3) or physically separated X-ray probing area in the "two-chamber" jar (type 4) displayed significantly lower background and absorption (**Figure 17a**). In designs 3 and 4, the size of the groove or the opening between the two chambers is smaller than the ball size, which eliminates the problem of X-ray scattering on milling balls and detection of the corresponding diffraction peaks. The sampling efficiency of 3D-printed jars

**3.4 Real-time in situ reaction monitoring**

the presence of a catalytic amount of water, using synchrotron powder X-ray diffraction (PXRD). Two acceleration settings of 50 G and 100 G were employed to investigate the effect of mixing intensity on the course of the cocrystallization reaction to form the known 1:1 cocrystal **CBZ·NIC**. Although solvent-free (neat) conditions gave no reaction, the addition of ca. 20 μL of water facilitated the formation of carbamazepine dihydrate (**CBZDH**) at a continuous rate as the kinetically controlled product at 50 G acceleration. The Rietveld refinement revealed around 40% conversion to the dihydrate form **CBZDH**, while only a 10% ca. of **CBZ·NIC** cocrystal was observed. Since water was present in excess, the 40% conversion plateau to **CBZDH** suggests the hydration of **CBZ** particle surfaces as the primary process during mixing, which prevents the complete hydration to take place in deeper layers. On the other hand, RAM at 100 G acceleration provided a completely different reaction profile. Most of the reactants were consumed within the first 30 seconds, and after Rietveld refinement, ca. 70% of **CBZ·NIC** cocrystal, as the thermodynamically favored phase, was detected, alongside 15–20% of the dihydrate **CBZDH** (**Figure 16d**). Throughout the first 9 minutes, the Bragg reflections corresponding to reactants stochastically appeared and disappeared, suggesting an inhomogeneous mixing and distribution of powder inside the reaction zone. Additionally, the presence of **CBZDH** in the mixture was probably due to the hydration of aggregated **CBZ** in the corners of the container, where mixing was not effective enough as the vessel was designed primarily for in situ PXRD measurements. The observed differences in solid-state reaction rates were attributed to more intimate mixing of reacting powders by particle comminution and dissociation of aggregates, disruption of intermediate product-coated reactant particles, and generation of more fresh reactive surfaces under higher RAM accelerations. This study also demonstrated that solid-state RAM mechanochemical reactions can be carried out gently in the absence of milling balls where the mechanical energy is

### *Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

*Organic Synthesis - A Nascent Relook*

conventional milling (**Figure 16c**).

**3.3 Ball-free milling: resonant acoustic mixing**

adapter capable of processing up to 12 samples at the same time [94]. The adapter can be made in different sizes to accommodate 4 vials of 100 mL, 8 vials of 20 mL, or 12 vials of 2 mL volume. In the case of a planetary ball mill equipped with four milling stations, this technical modification enables fast screening and optimization for up to 48 different reaction conditions. Besides high-throughput operation mode and time- and cost-effectiveness, "mechanochemical parallel synthesis" (1) avoids cleaning and cross contamination as the reaction mixtures can be stored or analyzed directly in the vial, (2) it allows reactions on a milligram scale (ca. 10 mg), (3) aluminum adapters serve as heat sinks and prevent reaction mixtures from overheating, and (4) the vials can be periodically loaded/unloaded to enable processing a large number of samples. Vials loaded into a multiposition adapter/ jar experience the so-called *lunar motion* due to the existence of a separate rotation axis in addition to the adapter/jar axis and the principal "sun" wheel axis characteristic for planetary ball milling. This results in a motion different in conventional planetary ball mills with a nonconstant force exerted on the vials and their content. When the vials are closer to the principal axis, this force becomes less intense, while in the opposite position on the outer rim of the adapter, the force is as strong as in

The development of mechanochemical parallel synthesis was successfully employed in the synthesis of a library of 3,4-dihydro-2H-benzo[e][1, 3] oxazines by a one-pot three-component reaction between a phenol, a paraformaldehyde, and a primary amine. More than 60 experiments per week were performed, as opposed to expected 6–8 weeks required for the same output using conventional milling. A typical experiment in a 2 mL vial was done on 0.53 mmol scale using 60 stainless steel balls (1 mm diameter), while 20 mL vials were charged with 3.19 mmol of a phenol/amine along with 60 glass beads (3 mm diameter). The reaction mixtures were milled at 550 rpm for 4 h affording yields comparable to solution synthesis.

The traditional paradigm of mechanochemistry is the use of milling balls to introduce mechanical and thermal energy into a system through mechanisms such as impact, shear, or their combination, depending on the milling mode. The number, mass, size, or material the balls are made of, as well as their relation to the volume of a milling jar, are all important variables in determining the outcome of a mechanochemical ball milling reaction. However, in a technique called the "resonant acoustic mixing" or RAM, solid-state reactions can be performed in the absence of milling bodies [95]. Unlike conventional ball milling, where the introduced energy causes physical damage to particles, generates defects, and often leads to aggregation of particulates, compaction, the so-called "snow balling," or even complete amorphization, RAM is a much softer technique for mixing solids with minimal damage to particles. It is therefore particularly convenient in cases where mixing of impact-sensitive materials such as explosives and propellants is required. In a resonant acoustic mixer device, effective mixing is accomplished by transferring the mechanical energy of a vibrating plate connected to a bed of springs to a sample container placed on top of the plate. The plate and the container are set into an oscillating motion at a fixed resonance frequency, resulting in local zones of intense mixing (**Figure 16d**). Since the frequency of plate vibration is fixed (ca. 61 Hz), the intensity of mixing is simply adjusted by changing the amplitude of the oscillation; hence the acceleration or the "G-force" exerted on a powder sample in

In 2018, Michalchuk and Boldyreva reported the first in situ study of a RAMinduced cocrystallization of nicotinamide (**NIC**) and carbamazepine (**CBZ**) in

**36**

the container can be controlled.

the presence of a catalytic amount of water, using synchrotron powder X-ray diffraction (PXRD). Two acceleration settings of 50 G and 100 G were employed to investigate the effect of mixing intensity on the course of the cocrystallization reaction to form the known 1:1 cocrystal **CBZ·NIC**. Although solvent-free (neat) conditions gave no reaction, the addition of ca. 20 μL of water facilitated the formation of carbamazepine dihydrate (**CBZDH**) at a continuous rate as the kinetically controlled product at 50 G acceleration. The Rietveld refinement revealed around 40% conversion to the dihydrate form **CBZDH**, while only a 10% ca. of **CBZ·NIC** cocrystal was observed. Since water was present in excess, the 40% conversion plateau to **CBZDH** suggests the hydration of **CBZ** particle surfaces as the primary process during mixing, which prevents the complete hydration to take place in deeper layers. On the other hand, RAM at 100 G acceleration provided a completely different reaction profile. Most of the reactants were consumed within the first 30 seconds, and after Rietveld refinement, ca. 70% of **CBZ·NIC** cocrystal, as the thermodynamically favored phase, was detected, alongside 15–20% of the dihydrate **CBZDH** (**Figure 16d**). Throughout the first 9 minutes, the Bragg reflections corresponding to reactants stochastically appeared and disappeared, suggesting an inhomogeneous mixing and distribution of powder inside the reaction zone. Additionally, the presence of **CBZDH** in the mixture was probably due to the hydration of aggregated **CBZ** in the corners of the container, where mixing was not effective enough as the vessel was designed primarily for in situ PXRD measurements. The observed differences in solid-state reaction rates were attributed to more intimate mixing of reacting powders by particle comminution and dissociation of aggregates, disruption of intermediate product-coated reactant particles, and generation of more fresh reactive surfaces under higher RAM accelerations. This study also demonstrated that solid-state RAM mechanochemical reactions can be carried out gently in the absence of milling balls where the mechanical energy is transferred by means other than impact or shear.

## **3.4 Real-time in situ reaction monitoring**

Since the introduction of real-time in situ techniques for monitoring mechanochemical reactions [92], based on synchrotron PXRD, Raman spectroscopy, and their combination, mechanistic details for a number of organic transformations, metalorganic framework (MOF) systems, and solid-state cocrystallizations have been studied and revealed [96]. These in situ studies also allow for kinetic considerations of solid-state milling reactions under LAG conditions [97], as well as investigations of the effect of milling parameters such as frequency [98], number of milling balls [99], or the ball to reactant ratio on the course of mechanochemical reactions [100]. On a technical side, such investigations go hand in hand with the development of equipment necessary to conduct them. In this respect, accessories such as milling jars for in situ studies deserve special attention. Filinchuk et al. have employed a 3D printer as a low-cost and rapid way to fabricate several types of plastic jars made of PMMA or polylactic acid (PLA) transparent to X-rays and showed how different geometries and material of the jars can reduce background (due to scattering) and minimize absorption, as well as improve the angular resolution during PXRD measurements [101]. In comparison with standard jars used in most experiments (type 0 and its modification type 1), jars with thinner walls (type 2) and added grooves (type 3) or physically separated X-ray probing area in the "two-chamber" jar (type 4) displayed significantly lower background and absorption (**Figure 17a**). In designs 3 and 4, the size of the groove or the opening between the two chambers is smaller than the ball size, which eliminates the problem of X-ray scattering on milling balls and detection of the corresponding diffraction peaks. The sampling efficiency of 3D-printed jars

was tested on the solvent-free mechanochemical PbO polymorph interconversion from β-PbO to α-PbO phase, as a suitable model system. The results showed that the jar design generally affects the rate of β-PbO to α-PbO conversion, with the lowest rate expectedly recorded in the type 4 "two-chamber" jar where the analyzed sample resides in the bottom chamber, while ball milling and intensive mixing take place in the upper chamber. The authors also noted that types 3 and 4 jars are not compatible with liquid-assisted grinding since wet powder materials would probably stick and aggregate in the groove or in the chamber corners.

Besides improving the design of milling jars, the development of instrumentation for mechanistic studies is essential, as exemplified by Casati's design of a new type of in situ ball mill intended for real-time probing of reactions in solids [102]. The new setup, characterized by a dual motion during milling in the form of vertical shaking (up to 50–80 Hz) and continuous slow rotation of the jar, is capable of collecting PXRD data with significantly reduced background and sharper Bragg reflections, which becomes important if high-resolution measurements are desired. Such a design also prevented the aggregation of powder material in the grooves, often encountered in devices where the only motion is shaking insufficient to push the powder out of the groove. In combination with the new design of a two-part milling chamber surrounded by a continuous probing ring where the milling balls cannot enter, it provides opportunities for collecting better resolved PXRD data, reaction monitoring, phase quantification, and line profile analysis (**Figure 17b**).

An interesting recent contribution to real-time in situ monitoring of organic transformations is the detection of a cocrystal between barbituric acid and vanillin that precedes the formation of C〓C bond in the final Knoevenagel product [103]. The reactant molecules in the cocrystal are positioned to allow nucleophilic attack of the methylene group in barbituric acid to the carbonyl group in vanillin. LAG using ethanol accelerated the reaction, while acetonitrile or nitromethane prolonged the life span of the cocrystal, the structure of which was elucidated from the laboratory PXRD data. Using *N*,*N*-diisopropylethylamine as the grinding liquid led to the Knoevenagel product directly, without the formation of intermediate cocrystal.

#### **Figure 17.**

*(a) Different types of 3D-printed plastic jars. (b) Casati's design of a probing jar and a dual motion ball mill. (c) Twin-screw extruder and its components.*

**39**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

out milling [105].

Since mechanochemical synthesis in ball mills is inherently associated with thermal effects accompanying the mechanical activation through impact or shear, a complete understanding of milling processes on a microscopic level must also take into consideration the corresponding evolution of heat. The Emmerling group described a combined in situ study of the Knoevenagel reaction between *p*-nitrobenzaldehyde and malononitrile by coupling PXRD, Raman spectroscopy, and temperature measurements using an IR thermal camera [104]. By employing custom-made PMMA milling jars equipped with an embedded aluminum plug that was in direct contact with the jar content, Užarević et al. demonstrated that the temperature profiles of milling reactions are mainly determined by the energy dissipated through friction between the moving balls, jar, and the sample contained within, whereas the reaction enthalpy contribution was relatively insignificant. Since frictional properties of the milled material change during the mechanochemical reaction, the dissipated energy will be more or less efficiently absorbed through-

One of the main drawbacks of mechanochemical synthesis is the lack of ability to perform milling reactions on large scales and in a continuous fashion. Industrial ball mills, which are typically used on these scales, can process tons of materials, whereas for laboratory use, planetary ball mills can deliver products up to several hundred grams. Currently, the most efficient way to increase the product output of mechanochemical reactions is the twin-screw extrusion (TSE), which has been successfully demonstrated in the large-scale solvent-free production of MOFs,

day<sup>−</sup><sup>1</sup>

for the Michael

for the vanillin-barbituric acid reaction,

day<sup>−</sup><sup>1</sup>

in the case of the aldol product were achieved [106].

obtained in the mixer mill [107]. The three-

) three

**3.5 Twin-screw extrusion: mechanochemistry grows in scale**

cocrystals, and deep eutectic solvents, in space time yields (kg m<sup>−</sup><sup>3</sup>

parameter that can be modified [106].

space time yields of >250,000 kg m<sup>−</sup><sup>3</sup>

day<sup>−</sup><sup>1</sup>

product, and 32,000 kg m<sup>−</sup><sup>3</sup>

day<sup>−</sup><sup>1</sup>

14,900 kg m<sup>−</sup><sup>3</sup>

of 3395 m<sup>−</sup><sup>3</sup>

**4. Conclusions**

synthesis is presented.

to four times greater than the corresponding solution methods. In a typical TSE design, powdered reactants are fed into the instrument at a certain rate and conveyed by a pair of co- or counter-rotating screws encased in the extruder barrel. As the material moves along the barrel, mixing and kneading elements incorporated into the TSE design exert shearing and compression forces on the reactants, resulting in the product phase which is collected at the exit port (**Figure 17c**). Besides the screw speed and feed rate, the extruder barrel temperature is another processing

James et al. have shown that organic molecules can be synthesized continuously on a large scale using TSE technique under solvent-free conditions. Four condensation reactions (the Knoevenagel reaction, the imine formation, the aldol reaction, and the Michael addition) were optimized by changing the screw speed, feed rate, and temperature, to provide a quantitative conversion to desired products. High-

day<sup>−</sup><sup>1</sup>

TSE was also applied in the large-scale synthesis of 2,2-difluoro-1,3-diphenylpropane-1,3-dione in the presence of Selectfluor as the fluorine source, with the space time yield

component solvent-free Biginelli reaction was successfully carried out using TSE, to afford 3,4-dihydropyrimidin-2-(1H)-ones/thiones in optimized yields of 85–91% [108].

A short review of recent literature dealing with organic mechanochemical

for the imine product, 35,000 kg m<sup>−</sup><sup>3</sup>

day<sup>−</sup><sup>1</sup>

day<sup>−</sup><sup>1</sup>

vs. only 29 m<sup>−</sup><sup>3</sup>

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

*Organic Synthesis - A Nascent Relook*

aggregate in the groove or in the chamber corners.

was tested on the solvent-free mechanochemical PbO polymorph interconversion from β-PbO to α-PbO phase, as a suitable model system. The results showed that the jar design generally affects the rate of β-PbO to α-PbO conversion, with the lowest rate expectedly recorded in the type 4 "two-chamber" jar where the analyzed sample resides in the bottom chamber, while ball milling and intensive mixing take place in the upper chamber. The authors also noted that types 3 and 4 jars are not compatible with liquid-assisted grinding since wet powder materials would probably stick and

Besides improving the design of milling jars, the development of instrumentation for mechanistic studies is essential, as exemplified by Casati's design of a new type of in situ ball mill intended for real-time probing of reactions in solids [102]. The new setup, characterized by a dual motion during milling in the form of vertical shaking (up to 50–80 Hz) and continuous slow rotation of the jar, is capable of collecting PXRD data with significantly reduced background and sharper Bragg reflections, which becomes important if high-resolution measurements are desired. Such a design also prevented the aggregation of powder material in the grooves, often encountered in devices where the only motion is shaking insufficient to push the powder out of the groove. In combination with the new design of a two-part milling chamber surrounded by a continuous probing ring where the milling balls cannot enter, it provides opportunities for collecting better resolved PXRD data, reaction monitoring, phase quantification, and line profile analysis (**Figure 17b**). An interesting recent contribution to real-time in situ monitoring of organic transformations is the detection of a cocrystal between barbituric acid and vanillin that precedes the formation of C〓C bond in the final Knoevenagel product [103]. The reactant molecules in the cocrystal are positioned to allow nucleophilic attack of the methylene group in barbituric acid to the carbonyl group in vanillin. LAG using ethanol accelerated the reaction, while acetonitrile or nitromethane prolonged the life span of the cocrystal, the structure of which was elucidated from the laboratory PXRD data. Using *N*,*N*-diisopropylethylamine as the grinding liquid led to the Knoevenagel product directly, without the formation of intermediate cocrystal.

*(a) Different types of 3D-printed plastic jars. (b) Casati's design of a probing jar and a dual motion ball mill.* 

**38**

**Figure 17.**

*(c) Twin-screw extruder and its components.*

Since mechanochemical synthesis in ball mills is inherently associated with thermal effects accompanying the mechanical activation through impact or shear, a complete understanding of milling processes on a microscopic level must also take into consideration the corresponding evolution of heat. The Emmerling group described a combined in situ study of the Knoevenagel reaction between *p*-nitrobenzaldehyde and malononitrile by coupling PXRD, Raman spectroscopy, and temperature measurements using an IR thermal camera [104]. By employing custom-made PMMA milling jars equipped with an embedded aluminum plug that was in direct contact with the jar content, Užarević et al. demonstrated that the temperature profiles of milling reactions are mainly determined by the energy dissipated through friction between the moving balls, jar, and the sample contained within, whereas the reaction enthalpy contribution was relatively insignificant. Since frictional properties of the milled material change during the mechanochemical reaction, the dissipated energy will be more or less efficiently absorbed throughout milling [105].

#### **3.5 Twin-screw extrusion: mechanochemistry grows in scale**

One of the main drawbacks of mechanochemical synthesis is the lack of ability to perform milling reactions on large scales and in a continuous fashion. Industrial ball mills, which are typically used on these scales, can process tons of materials, whereas for laboratory use, planetary ball mills can deliver products up to several hundred grams. Currently, the most efficient way to increase the product output of mechanochemical reactions is the twin-screw extrusion (TSE), which has been successfully demonstrated in the large-scale solvent-free production of MOFs, cocrystals, and deep eutectic solvents, in space time yields (kg m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> ) three to four times greater than the corresponding solution methods. In a typical TSE design, powdered reactants are fed into the instrument at a certain rate and conveyed by a pair of co- or counter-rotating screws encased in the extruder barrel. As the material moves along the barrel, mixing and kneading elements incorporated into the TSE design exert shearing and compression forces on the reactants, resulting in the product phase which is collected at the exit port (**Figure 17c**). Besides the screw speed and feed rate, the extruder barrel temperature is another processing parameter that can be modified [106].

James et al. have shown that organic molecules can be synthesized continuously on a large scale using TSE technique under solvent-free conditions. Four condensation reactions (the Knoevenagel reaction, the imine formation, the aldol reaction, and the Michael addition) were optimized by changing the screw speed, feed rate, and temperature, to provide a quantitative conversion to desired products. Highspace time yields of >250,000 kg m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> for the vanillin-barbituric acid reaction, 14,900 kg m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> for the imine product, 35,000 kg m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> for the Michael product, and 32,000 kg m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> in the case of the aldol product were achieved [106]. TSE was also applied in the large-scale synthesis of 2,2-difluoro-1,3-diphenylpropane-1,3-dione in the presence of Selectfluor as the fluorine source, with the space time yield of 3395 m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> vs. only 29 m<sup>−</sup><sup>3</sup> day<sup>−</sup><sup>1</sup> obtained in the mixer mill [107]. The threecomponent solvent-free Biginelli reaction was successfully carried out using TSE, to afford 3,4-dihydropyrimidin-2-(1H)-ones/thiones in optimized yields of 85–91% [108].

## **4. Conclusions**

A short review of recent literature dealing with organic mechanochemical synthesis is presented.

## **Acknowledgements**

The authors acknowledge funding by the Croatian Science Foundation grant No. IP-2018-01-3298, cycloaddition strategies towards polycyclic guanidines (CycloGu).

## **Author details**

Davor Margetić\* and Vjekoslav Štrukil Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia

\*Address all correspondence to: margetid@irb.hr

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**41**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

Chemistry. 2018:18-33. DOI: 10.1002/

Mechanochemical Organic Synthesis. Amsterdam: Elsevier; 2016. ISBN:

[11] Ranu B, Stolle A, editors. Ball Milling Towards Green Synthesis Applications, Projects, Challenges. RSC Green Chemistry No. 31. Cambridge; 2015. ISBN: 978-1-84973-945-0

[12] Cao Q, Howard JL, Wheatley E, Browne DL. Mechanochemical activation of zinc and application to Negishi cross-coupling. Angewandte Chemie, International Edition. 2018;**57**:11339- 11343. DOI: 10.1002/anie.201806480

[13] Đud M, Magdysyuk OV, Margetić D, Štrukil V. Synthesis of monosubstituted thioureas by vapour digestion and mechanochemical amination of thiocarbamoyl benzotriazoles. Green Chemistry. 2016;**18**:2666-2674. DOI:

Sagatov Y, Browne DL. One-pot multistep

[15] Portada T, Margetić D, Štrukil V. Mechanochemical catalytic transfer hydrogenation of aromatic nitro derivatives. Molecules. 2018;**23**:3163- 3180. DOI: 10.3390/molecules23123163

[16] Briš A, Đud M, Margetić D. Mechanochemical *N*-alkylation of imides. Beilstein Journal of Organic

10.1039/C6GC00089D

2017;**13**:1950-1956

[14] Howard JL, Nicholson W,

mechanochemical synthesis of fluorinated pyrazolones. Beilstein Journal of Organic Chemistry.

[9] Tan D, Garcia F. Main group mechanochemistry: From curiosity to established protocols. Chemical Society Reviews. 2019;**48**:2274-2292. DOI:

ejoc.201700961

10.1039/c7cs00813a

9780128021842

[10] Margetić D, Štrukil V.

[1] Ayoub G, Štrukil V, Fábián L, Mottillo C, Bao H, Murata Y, et al. Mechanochemistry vs. solution growth: Striking differences in bench stability of a cimetidine salt based on synthetic method. CrystEngComm. 2018;**45**:7242-

7247. DOI: 10.1039/C8CE01727A

[3] Do J-L, Friščić T. Chemistry 2.0: Developing a new, solventfree system of chemical; synthesis based on mechanochemistry. Synlett. 2017;**28**:2066-2092. DOI:

[4] Muñoz-Batista MJ, Rodriguez-Padron D, Puente-Santiago AR, Luque R. Mechanochemistry: Towards sustainable design of advanced nanomaterials for electrochemical energy storage and catalytic applications. ACS

Sustainable Chemistry & Engineering. 2018;**6**:9530-9544. DOI: 10.1021/

[5] Štrukil V. Mechanochemical organic synthesis: The art of making chemistry green. Synlett. 2018;**29**:1281-1288. DOI:

[6] Howard JL, Cao Q, Browne DL. Mechanochemistry as an emerging tool for molecular synthesis: What can it offer? Chemical Science. 2018;**9**:3080-

3094. DOI: 10.1039/c7sc05371a

Mechanochemistry and organic synthesis: From mystical to practical. Green Chemistry. 2018;**20**:1435-1443.

[8] Tan D, Friščić T. Mechanochemistry for organic chemists: An update. European Journal of Organic

[7] Andersen J, Mack J.

DOI: 10.1039/C7GC03797J

10.1055/s-0036-1590854

acssuschemeng.8b01716

10.1055/s-0036-1591868

acscentsci.6b00277

[2] Do J-L, Friščić T. Mechanochemistry: A force of synthesis. ACS Central Science. 2017;**3**:13-19. DOI: 10.1021/

**References**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

## **References**

*Organic Synthesis - A Nascent Relook*

**Acknowledgements**

**40**

**Author details**

Davor Margetić\* and Vjekoslav Štrukil

Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia

\*Address all correspondence to: margetid@irb.hr

provided the original work is properly cited.

Laboratory for Physical Organic Chemistry, Division of Organic Chemistry and

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

The authors acknowledge funding by the Croatian Science Foundation grant No. IP-2018-01-3298, cycloaddition strategies towards polycyclic guanidines (CycloGu).

[1] Ayoub G, Štrukil V, Fábián L, Mottillo C, Bao H, Murata Y, et al. Mechanochemistry vs. solution growth: Striking differences in bench stability of a cimetidine salt based on synthetic method. CrystEngComm. 2018;**45**:7242- 7247. DOI: 10.1039/C8CE01727A

[2] Do J-L, Friščić T. Mechanochemistry: A force of synthesis. ACS Central Science. 2017;**3**:13-19. DOI: 10.1021/ acscentsci.6b00277

[3] Do J-L, Friščić T. Chemistry 2.0: Developing a new, solventfree system of chemical; synthesis based on mechanochemistry. Synlett. 2017;**28**:2066-2092. DOI: 10.1055/s-0036-1590854

[4] Muñoz-Batista MJ, Rodriguez-Padron D, Puente-Santiago AR, Luque R. Mechanochemistry: Towards sustainable design of advanced nanomaterials for electrochemical energy storage and catalytic applications. ACS Sustainable Chemistry & Engineering. 2018;**6**:9530-9544. DOI: 10.1021/ acssuschemeng.8b01716

[5] Štrukil V. Mechanochemical organic synthesis: The art of making chemistry green. Synlett. 2018;**29**:1281-1288. DOI: 10.1055/s-0036-1591868

[6] Howard JL, Cao Q, Browne DL. Mechanochemistry as an emerging tool for molecular synthesis: What can it offer? Chemical Science. 2018;**9**:3080- 3094. DOI: 10.1039/c7sc05371a

[7] Andersen J, Mack J. Mechanochemistry and organic synthesis: From mystical to practical. Green Chemistry. 2018;**20**:1435-1443. DOI: 10.1039/C7GC03797J

[8] Tan D, Friščić T. Mechanochemistry for organic chemists: An update. European Journal of Organic

Chemistry. 2018:18-33. DOI: 10.1002/ ejoc.201700961

[9] Tan D, Garcia F. Main group mechanochemistry: From curiosity to established protocols. Chemical Society Reviews. 2019;**48**:2274-2292. DOI: 10.1039/c7cs00813a

[10] Margetić D, Štrukil V. Mechanochemical Organic Synthesis. Amsterdam: Elsevier; 2016. ISBN: 9780128021842

[11] Ranu B, Stolle A, editors. Ball Milling Towards Green Synthesis Applications, Projects, Challenges. RSC Green Chemistry No. 31. Cambridge; 2015. ISBN: 978-1-84973-945-0

[12] Cao Q, Howard JL, Wheatley E, Browne DL. Mechanochemical activation of zinc and application to Negishi cross-coupling. Angewandte Chemie, International Edition. 2018;**57**:11339- 11343. DOI: 10.1002/anie.201806480

[13] Đud M, Magdysyuk OV, Margetić D, Štrukil V. Synthesis of monosubstituted thioureas by vapour digestion and mechanochemical amination of thiocarbamoyl benzotriazoles. Green Chemistry. 2016;**18**:2666-2674. DOI: 10.1039/C6GC00089D

[14] Howard JL, Nicholson W, Sagatov Y, Browne DL. One-pot multistep mechanochemical synthesis of fluorinated pyrazolones. Beilstein Journal of Organic Chemistry. 2017;**13**:1950-1956

[15] Portada T, Margetić D, Štrukil V. Mechanochemical catalytic transfer hydrogenation of aromatic nitro derivatives. Molecules. 2018;**23**:3163- 3180. DOI: 10.3390/molecules23123163

[16] Briš A, Đud M, Margetić D. Mechanochemical *N*-alkylation of imides. Beilstein Journal of Organic Chemistry. 2017;**13**:1745-1752. DOI: 10.3762/bjoc.13.169

[17] Liu H-W, Xu H, Shao G, Wang G-W. Zinc-mediated reductive cyclization of [60] fullerene with enones and subsequent dehydration under solvent-free and ball-milling conditions. Organic Letters. 2019;**21**:2625-2628. DOI: 10.1021/acs.orglett.9b00612

[18] Xu H, Liu H-W, Chen K, Wang G-W. One-pot multicomponent mechanosynthesis of polysubstituted trans-2,3-dihydropyrroles and pyrroles from amines, alkyne esters, and chalcones. The Journal of Organic Chemistry. 2018;**83**:6035-6049. DOI: 10.1021/acs.joc.8b00665

[19] Lupacchini M, Mascitti A, Tonucci L, d'Alessandro N, Colacino E, Charnay C. From molecules to silicon-based biohybrid materials by ball-milling. ACS Sustainable Chemistry & Engineering. 2018;**6**:511-518. DOI: 10.1021/ acssuschemeng.7b02782

[20] Achar TK, Mal P. Transformation of contact-explosives primary amines and iodine(III) into a successful chemical reaction under solvent-free ball milling conditions. Advanced Synthesis and Catalysis. 2015;**357**:3977-3985. DOI: 10.1002/adsc.201500914

[21] Wu Y-H, Li Z-F, Wang W-P, Wang X-C, Quan Z-J. Mechanochemical synthesis of phosphinecarboxamides by reaction of 2-phosphaethynolate anion and amines under acidfree conditions: A combined scope and mechanism investigation. European Journal of Organic Chemistry. 2017;**37**:5546-5553. DOI: 10.1002/ejoc.201700867

[22] Li L, Wang G-W. Solvent-free rhodium(III)-catalyzed synthesis of 2-aminoanilides via C-H amidation of *N*-nitrosoanilines under ball milling conditions. Tetrahedron. 2018;**74**:4188- 4196. DOI: 10.1016/j.tet.2018.06.003

[23] Dokli I, Gredičak M. Mechanochemical Ritter reaction: A rapid approach to functionalized amides at room temperature. European Journal of Organic Chemistry. 2015;**12**:2727-2732

[24] Hermann GN, Becker P, Bolm C. Mechanochemical iridium(III) catalyzed C-H bond amidation of benzamides with sulfonyl azides under solvent-free conditions in a ball mill. Angewandte Chemie, International Edition. 2016;**55**:3781-3784. DOI: 10.1002/anie.201511689

[25] Wróblewska A, Paluch P, Wielgus E, Bujacz G, Dudek MK, Potrzebowski MJ. Approach toward the understanding of coupling mechanism for EDC reagent in solvent-free mechanosynthesis. Organic Letters. 2017;**19**:5360-5363. DOI: 10.1021/acs. orglett.7b02637

[26] Cummings AJ, Ravalico F, McColgan-Bannon KI, Eguaogie O, Elliott PA, Shannon MR, et al. Nucleoside azide-alkyne cycloaddition reactions under solvothermal conditions or using copper vials in a ball mill. Nucleosides Nucleotides and Nucleic Acids. 2015;**34**:361-370. DOI: 10.1080/15257770.2014.1001855

[27] Di Nardo T, Moores A. Mechanochemical amorphization of chitin: Impact of apparatus material on performance and contamination. Beilstein Journal of Organic Chemistry. 2019;**15**:1217.1225. DOI: 10.3762/ bjoc.15.119

[28] Grätz S, Beyer D, Tkachova V, Hellmann S, Berger R, Feng X, et al. The mechanochemical Scholl reaction—A solvent-free and versatile graphitization tool. Chemical Communications. 2018;**54**:5307-5310. DOI: 10.1039/ C8CC01993B

[29] Chen L, Bovee MO, Lemma BE, Keithley KSM, Pilson SL, Coleman MG,

**43**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

> for organic vapors. Beilstein Journal of Organic Chemistry. 2019;**15**:1154-1161.

[36] Su Q, Hamilton TD. Extending mechanochemical porphyrin synthesis to bulkier aromatics: Tetramesitylporphyrin. Beilstein Journal of Organic Chemistry. 2019;**15**:1149-1153. DOI: 10.3762/

[37] Ralphs K, Zhang C, James SL. Solventless mechanochemical metallation of porphyrins. Green Chemistry. 2017;**19**:102-105. DOI:

[38] Atoyebi AO, Brückner C.

Observations on the mechanochemical insertion of zinc(II), copper(II), magnesium(II), and select other metal(II) ions into porphyrins. Inorganic Chemistry. 2019;**58**:9631- 9642. DOI: 10.1021/acs.inorgchem.

[39] Hopgood H, Mack J. An increased understanding of enolate additions under mechanochemical conditions. Molecules. 2017;**22**:696. DOI: 10.3390/

[40] Lou S-J, Mao Y-J, Xu D-Q, He J-Q, Chen Q, Xu Z-Y. Fast and selective dehydrogenative C-H/C-H arylation using mechanochemistry. ACS Catalysis. 2016;**6**:3890-3894. DOI:

[41] Weng Y, Lan T, Sun C, Yang T, Su W, Xie Y. Mechanochemical palladium-

Chemistry Frontiers. 2018;**5**:2103-2107.

[42] Mantovani AC, Hernández JG, Bolm C. Synthesis of 3-iodobenzofurans by electrophilic cyclization under solventless conditions in a ball mill. European Journal of Organic Chemistry.

)-H homocoupling

DOI: 10.3762/bjoc.15.112

bjoc.15.111

9b00052

10.1039/c6gc02420c

molecules22050696

10.1021/acscatal.6b00861

DOI: 10.1039/c8qo00420j

of *N*-arylcarbamates: Synthesis of 2,2′-biaryldiamine. Organic

catalyzed C(sp2

et al. An inexpensive and recyclable

[30] Chen L, Leslie D, Coleman MG, Mack J. Recyclable heterogeneous metal foil-catalyzed cyclopropenation of alkynes and diazoacetates under solvent-free mechanochemical

reaction conditions. Chemical Science. 2018;**9**:4650-4661. DOI: 10.1039/

[31] Haley RA, Zellner AR, Krause JA, Guan H, Mack J. Nickel catalysis in a high speed ball mill: A recyclable mechanochemical method for

producing substituted cyclooctatetraene compounds. ACS Sustainable Chemistry & Engineering. 2016;**4**:2464-2469

[32] Sawama Y, Kawajiri T, Niikawa M, Goto R, Yabe Y, Takahashi T, et al. Stainless-steel ball-milling method for hydro−/deuterogenation using H2O/ D2O as a hydrogen/deuterium source. ChemSusChem. 2015;**8**:3773-3776. DOI:

[33] Sawama Y, Yasukawa N, Ban K, Goto R, Niikawa M, Monguchi Y, et al. Stainless steel-mediated hydrogen generation from alkanes and diethyl ether and its application for arene reduction. Organic Letters. 2018;**20**:2892-2896. DOI: 10.1021/acs.

[34] Đud M, Briš A, Jušinski I, Gracin D, Margetić D. Mechanochemical Friedel-Crafts acylations. Beilstein Journal of Organic Chemistry. 2019;**15**:1313-1320.

10.1002/cssc.201501019

orglett.8b00931

DOI: 10.3762/bjoc.15.130

[35] Grätz S, Zink S, Kraffczyk H, Rose M, Borchardt L. Mechanochemical

synthesis of hyper-crosslinked polymers: Influences on their pore structure and adsorption behaviour

cyclopropanation of alkenes with diazoacetates under mechanochemical condition. Angewandte Chemie, International Edition. 2015;**54**:11084- 11087. DOI: 10.1002/anie.201504236

silver-foil catalyst for the

c8sc00443a

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

et al. An inexpensive and recyclable silver-foil catalyst for the cyclopropanation of alkenes with diazoacetates under mechanochemical condition. Angewandte Chemie, International Edition. 2015;**54**:11084- 11087. DOI: 10.1002/anie.201504236

*Organic Synthesis - A Nascent Relook*

10.3762/bjoc.13.169

Chemistry. 2017;**13**:1745-1752. DOI:

[23] Dokli I, Gredičak M.

2015;**12**:2727-2732

10.1002/anie.201511689

orglett.7b02637

[25] Wróblewska A, Paluch P, Wielgus E, Bujacz G, Dudek MK, Potrzebowski MJ. Approach toward the understanding of coupling mechanism

for EDC reagent in solvent-free mechanosynthesis. Organic Letters. 2017;**19**:5360-5363. DOI: 10.1021/acs.

[26] Cummings AJ, Ravalico F, McColgan-Bannon KI, Eguaogie O, Elliott PA, Shannon MR, et al. Nucleoside azide-alkyne cycloaddition reactions under solvothermal conditions or using copper vials in a ball mill. Nucleosides Nucleotides and Nucleic Acids. 2015;**34**:361-370. DOI: 10.1080/15257770.2014.1001855

[27] Di Nardo T, Moores A.

Mechanochemical amorphization of chitin: Impact of apparatus material on performance and contamination. Beilstein Journal of Organic Chemistry.

2019;**15**:1217.1225. DOI: 10.3762/

[28] Grätz S, Beyer D, Tkachova V, Hellmann S, Berger R, Feng X, et al. The mechanochemical Scholl reaction—A solvent-free and versatile graphitization tool. Chemical Communications. 2018;**54**:5307-5310. DOI: 10.1039/

[29] Chen L, Bovee MO, Lemma BE, Keithley KSM, Pilson SL, Coleman MG,

bjoc.15.119

C8CC01993B

Mechanochemical Ritter reaction: A rapid approach to functionalized amides at room temperature. European

[24] Hermann GN, Becker P, Bolm C. Mechanochemical iridium(III) catalyzed C-H bond amidation of benzamides with sulfonyl azides under solvent-free conditions in a ball mill. Angewandte Chemie, International Edition. 2016;**55**:3781-3784. DOI:

Journal of Organic Chemistry.

[17] Liu H-W, Xu H, Shao G, Wang G-W. Zinc-mediated reductive

[18] Xu H, Liu H-W, Chen K, Wang G-W. One-pot multicomponent mechanosynthesis of polysubstituted trans-2,3-dihydropyrroles and pyrroles from amines, alkyne esters, and chalcones. The Journal of Organic Chemistry. 2018;**83**:6035-6049. DOI:

10.1021/acs.joc.8b00665

10.1002/adsc.201500914

DOI: 10.1002/ejoc.201700867

[22] Li L, Wang G-W. Solvent-free rhodium(III)-catalyzed synthesis of 2-aminoanilides via C-H amidation of *N*-nitrosoanilines under ball milling conditions. Tetrahedron. 2018;**74**:4188- 4196. DOI: 10.1016/j.tet.2018.06.003

[19] Lupacchini M, Mascitti A,

Charnay C. From molecules to silicon-based biohybrid materials by ball-milling. ACS Sustainable Chemistry & Engineering. 2018;**6**:511-518. DOI: 10.1021/ acssuschemeng.7b02782

Tonucci L, d'Alessandro N, Colacino E,

[20] Achar TK, Mal P. Transformation of contact-explosives primary amines and iodine(III) into a successful chemical reaction under solvent-free ball milling conditions. Advanced Synthesis and Catalysis. 2015;**357**:3977-3985. DOI:

[21] Wu Y-H, Li Z-F, Wang W-P, Wang X-C, Quan Z-J. Mechanochemical synthesis of phosphinecarboxamides by reaction of 2-phosphaethynolate anion and amines under acidfree conditions: A combined scope and mechanism investigation. European Journal of Organic Chemistry. 2017;**37**:5546-5553.

cyclization of [60] fullerene with enones and subsequent dehydration under solvent-free and ball-milling conditions. Organic Letters. 2019;**21**:2625-2628. DOI: 10.1021/acs.orglett.9b00612

**42**

[30] Chen L, Leslie D, Coleman MG, Mack J. Recyclable heterogeneous metal foil-catalyzed cyclopropenation of alkynes and diazoacetates under solvent-free mechanochemical reaction conditions. Chemical Science. 2018;**9**:4650-4661. DOI: 10.1039/ c8sc00443a

[31] Haley RA, Zellner AR, Krause JA, Guan H, Mack J. Nickel catalysis in a high speed ball mill: A recyclable mechanochemical method for producing substituted cyclooctatetraene compounds. ACS Sustainable Chemistry & Engineering. 2016;**4**:2464-2469

[32] Sawama Y, Kawajiri T, Niikawa M, Goto R, Yabe Y, Takahashi T, et al. Stainless-steel ball-milling method for hydro−/deuterogenation using H2O/ D2O as a hydrogen/deuterium source. ChemSusChem. 2015;**8**:3773-3776. DOI: 10.1002/cssc.201501019

[33] Sawama Y, Yasukawa N, Ban K, Goto R, Niikawa M, Monguchi Y, et al. Stainless steel-mediated hydrogen generation from alkanes and diethyl ether and its application for arene reduction. Organic Letters. 2018;**20**:2892-2896. DOI: 10.1021/acs. orglett.8b00931

[34] Đud M, Briš A, Jušinski I, Gracin D, Margetić D. Mechanochemical Friedel-Crafts acylations. Beilstein Journal of Organic Chemistry. 2019;**15**:1313-1320. DOI: 10.3762/bjoc.15.130

[35] Grätz S, Zink S, Kraffczyk H, Rose M, Borchardt L. Mechanochemical synthesis of hyper-crosslinked polymers: Influences on their pore structure and adsorption behaviour

for organic vapors. Beilstein Journal of Organic Chemistry. 2019;**15**:1154-1161. DOI: 10.3762/bjoc.15.112

[36] Su Q, Hamilton TD. Extending mechanochemical porphyrin synthesis to bulkier aromatics: Tetramesitylporphyrin. Beilstein Journal of Organic Chemistry. 2019;**15**:1149-1153. DOI: 10.3762/ bjoc.15.111

[37] Ralphs K, Zhang C, James SL. Solventless mechanochemical metallation of porphyrins. Green Chemistry. 2017;**19**:102-105. DOI: 10.1039/c6gc02420c

[38] Atoyebi AO, Brückner C. Observations on the mechanochemical insertion of zinc(II), copper(II), magnesium(II), and select other metal(II) ions into porphyrins. Inorganic Chemistry. 2019;**58**:9631- 9642. DOI: 10.1021/acs.inorgchem. 9b00052

[39] Hopgood H, Mack J. An increased understanding of enolate additions under mechanochemical conditions. Molecules. 2017;**22**:696. DOI: 10.3390/ molecules22050696

[40] Lou S-J, Mao Y-J, Xu D-Q, He J-Q, Chen Q, Xu Z-Y. Fast and selective dehydrogenative C-H/C-H arylation using mechanochemistry. ACS Catalysis. 2016;**6**:3890-3894. DOI: 10.1021/acscatal.6b00861

[41] Weng Y, Lan T, Sun C, Yang T, Su W, Xie Y. Mechanochemical palladiumcatalyzed C(sp2 )-H homocoupling of *N*-arylcarbamates: Synthesis of 2,2′-biaryldiamine. Organic Chemistry Frontiers. 2018;**5**:2103-2107. DOI: 10.1039/c8qo00420j

[42] Mantovani AC, Hernández JG, Bolm C. Synthesis of 3-iodobenzofurans by electrophilic cyclization under solventless conditions in a ball mill. European Journal of Organic Chemistry. 2018:2458-2461. DOI: 10.1002/ ejoc.201800027

[43] Lagoviyer OS, Krishtopa L, Schoenitz M, Trivedi NJ, Dreizin EL. Mechanochemical nitration of aromatic compounds. Journal of Energetic Materials. 2017;**36**:191-201. DOI: 10.1080/07370652.2017.1343407

[44] Guo F-C, Ji M-Z, Zhang P, Guo Z-X. Facile nitration of aromatic compounds using Bi(NO3)3·5H2O/ MgSO4 under mechanochemical conditions. Green Processing and Synthesis. 2017;**7**:453-459. DOI: 10.1515/ gps-2017-0069

[45] Ji M-Z, Guo F-C, Zhang P, Guo Z-X. The mechanochemical reaction of C60 and Bi(NO3)3·5H2O. Fullerenes, Nanotubes, and Carbon Nanostructures. 2018;**26**:487-490. DOI: 10.1080/1536383X.2018.1449746

[46] Đud M, Glasovac Z, Margetić D. The utilization of ball-milling in synthesis of aryl guanidines through guanidinylation and *N*-Boc-deprotection sequence. Tetrahedron. 2019;**75**:109-115. DOI: 10.1016/j.tet.2018.11.038

[47] Đud M, Margetić D. Solvent-free mechanochemical deprotection of *N*-Boc group. International Journal of Organic Chemistry. 2017;**7**:140-144. DOI: 10.4236/ijoc.2017.72011

[48] Awalt JK, Scammells PJ, Singer RD. Liquid assisted grinding (LAG) for the *N*-demethylation of alkaloids. ACS Sustainable Chemistry & Engineering. 2018;**6**:10052-10057. DOI: 10.1021/ acssuschemeng.8b01393

[49] Hernández JG, Turberg M, Schiffers I, Bolm C. Mechanochemical Strecker reaction: Access to α-aminonitriles and tetrahydroisoquinolines under ball milling conditions. Chemistry—A

European Journal. 2016;**22**:14513-14517. DOI: 10.1002/chem.201603057

[50] Bolm C, Mocci R, Schumacher C, Turberg M, Puccetti F, Hernández JG. Mechanochemical activation of iron cyano complexes: A prebiotic impact scenario for the synthesis of α-amino acid derivatives. Angewandte Chemie, International Edition. 2018;**57**:2423- 2426. DOI: 10.1002/anie.201713109

[51] Shao Q-L, Jiang Z-J, Su W-K. Solvent-free mechanochemical Buchwald-Hartwig amination of aryl chlorides without inert gas protection. Tetrahedron Letters. 2018;**59**:2277-2280. DOI: 10.1016/j.tetlet.2018.04.078

[52] Cao Q, Nicholson WI, Jones AC, Browne DL. Robust Buchwald-Hartwig amination enabled by ball-milling. Organic & Biomolecular Chemistry. 2019;**17**:1722-1726. DOI: 10.1039/ c8ob01781f

[53] Kubota K, Seo T, Koide K, Hasegawa Y, Ito H. Olefin-accelerated solid-state C-N cross-coupling reactions using mechanochemistry. Nature Communications. 2019;**10**:111

[54] Xu H, Chen K, Liu H-W, Wang G-W. Solvent-free *N*-iodosuccinimidepromoted synthesis of spiroimidazolines from alkenes and amidines under ball-milling conditions. Organic Chemistry Frontiers. 2018;**5**:2864-2869. DOI: 10.1039/c8qo00723c

[55] Mocci R, Murgia S, De Luca L, Colacino E, Delogu F, Porcheddu A. Ballmilling and cheap reagents breathe green life into the one hundredyear-old Hofmann reaction. Organic Chemistry Frontiers. 2018;**5**:531-538. DOI: 10.1039/C7QO01006K

[56] Weißbach U, Dabral S, Konnert L, Bolm C, Hernández JG. Selective enzymatic esterification of lignin model compounds in the ball mill. Beilstein Journal of Organic Chemistry.

**45**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

cross-coupling reaction of

DOI: 10.1021/acs.joc.6b00786

10.1002/chem.201805924

c5ob02061a

[65] Eguaogie O, Cooke LA,

[64] Appy L, Depaix A, Bantreil X, Lamaty F, Peyrottes S, Roy B. Straightforward ball-milling access to dinucleoside 5′,5′-polyphosphates through phosphorimidazolide

intermediates. Chemistry—A European Journal. 2019;**35**:2477-2481. DOI:

Martin PML, Ravalico F, Conway LP, Hodgson DRW, et al. Synthesis of novel pyrophosphorothiolate-linked dinucleoside cap analogues in a ball mill. Organic & Biomolecular Chemistry. 2016;**14**:1201-1205. DOI: 10.1039/

[66] Pang Y, Ishiyama T, Kubota K, Ito H. Iridium(I)-catalyzed C-H borylation in air using

mechanochemistry. Chemistry—A European Journal. 2019;**25**:4654-4659.

[67] Kumar R, Kumar S, Pandey MK,

Balakrishna MS. Synthesis of phosphinechalcogenides under solvent-free conditions using rotary ball mill. European Journal of Inorganic Chemistry. 2018:1028-1037. DOI:

[68] Wang Y, Wang H, Jiang Y, Zhang C, Shao J, Xu D. Fast, solvent-free and highly enantioselective fluorination of β-keto esters catalyzed by chiral copper complexes in a ball mill. Green Chemistry. 2017;**19**:1674-1677. DOI:

[69] Sánchez-Chávez AC, Mendoza-Figueroa HL, Oliveros-Cruz S, Torres-Cardona MD, Luján-Montelongo JA, Polindara-García LA. "Eco-friendly"

DOI: 10.1002/chem.201900685

Kashid VS, Radhakrishna L,

10.1002/ejic.201701414

10.1039/C6GC03306G

Benzothiazole/Thiazole derivatives with organophosphorus compounds under ball-milling conditions. The Journal of Organic Chemistry. 2016;**81**:5433-5439.

2017;**13**:1788-1795. DOI: 10.3762/

[57] Hernández JG, Ardila-Fierro KJ, Crawford D, James SL, Bolm C.

Mechanoenzymatic peptide and amide bond formation. Green Chemistry. 2017;**19**:2620-2625. DOI: 10.1039/

[58] Pérez-Venegas M, Reyes-Rangel G,

Mechanochemical enzymatic resolution

Beilstein Journal of Organic Chemistry. 2017;**13**:1728-1734. DOI: 10.3762/

[59] Hammerer F, Loots L, Do J-L, Therien JPD, Nickels CW, Friščić T, et al. Solvent-free enzyme activity: Quick, high-yielding mechanoenzymatic hydrolysis of cellulose into glucose. Angewandte Chemie, International Edition. 2018;**57**:2621-2624. DOI:

[60] Hernández JG, Frings M, Bolm C. Mechanochemical enzymatic kinetic resolution of secondary alcohols under ball-milling conditions. ChemCatChem.

2016;**8**:1769-1772. DOI: 10.1002/

[61] Pérez-Venegas M, Juaristi E. Mechanoenzymatic resolution of

racemic chiral amines, a green technique for the synthesis of pharmaceutical building blocks. Tetrahedron. 2018;**74**:6453-6458. DOI: 10.1016/j.

[62] Li AY, Segalla A, Li C-J, Moores A. Mechanochemical metal-free transfer hydrogenation of carbonyls using polymethylhydrosiloxane as hydrogen source. ACS Sustainable Chemistry & Engineering. 2017;**5**:11752-11760. DOI: 10.1021/

10.1002/anie.201711643

cctc.201600455

tet.2018.09.029

acssuschemeng.7b03298

[63] Li L, Wang J-J, Wang G-W. Manganese(III) acetate-promoted


Neri A, Escalante J, Juaristi E.

bjoc.13.173

c7gc00615b

bjoc.13.167

of *N*-benzylated-β<sup>3</sup>

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

2017;**13**:1788-1795. DOI: 10.3762/ bjoc.13.173

*Organic Synthesis - A Nascent Relook*

2018:2458-2461. DOI: 10.1002/

European Journal. 2016;**22**:14513-14517.

[50] Bolm C, Mocci R, Schumacher C, Turberg M, Puccetti F, Hernández JG. Mechanochemical activation of iron cyano complexes: A prebiotic impact scenario for the synthesis of α-amino acid derivatives. Angewandte Chemie, International Edition. 2018;**57**:2423- 2426. DOI: 10.1002/anie.201713109

DOI: 10.1002/chem.201603057

[51] Shao Q-L, Jiang Z-J, Su W-K. Solvent-free mechanochemical Buchwald-Hartwig amination of aryl chlorides without inert gas protection. Tetrahedron Letters. 2018;**59**:2277-2280.

DOI: 10.1016/j.tetlet.2018.04.078

[53] Kubota K, Seo T, Koide K,

Hasegawa Y, Ito H. Olefin-accelerated solid-state C-N cross-coupling reactions using mechanochemistry. Nature Communications. 2019;**10**:111

[54] Xu H, Chen K, Liu H-W, Wang G-W. Solvent-free *N*-iodosuccinimidepromoted synthesis of spiroimidazolines from alkenes and amidines under ball-milling conditions. Organic

Chemistry Frontiers. 2018;**5**:2864-2869.

[55] Mocci R, Murgia S, De Luca L, Colacino E, Delogu F, Porcheddu A. Ballmilling and cheap reagents breathe green life into the one hundredyear-old Hofmann reaction. Organic Chemistry Frontiers. 2018;**5**:531-538.

[56] Weißbach U, Dabral S, Konnert L, Bolm C, Hernández JG. Selective enzymatic esterification of lignin model compounds in the ball mill. Beilstein Journal of Organic Chemistry.

DOI: 10.1039/c8qo00723c

DOI: 10.1039/C7QO01006K

c8ob01781f

[52] Cao Q, Nicholson WI, Jones AC, Browne DL. Robust Buchwald-Hartwig amination enabled by ball-milling. Organic & Biomolecular Chemistry. 2019;**17**:1722-1726. DOI: 10.1039/

[43] Lagoviyer OS, Krishtopa L, Schoenitz M, Trivedi NJ, Dreizin EL. Mechanochemical nitration of aromatic compounds. Journal of Energetic Materials. 2017;**36**:191-201. DOI: 10.1080/07370652.2017.1343407

[44] Guo F-C, Ji M-Z, Zhang P, Guo Z-X. Facile nitration of aromatic compounds using Bi(NO3)3·5H2O/ MgSO4 under mechanochemical conditions. Green Processing and Synthesis. 2017;**7**:453-459. DOI: 10.1515/

[45] Ji M-Z, Guo F-C, Zhang P, Guo Z-X. The mechanochemical reaction of C60 and Bi(NO3)3·5H2O. Fullerenes,

[46] Đud M, Glasovac Z, Margetić D. The utilization of ball-milling in synthesis of aryl guanidines through guanidinylation and *N*-Boc-deprotection sequence. Tetrahedron. 2019;**75**:109-115. DOI:

[47] Đud M, Margetić D. Solvent-free mechanochemical deprotection of *N*-Boc group. International Journal of Organic Chemistry. 2017;**7**:140-144.

Nanotubes, and Carbon Nanostructures. 2018;**26**:487-490. DOI: 10.1080/1536383X.2018.1449746

10.1016/j.tet.2018.11.038

DOI: 10.4236/ijoc.2017.72011

[48] Awalt JK, Scammells PJ, Singer RD. Liquid assisted grinding (LAG) for the *N*-demethylation of alkaloids. ACS Sustainable Chemistry & Engineering. 2018;**6**:10052-10057. DOI: 10.1021/

acssuschemeng.8b01393

Strecker reaction: Access to α-aminonitriles and

[49] Hernández JG, Turberg M, Schiffers I, Bolm C. Mechanochemical

tetrahydroisoquinolines under ball milling conditions. Chemistry—A

ejoc.201800027

gps-2017-0069

**44**

[57] Hernández JG, Ardila-Fierro KJ, Crawford D, James SL, Bolm C. Mechanoenzymatic peptide and amide bond formation. Green Chemistry. 2017;**19**:2620-2625. DOI: 10.1039/ c7gc00615b

[58] Pérez-Venegas M, Reyes-Rangel G, Neri A, Escalante J, Juaristi E. Mechanochemical enzymatic resolution of *N*-benzylated-β<sup>3</sup> -amino esters. Beilstein Journal of Organic Chemistry. 2017;**13**:1728-1734. DOI: 10.3762/ bjoc.13.167

[59] Hammerer F, Loots L, Do J-L, Therien JPD, Nickels CW, Friščić T, et al. Solvent-free enzyme activity: Quick, high-yielding mechanoenzymatic hydrolysis of cellulose into glucose. Angewandte Chemie, International Edition. 2018;**57**:2621-2624. DOI: 10.1002/anie.201711643

[60] Hernández JG, Frings M, Bolm C. Mechanochemical enzymatic kinetic resolution of secondary alcohols under ball-milling conditions. ChemCatChem. 2016;**8**:1769-1772. DOI: 10.1002/ cctc.201600455

[61] Pérez-Venegas M, Juaristi E. Mechanoenzymatic resolution of racemic chiral amines, a green technique for the synthesis of pharmaceutical building blocks. Tetrahedron. 2018;**74**:6453-6458. DOI: 10.1016/j. tet.2018.09.029

[62] Li AY, Segalla A, Li C-J, Moores A. Mechanochemical metal-free transfer hydrogenation of carbonyls using polymethylhydrosiloxane as hydrogen source. ACS Sustainable Chemistry & Engineering. 2017;**5**:11752-11760. DOI: 10.1021/ acssuschemeng.7b03298

[63] Li L, Wang J-J, Wang G-W. Manganese(III) acetate-promoted cross-coupling reaction of Benzothiazole/Thiazole derivatives with organophosphorus compounds under ball-milling conditions. The Journal of Organic Chemistry. 2016;**81**:5433-5439. DOI: 10.1021/acs.joc.6b00786

[64] Appy L, Depaix A, Bantreil X, Lamaty F, Peyrottes S, Roy B. Straightforward ball-milling access to dinucleoside 5′,5′-polyphosphates through phosphorimidazolide intermediates. Chemistry—A European Journal. 2019;**35**:2477-2481. DOI: 10.1002/chem.201805924

[65] Eguaogie O, Cooke LA, Martin PML, Ravalico F, Conway LP, Hodgson DRW, et al. Synthesis of novel pyrophosphorothiolate-linked dinucleoside cap analogues in a ball mill. Organic & Biomolecular Chemistry. 2016;**14**:1201-1205. DOI: 10.1039/ c5ob02061a

[66] Pang Y, Ishiyama T, Kubota K, Ito H. Iridium(I)-catalyzed C-H borylation in air using mechanochemistry. Chemistry—A European Journal. 2019;**25**:4654-4659. DOI: 10.1002/chem.201900685

[67] Kumar R, Kumar S, Pandey MK, Kashid VS, Radhakrishna L, Balakrishna MS. Synthesis of phosphinechalcogenides under solvent-free conditions using rotary ball mill. European Journal of Inorganic Chemistry. 2018:1028-1037. DOI: 10.1002/ejic.201701414

[68] Wang Y, Wang H, Jiang Y, Zhang C, Shao J, Xu D. Fast, solvent-free and highly enantioselective fluorination of β-keto esters catalyzed by chiral copper complexes in a ball mill. Green Chemistry. 2017;**19**:1674-1677. DOI: 10.1039/C6GC03306G

[69] Sánchez-Chávez AC, Mendoza-Figueroa HL, Oliveros-Cruz S, Torres-Cardona MD, Luján-Montelongo JA, Polindara-García LA. "Eco-friendly"

epimerization of lutein to 3'-epilutein under solvent free mechanochemical conditions by using a strongly acidic cation-exchange resin. European Journal of Organic Chemistry. 2018:3202-3210. DOI: 10.1002/ejoc.201800244

[70] Andersen JM, Mack J. Decoupling the Arrhenius equation *via* mechanochemistry. Chemical Science. 2017;**8**:5447-5453. DOI: 10.1039/ c7sc00538e

[71] Mojzesová M, Mečiarová M, Almássy A, Marti R, Šebesta R. Assessment of non-standard reaction conditions for asymmetric 1,3-dipolar organocatalytic cycloaddition of nitrone with α,β-unsaturated aldehydes. Chemical Papers. 2015;**69**:737-746. DOI: 10.1515/chempap-2015-0020

[72] Xu H, Fan G-P, Liu Z, Wang G-W. Catalyst- and solvent-free mechanochemical synthesis of isoxazoles from *N*-hydroxybenzimidoyl chlorides and enamino carbonyl compounds. Tetrahedron. 2018;**45**:6607-6611. DOI: 10.1016/j. tet.2018.09.044

[73] Chacón-Huete F, Messina C, Chen F, Cuccia L, Ottenwaelder X, Forgione P. Solvent-free mechanochemical oxidation and reduction of biomass-derived 5-hydroxymethyl furfural. Green Chemistry. 2018;**20**:5261-5265. DOI: 10.1039/c8gc02481b

[74] Dabral S, Wotruba H, Hernández JG, Bolm C. Mechanochemical oxidation and cleavage of lignin β-O-4 model compounds and lignin. ACS Sustainable Chemistry & Engineering. 2018;**6**:3242-3254. DOI: 10.1021/ acssuschemeng.7b03418

[75] Mousavi H, Zeynizadeh B, Younesi R, Esmati M. Simple and practical synthesis of various new nickel boride-based nanocomposites and their applications for the green and expeditious reduction of nitroarenes to arylamines under wet-solvent-free mechanochemical grinding. Australian Journal of Chemistry. 2018;**71**:595-609. DOI: 10.1071/CH18200

[76] Menuel S, Léger B, Addad A, Monflier E, Hapiot F. Cyclodextrins as effective additives in AuNPs-catalyzed reduction of nitrobenzene derivatives in a ball-mill. Green Chemistry. 2016;**18**:5500-5509. DOI: 10.1039/ C6GC00770H

[77] Khaligh NG, Ling OC, Mihankhah T, Johan MR, Ching JJ. Mechanosynthesis of *N*-methyl imines using recyclable imidazole-based acid-scavenger: In situ formed ionic liquid as catalyst and dehydrating agent. Australian Journal of Chemistry. 2018;**72**:194-199. DOI: 10.1071/CH18408

[78] Khaligh NG, Mihankhah T, Johan MR. Synthesis of new low-viscous sulfonic acid-functionalized ionic liquid and its application as a Brönsted liquid acid catalyst for the one-pot mechanosynthesis of 4*H*-pyrans through the ball milling process. Journal of Molecular Liquids. 2019;**277**:794-804. DOI: 10.1016/j.molliq.2019.01.024

[79] Kumar S, Mukhopadhyay P. Ambient stable naphthalenediimide radical ions: Synthesis by solvent-free, sonication, mechanical grinding or milling protocols. Green Chemistry. 2018;**20**:4620-4628. DOI: 10.1039/ c8gc01614c

[80] Doi N, Sasai Y, Yamauchi Y, Adachi T, Kuzuya M, Kondo S. Kinetic analysis of mechanoradical formation during the mechanolysis of dextran and glycogen. Beilstein Journal of Organic Chemistry. 2017;**13**:1174-1183. DOI: 10.3762/bjoc.13.116

[81] Ku M-J, Huang S-J, Huang S-L, Liu Y-H, Lai C-C, Peng S-M, et al. Hemicarceplex formation allows ready identification of the isomers of the

**47**

jacs.8b09608

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

H

Mechanochemical solvent-free

2019:3401-3405. DOI: 10.1002/

[88] Stojaković J, Farris BS,

ejoc.201900153

c2cc33227b

conditions for the synthesis of pillar[5] arene-containing [2]rotaxanes.

European Journal of Organic Chemistry.

MacGillivray LR. Vortex grinding for mechanochemistry: Application for automated supramolecular catalysis and preparation of a metal-organic framework. Chemical Communications. 2012;**48**:7958-7960. DOI: 10.1039/

[89] Obst M, König B. Solvent-free, visible-light photocatalytic alcohol oxidations applying an organic photocatalyst. Beilstein Journal of Organic Chemistry. 2016;**12**:2358-2363.

[90] Obst M, Shaikh RS, König B. Solvent-free coupling of aryl halides with pyrroles applying visiblelight photocatalysis. Reaction

478. DOI: 10.1039/c6re00220j

[91] Štrukil V, Sajko I.

DOI: 10.1039/c7cc03510a

10.1038/nchem.1505

bjoc.13.144

[92] Friščić T, Halasz I, Beldon PJ, Belenguer AM, Adams F, Kimber SAJ, et al. Real-time and in situ monitoring of mechanochemical milling reactions. Nature Chemistry. 2013;**5**:66-73. DOI:

[93] Hernández JG. Mechanochemical borylation of aryldiazonium salts; merging light and ball milling.

Beilstein Journal of Organic Chemistry. 2017;**13**:1463-1469. DOI: 10.3762/

[94] Martina K, Rotolo L, Porcheddu A, Delogu F, Bysouth SR, Cravotto G, et al. High throughput mechanochemistry:

Chemistry & Engineering. 2017;**2**:472-

Mechanochemically-assisted solid-state photocatalysis (MASSPC). Chemical Communications. 2017;**53**:9101-9104.

DOI: 10.3762/bjoc.12.229

metallofullerene Sc3N@C80 using 1

[83] Rinaldi L, Binello A, Stolle A, Curini M, Cravotto C. Efficient mechanochemical complexation of various steroid compounds with α-, β- and γ-cyclodextrin. Steroids. 2015;**98**:58-62. DOI: 10.1016/j.

[84] Fumić F, Jablan J, Cinčić D, Zovko Končić M, Jug M. Cyclodextrin

encapsulation of daidzein and genistein by grinding: Implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts. Journal of

10.1080/02652048.2017.1409819

[85] Glembockyte V, Frenette M, Mottillo C, Durantini AM, Gostick J, Štrukil V, et al. Highly photostable and fluorescent microporous solids prepared via solid-state entrapment of boron dipyrromethene dyes in a nascent metal-organic framework. Journal of the American Chemical Society. 2018;**140**:16882-16887. DOI: 10.1021/

Microencapsulation. 2018;**35**:1-12. DOI:

[86] Kaabel S, Stein RS, Fomitšenko M,

Järving I, Friščić T, Aav R. Sizecontrol by anion templating in mechanochemical synthesis of hemicucurbiturils in the solid state. Angewandte Chemie, International Edition. 2019;**58**:6230-6234. DOI:

[87] Holler M, Stoerkler T, Louis A,

10.1002/anie.201813431

Fischer F, Nierengarten J-F.

DOI: 10.1039/c4cc04695a

c7sc03821f

steroids.2015.02.016

and 13C NMR spectroscopy. Chemical Communications. 2014;**50**:11709-11712.

[82] Journey SN, Teppang KL, Garcia CA, Brim SA, Onofrei D, Addison JB, et al. Mechanically induced pyrogallol[4] arene hexamer assembly in the solid state extends the scope of molecular encapsulation. Chemical Science. 2017;**8**:7737-7745. DOI: 10.1039/

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

metallofullerene Sc3N@C80 using 1 H and 13C NMR spectroscopy. Chemical Communications. 2014;**50**:11709-11712. DOI: 10.1039/c4cc04695a

*Organic Synthesis - A Nascent Relook*

DOI: 10.1002/ejoc.201800244

the Arrhenius equation *via*

c7sc00538e

epimerization of lutein to 3'-epilutein under solvent free mechanochemical conditions by using a strongly acidic cation-exchange resin. European Journal of Organic Chemistry. 2018:3202-3210.

expeditious reduction of nitroarenes to arylamines under wet-solvent-free mechanochemical grinding. Australian Journal of Chemistry. 2018;**71**:595-609.

[76] Menuel S, Léger B, Addad A, Monflier E, Hapiot F. Cyclodextrins as effective additives in AuNPs-catalyzed reduction of nitrobenzene derivatives in a ball-mill. Green Chemistry. 2016;**18**:5500-5509. DOI: 10.1039/

DOI: 10.1071/CH18200

[77] Khaligh NG, Ling OC,

Mihankhah T, Johan MR, Ching JJ. Mechanosynthesis of *N*-methyl imines using recyclable imidazole-based acid-scavenger: In situ formed ionic liquid as catalyst and dehydrating agent. Australian Journal of Chemistry. 2018;**72**:194-199. DOI: 10.1071/CH18408

[78] Khaligh NG, Mihankhah T,

Johan MR. Synthesis of new low-viscous sulfonic acid-functionalized ionic liquid and its application as a Brönsted liquid acid catalyst for the one-pot mechanosynthesis of 4*H*-pyrans

through the ball milling process. Journal of Molecular Liquids. 2019;**277**:794-804. DOI: 10.1016/j.molliq.2019.01.024

[79] Kumar S, Mukhopadhyay P. Ambient stable naphthalenediimide radical ions: Synthesis by solvent-free, sonication, mechanical grinding or milling protocols. Green Chemistry. 2018;**20**:4620-4628. DOI: 10.1039/

[80] Doi N, Sasai Y, Yamauchi Y, Adachi T, Kuzuya M, Kondo S. Kinetic analysis of mechanoradical formation during the mechanolysis of dextran and glycogen. Beilstein Journal of Organic Chemistry. 2017;**13**:1174-1183. DOI:

[81] Ku M-J, Huang S-J, Huang S-L, Liu Y-H, Lai C-C, Peng S-M, et al. Hemicarceplex formation allows ready identification of the isomers of the

C6GC00770H

c8gc01614c

10.3762/bjoc.13.116

[70] Andersen JM, Mack J. Decoupling

mechanochemistry. Chemical Science. 2017;**8**:5447-5453. DOI: 10.1039/

nitrone with α,β-unsaturated aldehydes. Chemical Papers. 2015;**69**:737-746. DOI:

[72] Xu H, Fan G-P, Liu Z, Wang G-W.

isoxazoles from *N*-hydroxybenzimidoyl

chlorides and enamino carbonyl compounds. Tetrahedron.

2018;**45**:6607-6611. DOI: 10.1016/j.

[73] Chacón-Huete F, Messina C, Chen F, Cuccia L, Ottenwaelder X,

mechanochemical oxidation and reduction of biomass-derived 5-hydroxymethyl furfural. Green Chemistry. 2018;**20**:5261-5265. DOI:

[74] Dabral S, Wotruba H, Hernández JG, Bolm C. Mechanochemical oxidation

Forgione P. Solvent-free

10.1039/c8gc02481b

and cleavage of lignin β-O-4 model compounds and lignin. ACS Sustainable Chemistry & Engineering. 2018;**6**:3242-3254. DOI: 10.1021/

acssuschemeng.7b03418

[75] Mousavi H, Zeynizadeh B, Younesi R, Esmati M. Simple and practical synthesis of various new nickel boride-based nanocomposites and their applications for the green and

[71] Mojzesová M, Mečiarová M, Almássy A, Marti R, Šebesta R. Assessment of non-standard reaction conditions for asymmetric 1,3-dipolar organocatalytic cycloaddition of

10.1515/chempap-2015-0020

Catalyst- and solvent-free mechanochemical synthesis of

tet.2018.09.044

**46**

[82] Journey SN, Teppang KL, Garcia CA, Brim SA, Onofrei D, Addison JB, et al. Mechanically induced pyrogallol[4] arene hexamer assembly in the solid state extends the scope of molecular encapsulation. Chemical Science. 2017;**8**:7737-7745. DOI: 10.1039/ c7sc03821f

[83] Rinaldi L, Binello A, Stolle A, Curini M, Cravotto C. Efficient mechanochemical complexation of various steroid compounds with α-, β- and γ-cyclodextrin. Steroids. 2015;**98**:58-62. DOI: 10.1016/j. steroids.2015.02.016

[84] Fumić F, Jablan J, Cinčić D, Zovko Končić M, Jug M. Cyclodextrin encapsulation of daidzein and genistein by grinding: Implication on the glycosaminoglycan accumulation in mucopolysaccharidosis type II and III fibroblasts. Journal of Microencapsulation. 2018;**35**:1-12. DOI: 10.1080/02652048.2017.1409819

[85] Glembockyte V, Frenette M, Mottillo C, Durantini AM, Gostick J, Štrukil V, et al. Highly photostable and fluorescent microporous solids prepared via solid-state entrapment of boron dipyrromethene dyes in a nascent metal-organic framework. Journal of the American Chemical Society. 2018;**140**:16882-16887. DOI: 10.1021/ jacs.8b09608

[86] Kaabel S, Stein RS, Fomitšenko M, Järving I, Friščić T, Aav R. Sizecontrol by anion templating in mechanochemical synthesis of hemicucurbiturils in the solid state. Angewandte Chemie, International Edition. 2019;**58**:6230-6234. DOI: 10.1002/anie.201813431

[87] Holler M, Stoerkler T, Louis A, Fischer F, Nierengarten J-F.

Mechanochemical solvent-free conditions for the synthesis of pillar[5] arene-containing [2]rotaxanes. European Journal of Organic Chemistry. 2019:3401-3405. DOI: 10.1002/ ejoc.201900153

[88] Stojaković J, Farris BS, MacGillivray LR. Vortex grinding for mechanochemistry: Application for automated supramolecular catalysis and preparation of a metal-organic framework. Chemical Communications. 2012;**48**:7958-7960. DOI: 10.1039/ c2cc33227b

[89] Obst M, König B. Solvent-free, visible-light photocatalytic alcohol oxidations applying an organic photocatalyst. Beilstein Journal of Organic Chemistry. 2016;**12**:2358-2363. DOI: 10.3762/bjoc.12.229

[90] Obst M, Shaikh RS, König B. Solvent-free coupling of aryl halides with pyrroles applying visiblelight photocatalysis. Reaction Chemistry & Engineering. 2017;**2**:472- 478. DOI: 10.1039/c6re00220j

[91] Štrukil V, Sajko I. Mechanochemically-assisted solid-state photocatalysis (MASSPC). Chemical Communications. 2017;**53**:9101-9104. DOI: 10.1039/c7cc03510a

[92] Friščić T, Halasz I, Beldon PJ, Belenguer AM, Adams F, Kimber SAJ, et al. Real-time and in situ monitoring of mechanochemical milling reactions. Nature Chemistry. 2013;**5**:66-73. DOI: 10.1038/nchem.1505

[93] Hernández JG. Mechanochemical borylation of aryldiazonium salts; merging light and ball milling. Beilstein Journal of Organic Chemistry. 2017;**13**:1463-1469. DOI: 10.3762/ bjoc.13.144

[94] Martina K, Rotolo L, Porcheddu A, Delogu F, Bysouth SR, Cravotto G, et al. High throughput mechanochemistry:

Application to parallel synthesis of benzoxazines. Chemical Communications. 2018;**54**:551-554. DOI: 10.1039/c7cc07758k

[95] Michalchuk AAL, Hope KS, Kennedy SR, Blanco MV, Boldyreva EV, Pulham CR. Ball-free mechanochemistry: In situ realtime monitoring of pharmaceutical co-crystal formation by resonant acoustic mixing. Chemical Communications. 2018;**54**:4033-4036. DOI: 10.1039/c8cc02187b

[96] Užarević K, Halasz I, Friščić T. Realtime and *in situ* monitoring of mechanochemical reactions: A new playground for all chemists. Journal of Physical Chemistry Letters. 2015;**6**:4129-4140. DOI: 10.1021/acs. jpclett.5b01837

[97] Stolar T, Batzdorf L, Lukin S, Žilić D, Mottillo C, Friščić T, et al. In situ monitoring of the mechanosynthesis of the archetypal metal−organic framework HKUST-1: Effect of liquid additives on the milling reactivity. Inorganic Chemistry. 2017;**56**:6599-6608. DOI: 10.1021/acs. inorgchem.7b00707

[98] Julien PA, Malvestiti I, Friščić T. The effect of milling frequency on a mechanochemical organic reaction monitored by in situ Raman spectroscopy. Beilstein Journal of Organic Chemistry. 2017;**13**:2160-2168. DOI: 10.3762/bjoc.13.216

[99] Fischer F, Fendel N, Greiser S, Rademann K, Emmerling F. Impact is important—systematic investigation of the influence of milling balls in mechanochemical reactions. Organic Process Research and Development. 2017;**21**:655-659. DOI: 10.1021/acs. oprd.6b00435

[100] Kulla H, Fischer F, Benemann S, Rademann K, Emmerling F. The effect of the ball to reactant ratio on mechanochemical

reaction times studied by in situ PXRD. CrystEngComm. 2017;**19**:3902- 3907. DOI: 10.1039/C7CE00502D

[101] Tumanov N, Ban V, Poulain A, Filinchuk Y. 3D-printed jars for ballmilling experiments monitored in situ by X-ray powder diffraction. Journal of Applied Crystallography. 2017;**50**:1-6. DOI: 10.1107/S1600576717006744

[102] Ban V, Sadikin Y, Lange M, Tumanov N, Filinchuk Y, Černy R, et al. Innovative *in situ* ball mill for X-ray diffraction. Analytical Chemistry. 2017;**89**:13176-13181. DOI: 10.1021/acs. analchem.7b02871

[103] Lukin S, Tireli M, Lončarić I, Barišić D, Šket P, Vrsaljko D, et al. Mechanochemical carbon-carbon bond formation that proceeds via a cocrystal intermediate. Chemical Communications. 2018;**54**:13216-13219. DOI: 10.1039/c8cc07853j

[104] Kulla H, Haferkamp S, Akhmetova I, Röllig M, Maierhofer C, Rademann K, et al. In situ investigations of mechanochemical one-pot syntheses. Angewandte Chemie, International Edition. 2018;**57**:5930-5933. DOI: 10.1002/anie.201800147

[105] Užarević K, Ferdelji N, Mrla T, Julien PA, Halasz B, Friščić T, et al. Enthalpy vs. friction: Heat flow modelling of unexpected temperature profiles in mechanochemistry of metal– organic frameworks. Chemical Science. 2018;**9**:2525-2532. DOI: 10.1039/ c7sc05312f

[106] Crawford DE, Miskimmin CKG, Albadarin AB, Walker G, James SL. Organic synthesis by twin screw extrusion (TSE): Continuous, scalable and solvent-free. Green Chemistry. 2017;**19**:1507-1518. DOI: 10.1039/ C6GC03413F

[107] Cao Q, Howard JL, Crawford DE, James SL, Browne DL. Translating solid

**49**

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

state organic synthesis from a mixer mill to a continuous twin screw extruder. Green Chemistry. 2018;**20**:4443-4447.

DOI: 10.1039/c8gc02036a

10.1039/c9gc00036d

[108] Carvalho RB, Shreerang JV. Solvent and catalyst free synthesis of 3,4-dihydropyrimidin-2(1H)-ones/ thiones by twin screw extrusion. Green Chemistry. 2019;**21**:1921-1924. DOI:

*Recent Advances in Mechanochemical Organic Synthesis DOI: http://dx.doi.org/10.5772/intechopen.90897*

state organic synthesis from a mixer mill to a continuous twin screw extruder. Green Chemistry. 2018;**20**:4443-4447. DOI: 10.1039/c8gc02036a

*Organic Synthesis - A Nascent Relook*

Application to parallel synthesis of benzoxazines. Chemical

[95] Michalchuk AAL, Hope KS, Kennedy SR, Blanco MV,

Boldyreva EV, Pulham CR. Ball-free mechanochemistry: In situ realtime monitoring of pharmaceutical co-crystal formation by resonant acoustic mixing. Chemical

Communications. 2018;**54**:4033-4036.

[96] Užarević K, Halasz I, Friščić T. Real-

DOI: 10.1039/c8cc02187b

jpclett.5b01837

inorgchem.7b00707

time and *in situ* monitoring of mechanochemical reactions: A new playground for all chemists. Journal of Physical Chemistry Letters. 2015;**6**:4129-4140. DOI: 10.1021/acs.

[97] Stolar T, Batzdorf L, Lukin S, Žilić D, Mottillo C, Friščić T, et al. In situ monitoring of the mechanosynthesis of the archetypal metal−organic framework HKUST-1: Effect of liquid additives on the milling reactivity. Inorganic Chemistry. 2017;**56**:6599-6608. DOI: 10.1021/acs.

[98] Julien PA, Malvestiti I, Friščić T. The

effect of milling frequency on a mechanochemical organic reaction monitored by in situ Raman spectroscopy. Beilstein Journal of Organic Chemistry. 2017;**13**:2160-2168.

[99] Fischer F, Fendel N, Greiser S, Rademann K, Emmerling F. Impact is important—systematic investigation of the influence of milling balls in mechanochemical reactions. Organic Process Research and Development. 2017;**21**:655-659. DOI: 10.1021/acs.

Emmerling F. The effect of the ball to reactant ratio on mechanochemical

DOI: 10.3762/bjoc.13.216

10.1039/c7cc07758k

Communications. 2018;**54**:551-554. DOI:

reaction times studied by in situ PXRD. CrystEngComm. 2017;**19**:3902- 3907. DOI: 10.1039/C7CE00502D

[101] Tumanov N, Ban V, Poulain A, Filinchuk Y. 3D-printed jars for ballmilling experiments monitored in situ by X-ray powder diffraction. Journal of Applied Crystallography. 2017;**50**:1-6. DOI: 10.1107/S1600576717006744

[102] Ban V, Sadikin Y, Lange M,

[103] Lukin S, Tireli M, Lončarić I, Barišić D, Šket P, Vrsaljko D, et al. Mechanochemical carbon-carbon bond formation that proceeds via a cocrystal intermediate. Chemical Communications. 2018;**54**:13216-13219.

analchem.7b02871

DOI: 10.1039/c8cc07853j

10.1002/anie.201800147

[104] Kulla H, Haferkamp S,

Akhmetova I, Röllig M, Maierhofer C, Rademann K, et al. In situ investigations of mechanochemical one-pot syntheses. Angewandte Chemie, International Edition. 2018;**57**:5930-5933. DOI:

[105] Užarević K, Ferdelji N, Mrla T, Julien PA, Halasz B, Friščić T, et al. Enthalpy vs. friction: Heat flow modelling of unexpected temperature profiles in mechanochemistry of metal– organic frameworks. Chemical Science.

2018;**9**:2525-2532. DOI: 10.1039/

[106] Crawford DE, Miskimmin CKG, Albadarin AB, Walker G, James SL. Organic synthesis by twin screw extrusion (TSE): Continuous, scalable and solvent-free. Green Chemistry. 2017;**19**:1507-1518. DOI: 10.1039/

[107] Cao Q, Howard JL, Crawford DE, James SL, Browne DL. Translating solid

c7sc05312f

C6GC03413F

Tumanov N, Filinchuk Y, Černy R, et al. Innovative *in situ* ball mill for X-ray diffraction. Analytical Chemistry. 2017;**89**:13176-13181. DOI: 10.1021/acs.

**48**

oprd.6b00435

[100] Kulla H, Fischer F, Benemann S, Rademann K, [108] Carvalho RB, Shreerang JV. Solvent and catalyst free synthesis of 3,4-dihydropyrimidin-2(1H)-ones/ thiones by twin screw extrusion. Green Chemistry. 2019;**21**:1921-1924. DOI: 10.1039/c9gc00036d

**Chapter 4**

**Abstract**

Approaches to the Total Synthesis

Puupehenones have been isolated from the marine sponge *Chondrosia chucalla*, which belong to a growing family of natural products with more than 100 members. These marine natural products have attracted increasing attention mainly due to their wide variety of biological activities such as antitumor, antiviral, and anti-HIV, and thus offer promising opportunities for new drug development. This chapter covers the approaches to the total synthesis of puupehenone-type marine natural products including puupehenol, puupehenone, puupehedione, and

halopuupehenones. The routes begin with the construction of their basic skeletons, followed by the modification of their C- and D-rings. The contents are divided into two sections in terms of the key strategies employed to construct the basic skeleton. One is the convergent synthesis route with two synthons coupled by nucleophilic or electrophilic reaction, and the other is the linear synthesis route with

**Keywords:** total synthesis, marine natural product, puupehenones, convergent

In recent years, the synthesis and application of marine natural products have become the focus of a much greater research effort, which is due in large part to the increased recognition of marine organisms as a rich source of novel compounds with biological applications [1–4]. The puupehenone-type marine natural products obtained from deep sea sponge have played a very important role in health care and

As shown in **Figure 1**, the most representative of this natural product family

includes puppehenone, halopuupehenones, puupehedione, puupehenol, 15-cyanopuupehenol, 15-oxopuupehenol, and bispuupehenonen. Structurally, puupehenones are tetracyclic compounds consisting of a bicyclic sesquiterpene A- and B-rings and a shikimic acid/O-benzoquinone/O-phenol D-ring connected by tetrahydropyran/dihydropyran C-ring. In addition, the chiral center of the C-8 of this series of natural products listed in the figure is 8S, which is also the structural

of Puupehenone-Type Marine

*Yan-Chao Wu, Yun-Fei Cheng and Hui-Jing Li*

Natural Products

polyene series cyclization as a key reaction.

synthesis, linear synthesis

prevention of diseases [5–14].

**1. Introduction**

specificity of them.

**51**

## **Chapter 4**
