CHAPTER 1: Carbon–Heteroatom Bond Forming Reactions and Heterocycle Synthesis under Ball Milling

Chemical transformations involving mechanochemical (grinding) reactions using a mortar and pestle were initiated long ago during the early stage of evolution of chemistry. But due to variable and relatively low grinding strength and speed, limited chemical reactions were successfully carried out by grinding. To overcome this limitation, a mixer/shaker mill or a planetary mill¹  has been developed and these devices provide much higher energy and are more reliable than hand grinding. Mixing in such a mill is generally referred to as “milling”. Mechanical grinding in these mills is aided by the milling balls and hence it is called ball milling. Mechanochemistry using ball milling has received intense attention in organic synthesis in recent decades and is now a fast growing branch. Mechanochemical reactions in a ball mill depend on several parameters like milling frequency, milling time, size and number of milling balls, and the material of milling balls and beakers. The first two have been found to be the most important parameters.¹  Basically two types of ball mills have been frequently used to perform organic transformations, i.e. mixer mill (MM) and planetary mill (PM) (for further details the reader is referred to Chapter 10).

The present chapter covers reactions involving carbon–heteroatom (C–N, C–O, C–S, C–Cl, C–Br, etc.) bond formation and synthesis of heterocycles under ball milling.

Kaupp and co-workers have reported the quantitative formation of imines by ball milling a stoichiometric mixture of aldehyde and amine in less than 30 min (Scheme 1.1).^2,3 

All the reactions were carried out below 0 °C except for the condensations of 4-nitroaniline with 4-hydroxybenzaldehyde and 4-nitrobenzaldehyde, which were performed at 60 and 80 °C, respectively.

The same group also investigated the solid-state reactions of hydrazine–hydroquinone (1 : 1 complex) and of hydrazine hydrochloride with solid aldehyde, ketone, carboxylic acid, thiohydantoin and 4-nitrophenyl isothiocyanate and found that only the hydrazine hydroquinone complex provides quantitative addition, condensation, ring opening and ring closure (Schemes 1.2 and 1.3).⁴ 

Naimi-Jamal, Kaupp and co-workers employed ‘‘kneading ball-milling’’ for the stoichiometric quantitative preparation of synthetically versatile 2,4-dinitrophenylhydrazones from low-melting aldehydes and ketones.⁵  Owing to the potential explosive nature of dry 2,4-dinitrophenylhydrazine, 50 wt% deionized water was added to wet the crystals. Water was used as an auxiliary to minimize the risk of explosive destruction. The stoichiometric reaction of 2,4-dinitrophenylhydrazine with aldehydes or ketones occurred rapidly in the kneading ball mill at 25–70 °C for 10–20 min, giving the desired hydrazones in 58–100% yields (Scheme 1.4). When these reactions are performed in solution, strong acid catalysts are required.⁶  However, they occur much faster in the kneading ball mill in the absence of catalyst.

Similarly, aldehydes and ketones were stoichiometrically ball-milled with hydroxylamine hydrochloride at 25–140 °C for 10–120 min to provide the hydrated oxime salts in sticky form, which were then treated with a base to obtain the oximes in 75–100% yields (Scheme 1.5).⁵  NaCl in water and CO₂ from carbonate were found to be the only wastes produced. Aldehydes were found to be more reactive than ketones towards hydroxylamine. The difference in reactivity of aldehydes and ketones can be utilized as a versatile method for selective protection of an aldehyde by oximation in the presence of a ketone.

Benzoylhydrazones were also obtained, by ball-milling benzhydrazide and solid aldehydes in a molar ratio of 1 : 1 for 1 h at 25–30 °C. However, the reaction of benzhydrazide with isatin required 3 h of ball milling for completion (Scheme 1.6).⁷ 

Liquid assisted grinding (LAG)⁸  has been applied for the synthesis of imine from 5-aminosalicylic acid and vanillin or 2-hydroxy-1- naphthaldehyde in a ball mill for 5–30 min in the presence of a small amount of EtOH or EtOH–NEt₃ (Scheme 1.7).

Wang and Gao have reported direct oxidative amidation of aldehydes with anilines under ball milling (Scheme 1.8).⁹  Oxone was used as an effective oxidant for the transformation of aldehydes into amides. Other oxidants like K₂S₂O₈ and I₂ failed to initiate the oxidative amidation.

MgSO₄ was found to be the best dehydrating agent for removing the water formed in the reaction. In addition, when the oxidative amidation reaction was performed in organic solvents such as acetonitrile or toluene, under identical reaction conditions, the yield of the corresponding product was comparatively lower than the reaction under solvent-free condition in a ball mill. Anilines bearing electron-donating and electron-withdrawing groups underwent facile reaction with aldehydes bearing electron-withdrawing groups only. Reactions with aldehydes containing electron-donating groups were unsuccessful, indicating the importance of the electronic character of aldehydes. Aliphatic anilines were also inert under the reaction conditions. The replacement of an aldehyde by the corresponding carboxylic acid did not afford the amides, thereby discarding the possibility of oxidation of aldehyde to carboxylic acid by Oxone followed by reaction with aniline to give amide.

A tentative mechanism for the amidation reaction of aldehydes with anilines based on the above results was proposed (Scheme 1.9). This direct oxidative amidation reaction may proceed via two pathways. In pathway A, the interaction of an aldehyde and aniline produces imine readily, which is then oxidized by Oxone to generate oxaziridine 1 as the key intermediate. Rearrangement of oxaziridine to amide is known for both photochemical and thermal reactions.¹⁰  Initial cleavage of the N–O bond followed by migration of the substituent (hydrogen) trans to the nitrogen lone pair results in the formation of amide 2. In pathway B, nucleophilic addition of aniline to aldehyde produces carbinolamine intermediate 3, which is then oxidized by Oxone to form the amide. Even though control experiments showed that imine could be employed to perform the amidation directly, the exact mechanism of this reaction remains obscure and both pathways could be operational.

A new methodology has been developed for the desymmetrization of aromatic diamines to non-symmetrical thiourea derivatives by click-mechanochemistry in a ball mill.¹¹  Phenylenediamines (o-, p-) were desymmetrized through a one-pot mechanochemical click reaction sequence to furnish mono- and bis(thio)ureas or mixed thiourea–ureas (Scheme 1.10).

o-Phenylenediamine reacted selectively with either one or two equivalents of phenyl isothiocyanate to yield the non-symmetrical amino-thiourea or the symmetrical bis-thiourea in 95% and >99% yields respectively. The excellent control of the stoichiometric composition of the product in mechanochemical click-thiourea coupling demonstrates that it provides a facile and clean one-pot route to desymmetrization of aromatic diamines, and to the synthesis of symmetrical and non-symmetrical bis-(thio)ureas that are obtained in poor yields in solution.¹² 

A chemoselective C–N bond formation has been achieved by the acylation of primary aliphatic amines using a vibrational ball mill in 10 min (120 min for aromatic amines). Azobenzene functionalized esters were employed to react with various amines (primary and secondary) in presence of a base, N,N-dimethyl-4-aminopyridine (DMAP), under vibrational ball-milling to synthesize the corresponding amides (Scheme 1.11).¹³ 

Jin et al. have reported an efficient solvent and catalyst-free aza-Michael addition of chalcone to amine under the high-speed vibration ball-milling in a short reaction time (Scheme 1.12).¹⁴  In general, excellent yields were obtained, eliminating the usual side reactions. It was also observed that the yields of the corresponding products obtained using anilines were lower compared to those using benzyl amine or piperidine.

Kaupp's group has reported quantitative synthesis of enamino ketones by the reaction of cyclic 1,3-dicarbonyl compounds such as 1,3-cyclohexanedione, dimedone and dehydroacetic acid with aniline derivatives without any catalyst under ball milling within 1 h, followed by drying at 0.01 bar at 80 °C (Scheme 1.13).⁷ 

Li and co-workers have reported the mechanochemical reaction of aliphatic primary amines with acyclic 1,3-dicarbonyl compounds such as 1,3-pentadione and ethyl acetoacetate in the absence of catalyst and solvent (Scheme 1.14).¹⁵  A series of enamino ketones and esters were obtained in 61–97% yields by ball milling the mixtures of amines and 1,3-dicarbonyl compounds in a ratio of 1 : 1 in a mixer mill at 30 Hz for 0.5–2 h.

Stolle et al. have developed a solvent-free methodology for the synthesis of enamines by the addition of amines to dialkyl acetylene dicarboxylates or alkyl propiolates using a planetary ball mill at 800 rpm (13.3 Hz) (Scheme 1.15).¹⁶  Fused quartz sand (SiO₂) was used as inert grinding auxiliary to facilitate the energy entry in the presence of liquid substrates by adsorbing them on the surface.¹⁷  Significantly, reactions with several anilines and secondary alkyl amines were complete within five minutes with excellent yield of products. Besides the (E-/Z)-isomers, no other product was formed. Interestingly, addition of aniline or p-toluidine to dialkyl acetylene dicarboxylate produced the (E)-enamine as the major product whereas addition of the same amine to alkyl propiolate produces the (Z)-enamine as the major product.

Lamaty and co-workers reported the condensation of aldehydes with equimolar amounts of N-substituted hydroxylamines in a ball mill at a frequency of 30 Hz for 0.5–2 h to obtain various C-aryl and C-alkyl nitrones in 71–100% yields (Scheme 1.16).¹⁸  Significantly, reactions were performed in the presence of air and moisture and the products were obtained pure.

Though urea is very unreactive toward alkylation, the reaction of urea with 4-bromobenzyl bromide under mechanical milling in the presence of NaOH produced di(4-bromobenzyl)urea with 41% conversion for a total milling time of 34 h (Scheme 1.17).¹⁹ 

Mechanochemical reaction of pyrazolone derivatives and phenacyl bromide under ball milling afforded the corresponding pyrazolyl ether derivative quantitatively within 1 h involving the C–O bond formation. The products were obtained after washing the crude with sodium carbonate solution followed by drying at 0.01 bar at 80 °C under vacuum (Scheme 1.18).²⁰ 

Mack and co-workers have reported the mechanochemical synthesis of dialkyl carbonates of various metal carbonates with the assistance of metal complexing reagents (Scheme 1.19).²¹  The reaction of various metal carbonates including Li₂CO₃, Na₂CO₃, K₂CO₃ and Cs₂CO₃ with 4-bromobenzyl bromide gave poor results (0–18% yields). However, the addition of 2 equivalents of 18-crown-6 improved the yield from 2% to 74%. The same product was obtained as the major one in the reaction of cyclohexanone with p-bromobenzyl bromide using K₂CO₃ as the base in the presence of 18-crown-6.²²  Under the optimal conditions, other aliphatic halides such as benzyl bromide, (2-bromoethyl)benzene and benzyl chloride provided dialkyl carbonates in 58–67% yields.²¹ 

Recently, Ranu et al. have developed an efficient procedure for transesterification in a ball mill in the absence of any solvent, acid/base or metal catalyst (Scheme 1.20).²³  The reactions were carried out on the surface of basic alumina, which plays a dual role of a grinding auxiliary and a base. A wide variety of esters such as methyl, ethyl and allyl esters were transesterified with various alcohols including benzyl, cinnamyl, alkyl (primary, secondary) etc. Heteroaryl (pyridine, thiophene and furan) substituted methanols participated in the transesterification reaction without any difficulty.

Mack et al. have reported the heterogeneous nucleophilic additions of alkali salts of thiocyanate, azide, acetate and halides to 4-bromobenzyl bromide with or without 18-crown-6 by ball milling (Scheme 1.21).²⁴  It was found that thiocyanate and azide provided excellent yields of the nucleophilic addition products, whereas the potassium and sodium salts of fluoride, chloride, acetate and cyanide provided relatively low yields of the corresponding addition products. On the other hand, 18-crown-6 can complex with K⁺ cation to increase the basicity and nucleophilicity of the employed nucleophiles, and thus the addition of 18-crown-6 led to a better conversion and increase in yield for all of the potassium salt nucleophiles including fluoride, acetate and cyanide,²⁵  which were previously unsuccessful.²⁴ 

Kaupp and co-workers have reported the quantitative formation of thiouronium salt from solid 2-mercaptobenzimidazole and phenacyl bromide under ball milling for 1 h (Scheme 1.22).⁷ 

Recently, Ranu et al. have developed a convenient and efficient procedure for the transition metal-, ligand- and solvent-free synthesis of aryl chalcogenides by employing a C–X (X=S, Se, Te) bond forming reaction between aryl diazonium tetrafluoroborates and diaryl dichalcogenides in the presence of KOH and neutral alumina as grinding auxiliary under ball milling (Schemes 1.23–1.25).²⁶  A wide variety of diaryl chalcogenides were synthesized within short reaction time (15–30 min) providing moderate to good yields (62–90%) of products.

1,2,3-Triazoles, five-membered nitrogen-containing heterocycles, have received considerable interest because of their useful applications as agrochemicals, dyes, corrosion inhibitors, photostabilizer, materials and in pharmaceutical industries.²⁷  Stolle and co-workers have reported the first ligand- and solvent-free mechanochemical synthesis of triazole from azides and alkynes using a planetary ball mill (Scheme 1.26).²⁸ 

The applicability of this protocol to a broad variety of substrates enables easy access to a wide range of complex triazoles. Click polymerization in a ball mill without destroying the polymer backbone is also successful (Scheme 1.27).

Ranu et al. introduced a different protocol where 1,4-disubstituted-1,2,3-triazoles were synthesized by a simple one-pot three-component reaction of alkyl halide/aryl boronic acid, sodium azide and terminal alkynes on the surface of Cu/Al₂O₃ catalyst by ball-milling under solvent-free conditions (Scheme 1.28).²⁹  Usually no chromatographic separation/purification was required and no toxic organic solvent is used in the entire process. This protocol avoids handling of hazardous organo-azide and provides easy access to aryl-alkyl and aryl-aryl substituted 1,2,3-triazoles. From the X-band EPR spectrum and XPS study it was found that the copper was present in the +2 oxidation state throughout the reaction cycle. SEM and AFM analysis exhibited the uniform spherical morphology of the catalyst.

Another nitrogen-containing five-membered heterocycle, pyrazoline, can be effectively synthesized from chalcones and phenyl-hydrazines in the presence of NaHSO₄·H₂O using high speed ball milling (HSBM) (Scheme 1.29).³⁰ 

It was found that better yield of pyrazolines was obtained when the substrates contained electron–donating groups. The easy catalyst recovery and its reusability make this procedure more attractive. When other α,β-unsaturated ketones were treated with thiosemicarbazide/phenyl hydrazine in the presence of this catalyst the corresponding 2-pyrazoline derivatives were obtained in good yields (Scheme 1.30),³⁰  which demonstrates the general applicability of this protocol.

In 1999, Kaupp and co-workers reported a one-pot synthesis of highly substituted pyrroles (Scheme 1.31), which gives moderate yields in solution, but quantitative yields in solid–solid variant at much lower temparatures.³¹  Mechanochemical reaction of primary or secondary enamine esters 4a–d or the enamine ketone 7 with trans-1,2-dibenzoylethene (5) under ball milling afforded pyrroles 6 or indole 9 quantitatively within 3 h despite the multistep course of the reaction.

A plausible reaction pathway is depicted in Scheme 1.32. In the first step, Michael addition followed by the hydrogen transfer produces 11, which undergoes an imine/enamine rearrangement to give 12. The generated amino group then interacts with the carbonyl function leading to the formation of a five-membered ring 13, which provides pyrrole 14 by the elimination of water. An analogous mechanism was postulated for indole starting from 7. Furthermore, the quantitative formation of thioorotic acid amide 17 from a cascade reaction between the thiohydantoin 15 and methyl amine shows the versatility of this method (Scheme 1.33).

Kaupp and co-workers have reported the quantitative formation of (R)-thiazolidine by ball-milling a stoichiometric mixture of l-cysteine and (HCHO)_n for 1 h (Scheme 1.34).³²  It has been observed that a 1 : 1 mixture of phthalic anhydride and 4-toluidine when subjected to ball milling affords the corresponding imide in high yields. Interestingly, cyclic thiourea was obtained quantitatively when bifunctional isothiocyanates and amine were ball milled.

A series of heterocycles can be obtained by condensation of o-phenylenediamines with various 1,2-dicarbonyl compounds under ball milling.³³  The condensation of substituted o-phenylenediamines and benzil produced the corresponding quinoxaline derivatives within 1 h (Scheme 1.35). Similarly, condensation between 2-hydroxy-1,4-naphthoquinone and o-phenylenediamine furnished the benzo[a]phenazin-5-ol within 15 min at 70 °C (Scheme 1.36). The yields are almost quantitative in all these reactions.

Kaupp and co-workers also investigated the solid state condensation of o-phenylenediamine with oxoglutaric acid, oxalic acid, 1,4-dihydroquinoxaline-2,3-dione and parabanic acid and found that in each case the corresponding products were obtained in high yields (Scheme 1.37).³³ 

Pyrimidine derivatives were synthesized by the direct condensation of an equimolar amount of an aldehyde, malononitrile, and thiourea/urea under ball milling within 40 min (Scheme 1.38).³⁴  This protocol offers a wide variety of substituted pyrimidine derivatives in pure form without further purification and in quantitative yields.

In the last decade, much work has been done in the area of oxygen containing heterocycle synthesis under ball milling. It was observed that use of a ball mill not only allowed a net enhancement of the reaction yields but also in some cases resulted in different chemoselectivities compared to conventional solution-phase synthesis. Xanthone and its isomers are six-membered oxygen-containing heterocycles and can be synthesized in a ball mill by a one-pot domino oxa-Michael–aldol reaction (Scheme 1.39).³⁵ 

Bräse made a systematic study of the ball milling reaction to determine the influence of the ratio of the reactants, the rotational frequency of the mill, the number of balls, the milling time on the reactivity and chemoselectivity. The best yield was obtained using salicaldehyde and cyclohexenone in 1 : 2 molar ratio. It has been found that increasing the reaction time does not increase the yields linearly, probably because the high temperature generated during the milling procedure can be nullified by using water. Concerning the chemoselectivity, it has been observed that changing the base from DABCO to Et₃N increases the yield of dihydrobenzopyran, while use of DABCO gives the chromene derivative as a major product (Scheme 1.40).³⁵  The above experimental observation clearly established the fact that some parameters intrinsically linked to the ball-milling process largely influence the yield and sometimes chemoselectivity of a reaction.

Another heterocycle that contains a six-membered oxygen ring is naphthopyran, the derivatives of which have attracted considerable attention due to their interesting photochromic properties and biological applications.^36–38  An efficient solid state synthesis of naphthopyran was achieved by the cycloaddition reaction of propargylic alcohols with 2-naphthol in the presence of a Lewis acid catalyst (InCl₃^.4H₂O) under ball milling within 1 h (Scheme 1.41).³⁹  Other Lewis acids such as ZnCl₂ or SnCl₄ also catalyzed the cycloaddition reaction but the yields of the corresponding naphthopyrans were poor. Using this methodology several substituted naphthopyrans were synthesized. When propargyl alcohols bearing either a pyrazinyl group or a pyridyl group were used the expected naphthopyrans were not formed. This may happen due to the unwanted coordination of the pyrazinyl or pyridyl ligand to the indium metal.

Although there are several routes for the synthesis of flavone, containing a six-membered oxygen-containing ring, mechanically activated solid-state synthesis of flavones by high-speed ball milling (HSBM) received considerable attention as it avoids the use of solvent and provides waste-free products in almost quantitative yields. The synthesis of flavones was accomplished by cyclodehydration of 1-(2-hydroxyphenyl)-3-aryl-1,3-propanediones in the presence of KHSO₄ by HSBM within 15 min (Scheme 1.42).⁴⁰ 

Kaupp and co-workers have reported the quantitative formation of six-membered oxygen containing heterocycles by Michael addition followed by rearrangement and cyclization under ball milling (Scheme 1.43).⁴¹  Quantitative yields of products were obtained without using any catalyst in a waste free manner.

The two-component straightforward synthesis of 2,3,6,7-tetrahydro-4(5H)-benzofuranone derivatives under solvent-free ball-milling was initiated by Mn(OAc)₃·2H₂O, which acts both as an oxidant and as a Lewis acid (Scheme 1.44).⁴²  In the standardized conditions oxidative radical reactions of 1,3-dicarbonyl compounds (dimedone, cyclohexane-1,3-dione) with (aza)chalcones catalyzed by Mn(OAc)₃·2H₂O afforded the products in moderate to high yields within 1 h without the need of any external base. This protocol is found to be widely applicable for a variety of chalcones. With the isolation of a key intermediate 30 (Scheme 1.45) after running the reaction for 5 min, the reverse regioselectivity of the product in the case of 1-(pyridin-2-yl)-enones was established in comparison with the radical reaction of 1,3-dicarbonyl compounds and α,β-unsaturated compounds. The intermediate 30 is a Michael addition product, which was gradually converted into 2,3,6,7-tetrahydro-4(5H)-benzofuranone derivatives with prolonged reaction time. The reaction was initiated by the chelation of carbonyl and pyridinyl moieties of 1-(pyridin-2-yl)-enones with Mn(iii), followed by 1,4 addition of 1,3-dicarbonyl compounds (Scheme 1.46). The enolization of intermediate 33 facilitates formation of radical 35 with loss of Mn(ii) species. Oxidation of radical 35 affords the carbocation 36, cyclization of which generates the final product.

Oxazolidinone, a five-membered heterocycle containing nitrogen and oxygen, is an important class of compounds that has applications as chiral auxiliaries, metal ligands, and pharmaceuticals (specifically as antibiotics).^43,44  A simple way to synthesize the oxazolidinone ring is by the reaction of an unactivated 2-alkyl or 2-aryl aziridine with carbon dioxide in the absence of any catalyst or solvent under high speed ball milling (Scheme 1.47).⁴⁵  When the reaction of 2-aryl substituted aziridine with CO₂ was performed in a conventional way the corresponding oxazolidinone 38 was obtained. However, when the same reaction was performed with an alkyl-substituted aziridine 39, it afforded a mixture of oxazolidinones 40 and 41. Interestingly, the reaction under high speed ball milling produced only one oxazolidinone 40 regioselectively within 17 h.

Protection–deprotection is an important tool in organic synthesis as in many cases the molecules such as bi-or poly-functional alcohols, acids, amines, and thiols are required to be protected and subsequently deprotected to obtain the target molecule. Both protection and deprotection step should be simple and quantitative to make the synthetic procedure more economical and industrially suitable. Boronic acid reacts in the solid state with suitably substituted amines, amino acids, diols and polyhydroxy compounds like mannitol and inositol under ball milling to form the corresponding five- or six-membered boron containing heterocycles, which provides good protection to the functionalities.

Free amines were protected via the formation of six-membered diazaborinine by the reaction with phenyl boronic acid in solid state under ball milling (Scheme 1.48).⁴⁶  The formed diazaborinine is stable towards strong acid or strong base and it may be useful for electrophilic aromatic substitutions. The amine in anthranilic acid, with its free carboxylic functional group, was protected by reaction with boronic acid.

Suitably substituted diols are protected with boronic acid by the formation of corresponding five-membered heterocycles. For example, pyrocatechol and pyrogallol react with phenyl boronic acid when stoichiometric mixtures are ball milled at 80 °C (Scheme 1.49).⁴⁶  Deprotection also follows the same procedure by treatment with aqueous NaHCO₃ at 40 °C for 2 h.

The cyclization reaction of aliphatic 1,2-diols with boronic acid is equally versatile and waste-free. Ball milling of a stoichiometric mixture of aliphatic 1,2-diols (pinacol or 2,2-dimethylpropane-1,3-diol) and boronic acids at room temperature provided the corresponding heterocycles quantitatively (Scheme 1.50).^46,47 

Quantitative formation of five- and six-membered ring heterocycles in a waste-free manner by sugar alcohols and cyclic polyalcohols with phenyl boronic acid in the solid state eases the protection–deprotection step in carbohydrate chemistry.⁴⁶  For example, d-mannitol reacts with three molecules of phenyl boronic acid in a ball mill to give the corresponding product 42, the structure of which has been further confirmed by X-ray crystal structure analysis (Scheme 1.51). Similarly, the racemic tris-borolic ester 43 with one five-membered and two six-membered rings was formed by the solid state reaction between cyclic hexol myo-inositol with phenyl boronic acid (1 : 3) at 95 °C (Scheme 1.51). Deprotection is performed by dissolving 43 in 0.01(N) HCl for 1 h at room temperature.

During the last two decades, significant development has been made in the field of fullerene chemistry to study their chemical functionalizations and practical applications. Carbon allotropes are highly hydrophobic in nature. Thus, chemical reactions with fullerenes in solution are difficult to perform. Ball milling not only gives the opportunity to perform the reaction in the solid state but also provides an alternative where reactions furnish unexpected results that are not observed when the same reaction was performed in solution. Here comprehensive coverage on the oxygenation and cycloaddition reaction of fullerene is provided.

C₆₀ was reported to be oxidized by high speed vibrational milling (HSVM) under oxygen at 1 atm. (Scheme 1.52).⁴⁸  In the formed poly-oxidized fullerene C₆₀O_n containing the C–O–C and C=O bonds, n ranges from 1.4 to 12.4, depending on the milling time, amplitude and ball density. Interestingly ¹O₂ was generated during the mechanochemical oxidation of C₆₀ and it played a crucial role in this process. High speed ball milling of the poly-oxidized C₆₀O under an Ar atmosphere afforded insoluble polymeric species. HPLC analysis revealed the co-existence of higher epoxides, C₆₀O_n (2 ≤ n ≤ 5) and bare fullerene, as minor products possibly produced by the reverse reaction.

Triazoline derivatives were obtained by the [2+3] cycloaddition of organic azide and C₆₀ at high speed ball milling within 30 min (62–76%).⁴⁹  If the triazoline derivative was heated at 120 °C for 2 h in the solid state, the corresponding 5,6-open and 6,6-closed aza fullerenes were obtained (Scheme 1.53).

Mechanochemical [2+3] cycloaddition reaction of fullerene with diazo compound gives the corresponding C₆₀-fused-2-pyrazoline 46 within 30 min. 2-Pyrazoline 46 was obtained via isomerization of 1-pyrazoline 45, which was formed directly by the 1,3-dipolar cycloaddition of C₆₀ with ethyl diazoacetate generated in situ from the glycine ester hydrochloride and NaNO₂ (Scheme 1.54).⁵⁰ 

The use of mechanochemistry in the formation of metallomacrocycles and cages is not very common in structural supramolecular chemistry. However, ball milling provides a solvent-free route for the synthesis of macrocycles with better yield than any classical solution based method.

To synthesize complex molecular architectures based on boronic acids, Severin and co-workers reported a one-pot condensation of 4-formylphenyl-boronic acid 47, pentaerythritol (48) and tris(2-aminoethyl)amine (tren) to afford a macrobicyclic structure.⁵¹  Solid state structure determination of this macrobicyclic compound revealed a “collapsed” geometry with no accessible space inside the cage. To make larger and more expanded cage structures, the same condensation reaction was performed by exchanging the flexible tren building block for more rigid 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene (49). Mechanochemical condensation reaction between the boronic acid 47, tetraol 48 and triamine 49 produced cage 50 quantitatively within 1 h at milling frequency 20 Hz. Furthermore, if a more elongated boronic acid, i.e. 4-(4-formylphenyl)phenylboronic acid (51) was used, it provided the corresponding cage 52 in good yield within 1 h (Scheme 1.55).⁵²  In comparison with solution phase, the yields of these reactions were always low (<40%) and the products also were always contaminated with significant amounts of an incomplete condensation product. The overall geometry and characterization of cages 50 and 52 were obtained from multinuclear NMR spectroscopy, mass spectrometry and single-crystal X-ray diffraction data.

In continuation with macrocycle preparation in a ball mill, a multicomponent polycondensation reaction of 4-formylbenzene boronic acid (53), t-Bu₂Si(OH)₂ (54) and diamines (4,4′-bis(aminomethyl)biphenyl (55) and (1R,2R)-1,2-diaminocyclohexane (56)) was performed under ball milling to produce the corresponding borasiloxane-based macrocycles 57 and 58 with an isolated yields of 85% and 65% respectively (Scheme 1.56).⁵³  Here, first the condensation of silane diols with boronic acids gave the cyclic borosiloxanes, and subsequent combination with the diamines produced the corresponding borosiloxane-based macrocycles.

Another class of macrocyclic compound, rotaxanes, has shown potential applicability as molecular actuators and switches within mesoscale molecular electronic devices. In recent times Chiu and co-workers have developed several methods where rotaxanes can be synthesized by ball-milling in solid state with high yields. The solid state condensation of 1,8-diaminonaphthalene and benzaldehyde under ball milling provides an efficient, waste-free procedure for synthesizing interlocked molecules such as [2]- and [4]-rotaxanes due to the steric bulk and stability of the resulting dihydropyrimidine stopper units (Scheme 1.57).⁵⁴ 

Furthermore, with rotaxane preparation, the smallest rotaxane was achieved in a ball mill by utilizing the Diels–Alder reaction of 1,2,4,5-tetrazine with the terminal alkyne units of a 21-crown-7 (21C7)-based [2]pseudorotaxane to produce pyridazine end groups as stoppers in a 21C7-containing [2]rotaxane in 81% yield (Scheme 1.58).⁵⁵  The same strategy is effective for preparing both non-symmetric and symmetric [2]rotaxanes incorporating either 24- or 25-membered-ring macrocycles (Scheme 1.59).⁵⁶ 

In the present chapter, the efficacy of a ball mill for carbon–heteroatom bond formation and synthesis of heterocycles has been highlighted. In general, the ball milling mediated reactions possess several green aspects including solvent-free reaction, mild conditions, purification without chromatography and high yields. Certainly, ball milling can be used as an important tool in the synthesis of useful compounds and natural products, as an attractive alternative to conventional energy sources such as heating, microwave irradiation and sonication.