Solvent-Free and Catalysts-Free Chemistry: A Benign Pathway to Sustainability


  • Dr. Manoj B. Gawande,

    Corresponding author
    1. REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550
    2. current address: Regional Centre of Advanced Technologies and Materials, Faculty of Science, Department of Physical Chemistry, Palacky University, 17. listopadu 12, 771 46 Olomouc (Czech Republic)
    • Manoj B. Gawande, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550

      Vasco D. B. Bonifácio, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550

      Rajender S. Varma, Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443, 26 West Martin Luther King Drive, Cincinnati, Ohio, 45268 (USA)

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  • Dr. Vasco D. B. Bonifácio,

    Corresponding author
    1. REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550
    • Manoj B. Gawande, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550

      Vasco D. B. Bonifácio, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550

      Rajender S. Varma, Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443, 26 West Martin Luther King Drive, Cincinnati, Ohio, 45268 (USA)

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  • Prof. Rafael Luque,

    1. Departamento de Quimica Organica, Universidad de Cordoba, Edif. Marie Curie, Ctra Nnal IVa, Km 396, 14014 Cordoba (Spain)
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  • Prof. Paula S. Branco,

    1. REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550
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  • Prof. Rajender S. Varma

    Corresponding author
    1. Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443, 26 West Martin Luther King Drive, Cincinnati, Ohio, 45268 (USA)
    • Manoj B. Gawande, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550

      Vasco D. B. Bonifácio, REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica (Portugal), Fax: (+351) 21-2948550

      Rajender S. Varma, Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency, MS 443, 26 West Martin Luther King Drive, Cincinnati, Ohio, 45268 (USA)

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In the past decade, alternative benign organic methodologies have become an imperative part of organic syntheses and chemical reactions. The various new and innovative sustainable organic reactions and methodologies using no solvents or catalysts and employing alternative energy inputs such as microwaves, sonication, conventional and room temperature heating conditions, mechanochemical mixing, and high-speed ball milling are discussed in detail. Environmentally benign and pharmaceutically important reactions such as multicomponent, condensation, and Michael addition reactions; ring opening of epoxides; and oxidation and other significant organic reactions are discussed. An overview of benign reactions through solvent- and catalyst-free (SF–CF) chemistry and a critical perspective on emerging synergies between SF–CF organic reactions are discussed.

1. Introduction

Organic synthetic processes have been at the core of the chemical industry for hundreds of years. From acid/base, redox, and coupling processes as well as related chemistries, these have offered a wide range of possibilities for the preparation of high added-value compounds that have found applications in areas including medicine and pharmacy, agriculture, dye industry, and many others.1 The field of organic synthesis has, however, experienced profound changes in recent years with the goal to switch to equally efficient more sustainable processes that avoid the extensive use of toxic and hazardous reagents and solvents, harsh reaction conditions, and expensive and sophisticated catalysts.2 In the dawn of the 21st century, green chemical methodologies applied to organic synthetic protocols can offer innovative and highly appropriate alternatives to traditional synthetic processes extensively investigated in the past.2c, 3 These are not only related to the replacement of reagents and catalysts but also to the utilization of more environmentally sound alternative ways that promote the desired chemistries including microwaves (MWs) irradiation, ultrasound, mechanochemistry, and other interesting catalyst-free and/or solventless protocols.4 A complete rethinking of the organic synthetic scenario was made possible in recent years because of the utilization of the proposed alternatives that often also offer the possibility to switch the production of a certain final product by means of a careful selection of reaction conditions.5

Of particular interest is the coupling of the aforementioned alternative benign methodologies with solvent- and catalyst-free (SF–CF) synthetic processes.6 This sound partnership ensures the design of improved environmentally compatible processes that minimize side-reactions and effectively lead to target products in high yields.7 A significant number of efforts have been implemented to minimize waste, avoid the utilization of catalysts and/or solvents,4o, 8 minimize energy consumption, and include various alternatives such as magnetically recoverable catalysts,9 deep-eutectic mixtures, (DEM), ionic liquids,10 aqueous-promoted chemistries,3b, 4b, 11 the utilization of benign solvents including glycerol12 or polyethylene glycol (PEG),5a as well as other eco-friendly protocols.4p, 13 In addition, recently water-mediated reactions have been termed as “in-water” and “on-water” reactions because of the nature of the reactants (solubility) during chemical reactions.14 Although the concept is not new, the original work by Breslow15a and Riedout and Breslow15b proved that hydrophobic effects could strongly enhance the rate of chemical reactions.

In this contribution, the goal is to provide a general overview of selected key organic synthetic processes that maximize the value of the proposed partnership. This would not only grant access to a plethora of old and new compounds of industrial importance but, also take advantage of the elegance and beauty of shaping a more sustainable future in the field of synthetic organic chemistry. In this regard, this manuscript has been divided into different sections that correspond to SF–CF reactions promoted under MWs, ultrasound irradiation, mechanochemistry, high-speed ball milling (HSBM), and other protocols of interest to the area of organic synthesis.

2. Focus of this Review

In this Review, the focus is on the SF–CF organic syntheses under ambient and mild conditions. Organic chemistry is a major and important discipline of chemistry because of its importance in fine chemicals, petrochemicals, and most importantly in drug discovery and pharmaceuticals. The synthesis of products or compounds in a benign way is a great challenge to organic chemists and young researchers. In the last decade, a tremendous effort has been expended to design benign organic reaction methodologies that mainly focus on the elimination of waste from reactions, especially catalysts or reagents and solvents. The main theme of this Review is to present SF–CF organic reactions over the last decade in a comprehensive way. These reactions are categorized according to their reaction conditions and alternative energies used during the reactions. Catalyst-free reactions with solvents and solvent-free reactions with catalysts (reagents) are not discussed in this Review, and no results of any spectroscopic or analytical techniques are presented as they are very adequately defined in the original papers and are out of the scope of this article.

In the introductory section, various sustainable issues such as green solvents, alternative energy sources, and use of materials in organic reactions are discussed with selected key references in the field. In a separate section, limitations of these reactions and how SF–CF reactions work with MWs, conventional heating, mechanochemical mixing, and HSBM are presented with key figures. In addition, whether these reactions can be termed as solvent free or not is also discussed by using examples and references including an array of organic reactions and important drug intermediates.

3. What are the Limitations of SF–CF Reactions?

SF–CF reactions have always been a prime focus in organic chemistry. Various important protocols have been designed and reported in recent years for the synthesis of valuable drug intermediates, active pharmaceutical ingredients, and other organic compounds. From these, the relevance of this field is clear, but where it is heading in the near future?

There are various existing limitations for SF–CF reactions (Figure 1). These include:

Figure 1.

Limitations of SF–CF chemistry.

⋅ Solubility of reactants or reagents

⋅ Use of high temperature, pressure, etc.

⋅ Selection of active starting raw materials

⋅ Long reaction time and formation of by-products

⋅ Use of excess of reactants or reagents

⋅ Selectivity of products

⋅ Less applicability in solid-phase synthesis.

Such limitations and drawbacks in SF–CF reactions should be taken into account to direct subsequent efforts in future years.

4. How Do SF–CF Reactions Work?

In recent years, SF–CF reactions have received considerable attention among scientists and green chemists because of the possibility of avoiding the utilization of expensive catalysts/reagents and solvents (chlorinated or toxic). It is well known that catalysts/reagents promote faster chemical reactions and that, for some reactions, the desired selectivities (regioselectivity or chemoselectivity) can be obtained by using specific selective sites of catalysts or reagents. SF–CF reactions have been promoted because of a number of energy methodologies that are alternatives to conventional heating and classical methods. These include MW heating, sonication, mechanochemical mixing, and HSBM (Figure 2).

Figure 2.

Alternative energy methodologies for SF–CF reactions.

In addition, the selection of active starting raw materials (reactants) is important for these reactions, so that the proposed reaction can occur upon heating (MWs vs. conventional) or grinding.

5. Can an Integrated Organic Synthesis Process Be Really Solvent-Free?

With the increasing awareness in academia and industry for sustainable development under comparable and cost-competitive efficient alternatives, the international chemical community is under pressure to redesign current working practices and to discover greener options. Sustainable protocols have been promoted worldwide by an increasing number of research platforms because they deliver environmentally benign transformations.4k, 13a

Catalyst- and solvent-less reactions are old and well accepted terms in the scientific community. Clearly, traditional catalysts or solvents are avoided in these reactions. But are these reactions really solvent-free? The answer is no. In solvent-free reactions (neat), solvents are still extensively utilized for the isolation and purification of products. Although a 10 mmol reaction performed in solvent generally uses 10–20 mL of solvent, 300–2000 mL solvent are used for product isolation and purification. In SF–CF reactions, a similar amount of solvent is used, only the reaction solvent is eliminated, which is a very small amount (10–50 mL). Recently, Curran commented on the frequently termed “free” reactions used in science and technology, particularly in organic synthesis.16 According to him, “in this brave new world, every reaction may not yet be an ideal reaction, but at least any paper can be an ideal paper”. This viewpoint supports the fact that even in SF–CF reactions, there are several issues to be addressed. In light of these comments, the same authors reported transition-metal-free hydrolysis of esters promoted by inexpensive sodium hydroxide in aqueous media and faced major obstacles to successfully achieve the proposed chemistry, including the use of uncontaminated pure water and sodium hydroxide (free of contamination with transition metal traces). Therefore, it is questionable and arguable that the utilization of “free” in organic reactions should be approached with care, taking into account the additional steps required to satisfactorily obtain the final product (Figure 3).

Figure 3.

Factors that should be considered when designing reactions.

6. Solvent- and Catalyst-Free Reactions

6.1. MW irradiation

MWs, which have been used for heating food for almost 50 years, are a very useful heating alternative in organic synthesis and have started to play an increasingly important role for a variety of chemical applications since the early 1980s, including organic synthesis.4b,d, 8b, 17 Under MW irradiation conditions, chemical reactions can be accelerated and selectivities can be often switched to a particular product depending on MW parameters.4a,b, 17h,p,q, 18 MW irradiation offers several advantages over conventional heating, such as instantaneous and rapid heating (deep-inside heating), high temperature homogeneity, and selective heating. The use of MWs in organic synthesis has been reviewed in great detail elsewhere.4b, 17q

MW protocols can replace many organic solvents, as well as water, enabling the reactions to proceed under solvent-free conditions with maximum efficiency.4a,b, 17q, 19 Furthermore, the possibility to translate high temperature and pressure conditions under MW irradiation to continuous-flow processes (the so-called MW-to-flow paradigm), has recently been highlighted.20 This development will lead to a more extended use of MW irradiation protocols to swiftly optimize reaction conditions in view of their translation into flow chemistry. In general, the absence of solvents under MW conditions has been reported to reduce the times of reaction and, generally, to improve yields of products. Moreover, there are many reactions traditionally requiring long reaction times that could be dramatically accelerated under solvent-free MW irradiation conditions.21

Kappe et al. recently addressed a remaining issue on microwave effects in organic synthesis.22 The terms “MW-accelerated” and “MW-induced” reactions have been frequently used in organic synthesis (that is, an electromagnetic field that accelerates and/or induces the chemical reactions). This is confusing if one assumes that any reaction enhancement is caused by a thermal MW effect, which has in many cases been exclusively proved to be a simple thermal effect related to the fast and homogeneous heating achieved under MW irradiation.

A general synthesis of several hydrazones that are not readily available was achieved through MW irradiation of 5- or 8-oxobenzopyran-2(1 H)-ones using a variety of aromatic and heteroaromatic hydrazines. Ješelnik and Varma et al. reported that the reactions occurred within minutes and in high yields (61–98 %) in open vessels when using an unmodified household MW oven.23 The rate enhancement for the reactions conducted under MW irradiation, over conventional heating, was rationalized based on the polarity increase of the reaction medium after the transition from the solid to the liquid phase. Therefore, rapid syntheses of a variety of hydrazones could be performed below the melting points of starting materials. A selective synthesis of quinazolines and benzo[g]quinazolines using a conventional MW oven was also developed by Kumar et al.24 Under optimized reaction conditions, N-arylamidines reacted with various aldehydes in the absence of any Lewis acid catalyst, leading to the formation of quinazolines in good yields (Scheme 1).

Scheme 1.

Synthesis of quinazolines using MW irradiation under SF–CF conditions.

The aminoquinoline moiety is a versatile structural framework that confers a broad spectrum of biological activities.25 Motiwala and co-workers achieved a highly regioselective synthesis of 4-aminoquinolines by nucleophilic aromatic substitution of 4,7-dichloroquinoline with different amines (Scheme 2).26 The reaction was performed using MW irradiation under solvent-free conditions in the absence of any added protic/Lewis acid catalyst.

Scheme 2.

Regioselective synthesis of 4-aminoquinolines using MW irradiation under SF–CF conditions.

The same methodology was applied to the synthesis of aminobenzothiazoles, leading to quantitative yields of products after 15 s–15 min in 70–80 % yields.

Quinoxalines are valuable heterocycles, which possess a wide range of biological activities.27 To avoid the conventional methodologies that use volatile organic solvents, expensive and detrimental metal precursors, and harsh reaction conditions, Zhou and co-workers28 have used solvent- and catalyst-free MW irradiation to prepare quinoxalines. The reaction of 3-(ω-bromoacetyl)coumarins with substituted 1,2-diaminobenzenes afforded the target compounds in moderate to excellent yields (Scheme 3).

Scheme 3.

Synthesis of quinoxalines under SF–CF conditions.

The results demonstrated that the scope of the reaction is broad with regard to 1,2-diaminobenzene derivatives. A variety of substituted quinoxalines were prepared at short reaction times (2–8 min) and high yields (71–98 %) starting from benzylic and 1,2-diaminobenzene derivatives.29 Compounds having quinoline and naphthyridine moieties show antibacterial, antimalarial, and potent anticancer properties.30 An efficient synthesis of quinolines and dihydroquinolines, involving the reaction of alkyl vinyl ketones with aniline derivatives on the surface of a silica gel impregnated with InCl3 was reported.31 Goswami and co-workers32 have reported the reaction of a variety of aryl or heteroaryl amines and aryl vinyl ketones using MW irradiation to afford quinolines and naphtopyridines in good yields (Scheme 4). One interesting aspect of this type of reaction is that less MW energy is required when the heteroaromatic ring contains an extra amine group.

Scheme 4.

Synthesis of quinolines and naphtopyridines under MW irradiation.

Catalyst-free Kabachnik–Fields reactions under solvent-free conditions were explored for the synthesis of α-amino phosphonates. The reaction between dimethylphosphonate and different aldehydes and amines (Scheme 5) investigated by Mu et al.33 proceeded in high yields (76–98 %), with the exception of the reactions with tert-butyl aldehyde (40–53 %).

Scheme 5.

Synthesis of α-amino phosphonates using MW irradiation under SF–CF conditions.

A high-yield synthesis of ring-fused aminals was achieved by Polshettiwar and Varma using a series of cyclic amines and amino benzaldehydes;34 unsubstituted as well as substituted aminoaldehydes underwent α-amination reaction, thus proving the general applicability of this protocol (Scheme 6).

Scheme 6.

Synthesis of ring-fused aminals using MW irradiation under SF–CF conditions.

An efficient method for the synthesis of 2,4,5-triarylimidazoles under catalyst-free, solvent-free MW irradiation conditions has been developed.35 The one-step condensation of benzil, an aromatic aldehyde, and ammonium acetate was found to occur at 120 °C at short reaction times (3–5 min) with good products yields (80–99 %; Scheme 7). The results showed that the scope of the reaction is broad, which is amenable to a wide range of benzylic and aromatic aldehydes.

Scheme 7.

Synthesis of 2,4,5-triarylimidazoles using MW irradiation under SF–CF conditions.

Using a different approach, Zhan and co-workers36 developed a highly efficient, solvent- and catalyst-free, three-component Biginelli synthesis of dihydropyrimidinones (DHPMs). Under optimized reaction conditions (130 °C and 18 min), DHPMs were obtained through a one-pot condensation of aromatic aldehydes (with electron-donating or electron-withdrawing substituents), 1,3-dicarbonyl compounds, and urea or thiourea (Scheme 8).

Scheme 8.

Synthesis of DHPMs derivatives using MW irradiation under SF–CF conditions.

2,3-Dihydroquinazolines are versatile compounds that exhibit a wide spectrum of biological activities.37 Moreover, as they can be easily oxidized to quinazolin-4(3 H)-one analogues, their synthesis has been actively investigated. A recent report by Sarma and Prajapati38 described a solvent- and catalyst-free MW-assisted system for the synthesis of such compounds starting from 2-aminobenzophenone and aldehydes (Scheme 9). The authors found that the nature of the substituent present in aromatic aldehydes had an important impact on the yield of the reaction. Electron-donating substituents reduced the overall yields compared to the increase in yields (relative to benzaldehyde) observed for electron-withdrawing substituents. This methodology worked equally well when ammonium acetate was used as the source of ammonia instead of urea. An efficient MW-assisted synthesis of 1-carboxymethyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles in good to excellent yields and in short reaction times was developed by Martins and co-workers.39

Scheme 9.

Synthesis of 2,3-dihydroquinazolines using MW irradiation.

2-Thiazolines can be synthesized from carboxylic acids and substituted or unsubstituted 1,2-aminoalcohols in the presence of Lawesson’s reagent (LR) under solventless conditions40 (Scheme 10). The transformation is performed in a one-pot reaction with good yields and shorter reaction times.

Scheme 10.

Synthesis of 2-thiazolines using MW irradiation under SF–CF conditions.

Styrylquinolines and their derivatives are valuable imaging agents for β-amyloid plaques on human brain sections in Alzheimer patients.41 The most common method for the synthesis of styrylquinolines is based on acid- or base-catalyzed condensation of 2-methylquinolines with aromatic aldehydes.42 Menéndez and co-workers reported a solvent-free synthesis of 2-styrylquinolines43 by reaction between 2-methylquinolines and benzaldehydes or cinnamaldehydes in the presence of acetic anhydride (Scheme 11). The nature of the substituent in the aromatic ring of the styryl chain, which can be either electron-donating or electron-withdrawing, affects the yield slightly where the range was good (63–95 %).

Scheme 11.

Synthesis of 2-styrylquinolines in SF–CF conditions under MW irradiation.

Pyridine and its derivatives are an important class of heterocycles present in various natural products, functional materials, and active pharmaceuticals.44 These have attracted continuous interest to design protocols for the construction of the pyridine ring.45 Yin et al.45c investigated the synthesis of a series of new hydroxylated 2,4,6-trisubstituted pyridines under SF–CF conditions in MW irradiation. 4-(2,6-Diphenylpyridin-4-yl)phenol and its derivatives can be synthesized through a one-pot–three-component condensation of 4-hydroxybenzaldehyde, acetophenone, and ammonium acetate under optimized reaction conditions (Scheme 12). Furthermore, the hydroxyl-substituted aryl ketone 4-acetylphenol was used for the synthesis of bis- and multihydroxyl compounds (Scheme 12). Various substrates [benzaldehyde, 4-(dimethylamino)benzaldehyde, and 2-furaldehyde] worked well under these conditions to obtain the corresponding products in good yields. Products were obtained without protection of the hydroxyl groups and with a simple isolation procedure.

Scheme 12.

Synthesis of substituted pyridines and bis- and multi-hydroxyl compounds.

1,4-Pyranonaphthoquinone and its derivatives exhibit a high anticancer activity against human cervical carcinoma (HeLa), human epidermoid carcinoma KB,46 and human hepatocellular carcinoma (HepG2) cell lines.47 More precisely, the 1,4-pyranonaphthoquinone derivative, α-lapachone, exhibited antitumor activity; C-ring modifications furnished compounds with low toxicity and enhanced bioactivity48 (Scheme 13). Functionalized 1,4-pyranonaphthoquinones were synthesized stereoselectively through one-pot sequential reactions of benzaldehydes, anilines, diethyl acetylenedicarboxylate, and 2-hydroxynaphthalene-1,4-dione under MW irradiation.49 No solvent or catalyst were used for the transformation to biologically relevant heterocycles such as dihydropyrido-[4,3-d]pyrimidines, which were obtained by performing two Michael additions, aldol condensation, and annulation reactions. The salient features of these protocols are simple and easily available starting materials, no catalysts or solvent, water as a byproduct, and the possibility to obtain the corresponding products by recrystallization in ethanol, which reduces the waste at the end of the reactions.

Scheme 13.

Synthesis of 1,4-pyranonaphthoquinones under MW irradiation.

The hetero Diels–Alder reaction is a versatile method for the construction of six-membered heterocycles.50 Prajapati et al. designed a MW-promoted aza-Diels–Alder reaction between aldimines and 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil for the synthesis of dihydropyrido-[4,3-d]pyrimidines.51 Notably, urea is effectively used as a benign source of ammonia in the absence of any solvent or catalyst. It is important to point out that, when the reaction time was increased from 2 to 5 min, a mixture of two products was formed. Along with the 5,6-dihydro compound, a small amount of the corresponding aromatic pyridopyrimidine derivative was also formed (Scheme 14). When the reaction of 6-(2-morpholinovinyl)-1,3-dimethyl uracil with benzaldehyde and urea was performed under identical conditions for 12 min using MWs, 1,3-dimethyl-5-phenyl-pyrido[4,3-δ]pyrimidine-2,4-dione was obtained as the sole product (Scheme 15). The substrate scope was explored for various aldehydes and uracils to develop a library of the corresponding compounds.

Scheme 14.

Synthesis of 5,6-dihydropyrido[4,3-d]pyrimidines.

Scheme 15.

Synthesis of pyrido[4,3-d]pyrimidines.

Perumal et al. reported regioselective Biginelli reactions under SF–CF conditions and MW irradiation.52 A series of ethyl 2-oxo/thio-4-aryl-6-(arylsulfonylmethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylates was synthesized under optimized conditions in good to excellent yield. Notably, under MW irradiation, the reactions were considerably faster compared to thermal conditions (Scheme 16). The present protocol proceeded regioselectively and yielded exclusively one regioisomer (Figure 4).

Scheme 16.

Synthesis of tetrahydropyrimidines under thermal and MW irradiation.

Figure 4.

Possible regioisomer products in the synthesis of tetrahydropyrimidines.

Pyrazoles and their derivatives are important drug moieties in pharmaceutical and medicinal chemistry.53 In general, for the synthesis of pyrazoles, various types of acids or heterogeneous catalysts are used. Pyrazoles and diazepines were investigated under MW irradiation and SF–CF conditions.54 The reaction mixture was first ground in a mortar using a pestle, yielding almost 40 % of the corresponding product; further heating (80 °C, 30 min) of the reaction mixture increased the conversion to 70 %. Under MW irradiation at 120 °C and for 5–15 min, complete conversion of the products was achieved (Scheme 17). This protocol could be used for the synthesis of other fused pyrazoles and diazepines and other important heterocyclic reactions.

Scheme 17.

Synthesis of pyrazoles and diazepines under microwave irradiation.

6.2. Ultrasound irradiation

Over the past decade, many efforts have been made both in industry and academia to protect the environment and prevent waste.4j,q, 55 Sonication chemistry has gained considerable importance in many research areas such as nanomaterial synthesis,56 biodiesel production,57 spent nuclear fuel,58 and even in food and beverage pasteurization.59 Ultrasound-promoted organic synthesis is a powerful and important green synthetic methodology.60 The implementation of ultrasound irradiation in organic reactions provides a specific activation based on physical properties such as acoustic cavitation. Because of these versatile properties, ultrasound can be used as an important tool to perform a number of chemical reactions in high yield at shorter reaction times and with simpler and easier workup conditions compared to some conventional methods.14b, 61

Using ultrasound irradiation, Yang et al.62 successfully performed a simple, high yielding, and efficient Michael addition of ferrocenylenones to aliphatic amines in the absence of solvents and catalysts at room temperature in 0.5–2 h reaction time (Scheme 18). The reaction worked well for primary and secondary aliphatic amines, but failed for less nucleophilic aromatic amines, a selectivity that could be useful to discriminate between the two types of amines. The authors performed a comparative study using aqueous-phase transformations and found that prolonged reaction times and lower yields were obtained under these conditions. The scope of the reaction was extended to 3-ferrocenylchalcones, ethylacrylates, and acrylonitriles, affording Michael adducts that were direct precursors of β-amino acids.

Scheme 18.

Synthesis of Michael adducts using ultrasound irradiation under SF–CF conditions.

Another green alternative for the synthesis of α-amino phosphonates was presented by Xia and Lu.63 In this work, the authors reported a one-pot procedure using aldehydes, amines, and diethylphosphite under ultrasound-assisted SF–CF conditions; aromatic amines yielded the best results (83–92 %). Guo et al. described a highly efficient (80–99 % yield) and facile method for the condensation reaction of heterocyclic as well as aliphatic 1,2-diketones with 1,2-diamines.64 The ultrasound-promoted synthesis of rhodanine derivatives, of potential pharmacological and biological interest, was explored by Rostamnia and Lamei.65 The reaction was performed in water by simple mixing of dimethyl or ethyl acetylenedicarboxylate, carbon disulfide, and an amine; products were isolated in high yields (86–94 %) and in short reaction times (3–5 min) by straightforward filtration (Scheme 19).

Scheme 19.

Catalyst-free synthesis of rhodanines in water using ultrasound irradiation.

The protection of alcohols was successfully achieved using hexamethyldisilazane under ultrasound irradiation. Mojtahedi and co-workers66 developed a protocol that enabled the chemoselective protection (in favor of less hindered hydroxyls) of various types of alcohols and phenols in good to excellent yields (60–99 %) at room temperature and without a solvent. The ring-opening reaction of epoxides was easily performed under ultrasound irradiation conditions. Palmisano et al.67 found that under simultaneous ultrasound/MW irradiation a series of mono-, di-, and trisubstituted oxiranes reacted rapidly and highly regioselective with sodium azide or 1-(3-chlorophenyl)piperazine in acceptable-to-high yields (50–95 %). In another study, Abaee et al. achieved the stereoselective ring opening of various epoxides using aromatic and aliphatic amines under aqueous conditions.68 The reaction proceeded smoothly in good yields (80–98 %) and at short reaction times (10–30 min.). Azarifar and Sheikh reported a new approach for the synthesis of 4H-3,1-benzoxazin-4-one scaffolds, which offered a simple and versatile one-pot procedure for the condensation of anthranilic acids with terephthalaldehyde in the presence of excess of acetic anhydride.69 The reactions proceeded smoothly in very good yields (70–85 %) and at relatively short reaction times (45–65 min.). Mulakayala and co-workers70 reported the synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones from 4-chloro-2-oxo-2H-chromene-3-carbaldehyde and aromatic amines (another example of an ultrasound-promoted reaction) at very short reaction times (5–9 min) and high yields (Scheme 20).

Scheme 20.

Catalyst-free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones using ultrasound irradiation.

Bandyopadhyay et al. explored a new protocol for an efficient and simple ultrasound-assisted aza-Michael reaction in water.71 Several examples of ultrasound-induced addition of amines to α,β-unsaturated ketones, esters, and nitriles were shown to occur in high yields (86–98 %) and in an expeditious manner (5–10 min).

6.3. Mechanochemical mixing

Mechanochemical reactions under ball milling conditions have been ascribed to the heat generated in the milling process, favored by the large area of contact between the solids. However, towards the end of the last century, it was noticed that mechanochemical processes were completely different from thermal processes.72 Mechanochemical reactions or mechanosyntheses are usually performed by using mechanical sources, such as grinding in ball mills. It is recognized that co-grinding and co-milling of solid reactants are feasible greener methods for the synthesis of molecular compounds and crystal engineering,73 for solventless synthesis of supramolecular aggregates,74 co-crystals, or a coordination framework.75

Interest in mechanochemical synthesis approach is growing rapidly because of its prospective to bring together both convenient and greener routes for the synthesis of chemical compounds and pharmaceutical drug intermediates.74c, 76 Many reports can be found on solventless conditions, with reactions performed by using a mortar and a pestle,77 whereas high-speed ball milling (HSBM) is a comparably attractive solvent-free method gaining considerable interest in recent years. In the HSBM method, balls located inside the vessel are generally shaken with the chemicals at very high speed.78 The high speed achieved under ball milling conditions results in a homogeneous mixture of reactants, which successively facilitates chemical reactions. The method has been successively applied to number of organic chemical reactions.

Mack et al. reported several solvent-free protocols using mechanochemical techniques, including the synthesis of dialkyl carbonates using HSBM,78b the reduction of esters by HSBM,72d solvent-free Tishchenko reactions,79 the synthesis of α,β-unsaturated esters,80 and some related environmentally benign protocols.72c, 78b

By using a simple grinding mode, Kumar et al.81 could perform the multicomponent synthesis of polyhydroquinoline derivatives via Hantzsch condensation. The main advantages of this procedure are mild reaction conditions, short reaction times, efficient yields, and easy workup of the final mixture. Several aldehydes and several active methylene compounds (β-ketoesters, malononitrile, and ethyl cyanoacetate) in the presence of dimedone and ammonium acetate (Scheme 21) were utilized; good-to-excellent yields were obtained after purification through simple recrystallization from ethanol.

Scheme 21.

Multicomponent synthesis of hexahydroquinoline derivatives through grinding under SF–CF conditions.

Kumar and Sharma developed a SF–CF multicomponent domino reaction for the synthesis of 1,4-dihydropyridines using aldehydes, amines, (diethyl acetylenedicarboxylate), and malononitrile/ethyl cyanoacetate by grinding.82 In a typical synthesis protocol, the corresponding reagents were ground in a porcelain mortar using a pestle under catalyst-free conditions. It is important to point out that the 100 % conversions were observed under solvent-free conditions, but in ethanol no corresponding product was observed. Overall, the reactions are exothermic, resulting in the liquefaction of the reaction mixture and solidification of the products at the end of the reaction (Scheme 22). Furthermore, the synthesized dihydropyridines were coupled with cyclohexanone for the synthesis of hexahydrobenzo[b][1,8]naphthyridine in the presence of sodium dodecyl sulfate (SDS) in aqueous medium.

Scheme 22.

Synthesis of 1,4- dihydropyridines and hexahydrobenzo[b][1,8]naphthyridines.

Nitroamines are also an important family of intermediates with the possibility to be reduced to 1,2-diamines or oxidized to α-amino acids. These compounds are typically synthesized by the addition of nitro compounds to an azomethine function through an aza-Henry reaction mechanism; many examples of catalyzed reactions are reported in the literature. A simple, atom economical, and efficient green protocol was developed by Choudhary and Peddinti83 for the preparation of nitroamines and nitrosulfides in quantitative yields by the Michael addition of amines and thiols to nitroalkenes through simple mixing or grinding (Scheme 23) within minutes at room temperature.

Scheme 23.

Synthesis of nitroamines and nitrosulfides via grinding under SF–CF conditions.

Thiazole derivatives exhibit important biological properties such as antibacterial, antifungal, and anti-inflammatory activities.84 Recently, the efficient, facile and high yielding synthesis of 2,4-disubstituted thiazoles was achieved by a one-pot reaction of aldehydes and α-bromoketones with thiosemicarbazide by grinding under SF–CF conditions.85 A variety of α-bromoacetophenone-bearing electron-withdrawing or electron-donating groups on the aromatic ring were tested (Scheme 24) as well as a series of substituted aromatic aldehydes bearing both electron-withdrawing and electron-donating groups tethered to an aromatic ring. All reactions proceeded smoothly, and the desired products were obtained in excellent yields.

Scheme 24.

Multicomponent synthesis of 2,4-disubstituted thiazoles via grinding under SF–CF conditions.

A similar approach was followed by Mashkouri and Naimi-Jamal, which used ball-milling to prepare pyrano[2,3-d]pyrimidine-2,4(1 H,3 H)-diones86 from a stoichiometric mixture of an aldehyde, malononitrile, and barbituric acid (Scheme 25). A plausible mechanism involving a Knoevenagel condensation followed by a Michael addition and final intramolecular cyclization was proposed.

Scheme 25.

Multicomponent synthesis of pyrano[2,3-d]pyrimidine-2,4(1 H,3 H)-diones through ball milling under SF–CF conditions.

The synthesis of α,β-dipeptides and several new β,β-dipeptides under solvent-free conditions, starting with the urethane-protected β-amino acid N-carboxyanhydrides and α- or β-amino esters (Scheme 26), was recently reported by Hernández and Juaristi.87 The peptides were obtained in high yields (79–96 %), and no racemization or epimerization were observed. Substituted aldehydes and ketones were quantitatively converted into their oxime hydrochloride hydrates, phenylhydrazones, and 2,4-dinitrophenylhydrazones under SF–CF conditions by Mokhtari and co-workers (Scheme 27).76d They also developed a new and effective gas–solid deprotection methodology for oximes using nitrogen dioxide as the reagent. It is important to note that the corresponding products were obtained by melting of the reactant (phenyl hydrazine).

Scheme 26.

Multicomponent synthesis of α,β-dipeptides and β,β-dipeptides through ball milling under SF–CF conditions.

Scheme 27.

Synthesis of phenylhydrazones through melting or ball milling under SF–CF conditions.

Giri and co-workers88 successfully performed the persilylation of phenols, ribonucleosides (Scheme 28), and protected nucleosides under solvent-free conditions using ball-milling. The authors found that under the investigated conditions and for this particular type of process, the grinding frequency (30 Hz for better results) was found to be an important parameter.

Scheme 28.

Nucleoside protection under SF–CF conditions.

A solvent-free Wittig reaction was reported for the first time by Balema and co-workers in 2002.89 It was found that phosphorus ylides could be generated under a mechanically induced solid-state reaction with good-to-excellent yields (70–99 %). The reaction can also be performed in one pot, starting with triphenylphosphine, an organic halogenide, and an organic carbonyl reagent in the presence of K2CO3. An important feature of this methodology is the discrimination of Z- and E-substituted products in favor of more thermodynamically stable E-stilbenes. It should be highlighted that in solution Z-stilbenes (or E:Z mixtures) are preferably formed.

In a recent report, Métro and co-workers90 used N,N′-carbonyldiimidazole (CDI) as a carboxylic-acid activator in the mechanosynthesis of amides in the complete absence of an organic solvent. Primary and secondary amine hydrochlorides were efficiently converted to the corresponding amides, and the reaction was found to be accelerated when performed under solvent-free conditions (Scheme 29).

Scheme 29.

CDI-mediated amide synthesis through ball milling under SF–CF conditions.

The process allows the preparation of sterically hindered amines (e.g., 1-adamantane carboxylic acid was converted in 77 % yield), hydroxylamines, and hydrazines. Moreover, the synthesis is highly stereoselective (when using either enantiopure amines or enantiopure carboxylic acids) and can be performed on a multigram scale.

Complex molecular architectures based on boronic acids can be easily achieved through the condensation of phenyl-based boronic acids, pentaerythritol, and a triamine (Scheme 30). Severin and co-workers found that the reaction proceeded in good-to-excellent yields after 1 h of ball milling.91

Scheme 30.

Synthesis of boranate-based cages through ball milling under SF–CF conditions.

Large macrocycles with imine and borasiloxane linkages can be also obtained by using mechanosynthesis. These macrocycles, reported by Pascu and co-workers,92 were obtained from a simple multicomponent condensation of tBu2Si(OH)2, 4-formylbenzeneboronic acid, and diamines in good yields (Scheme 31).

Scheme 31.

Synthesis of borasiloxane-based macrocycles through ball milling under SF–CF conditions.

A solventless mechanochemical-promoted oxidation of sulfones and thioether using Oxone as the oxidant was developed by Cravotto and co-workers.93 The method is scalable, and Oxone can be reused when it is used in stoichiometric excess. Another interesting feature is the chemoselectivity of the reaction for which sulfones could be isolated in excellent yields without traces of sulfoxides (Scheme 32).

Scheme 32.

Solvent-free chemoselective oxidation of thioethers and thiophenes through ball milling.

Desymmetrization of ortho- and para-phenylenediamines is another example of the potential of mechanochemical-assisted reactions. In a recent report, Štrukil and co-workers94 were able to quantitatively convert the amines into nonsymmetrical mono- and bis-(thio)ureas or mixed thiourea–ureas in high yield (>95 %) in two steps without isolating the intermediates.

Aakeröy and co-workers95 used a mechanochemical approach to develop a library of aldoximes (22 examples, 59–100 %) from aldehydes and hydroxylamine hydrochloride in the presence of sodium hydroxide. The protocol is highly versatile as it allows the use of aldehydes both with electron-withdrawing or electron-donating groups. Moreover, the conversion is not affected by the presence of functional groups such as [BOND]COOH or [BOND]OH, occurs at room temperature, is scalable, and uses a simple workup.95

The first synthesis of chemically stable isoreticular covalent organic frameworks (COFs) using a mechanochemical approach (grinding) was developed very recently by Biswal and co-workers.96 The reaction is fast, solvent-free, and occurs at room temperature. Interestingly the structures obtained by this methodology showed a graphene-like layered morphology (exfoliated layers), which was not observed when the reaction was performed under conventional (solvent-assisted) conditions.

6.4. Conventional heating and room temperature

Miesch and Wendling97 reported one-pot nonphotochemical [2+2] cycloadditions at room temperature between readily available cyclic ketene trimethylsilyl and electrophilic acetylenes (Scheme 33) using CCl4/ZrCl4 and CCl4 under SF–CF conditions and found that in this case higher yields than for conventional methods were obtained.

Scheme 33.

[2+2] Cycloaddition of cyclic ketene trimethylsilyl acetals and electrophilic acetylenes under SF–CF conditions.

The noncatalyzed aldol addition of 1,3-dicarbonyl compounds with activated aldehydes was reported by Rohr and Mahrwald,98 which proceeded at room temperature in nearly quantitative yields and with high regioselectivity. However, no aldol reactions were observed when unactivated aldehydes were used.

A mild and efficient synthesis of dithiocarbamates avoiding multistep procedures and the use of costly toxic reagents and catalysts was developed99 (Scheme 34) using commercially available alkyl halides and amines; one-pot reactions were completed at room temperature after 3–12 h, affording 68–97 % yields. Moreover, a wide range of S-alkyl dithiocarbamates were obtained on a multigram scale, and the compounds could be subsequently isolated by simple extraction. The reaction accommodated epoxides as well.100

Scheme 34.

Synthesis of dithiocarbamates under catalyst-free conditions.

Michael addition of thioacetic acid to a variety of conjugated alkenes under SF–CF conditions was found to proceed in short reaction times (5–60 min) and in good-to-high yields. Sobhani and Rezazadeh found that the best results were obtained when the reaction was performed in the presence of an excess amount of thioacetic acid at room temperature.101 The one-pot synthesis of 3,3′-(benzylene)-bis(4-hydroxy-2H-chromen-2-one) derivatives under uncatalyzed and solvent-free conditions was reported by Shaterian and Honarmand (Scheme 35).102 The authors found that substituents on the aromatic ring (both with electron-donating and electron-withdrawing groups) do not show any electronic effects; using this methodology, the bis-adducts were produced in excellent yields. A favorable comparison with conventional methods and a plausible mechanism for the reaction were also interesting features of this work.

Scheme 35.

Synthesis of 3,3′-(benzylene)-bis(4-hydroxy-2H-chromen-2-one) derivatives under SF–CF conditions.

A simple procedure for the solvent-free ring opening of epoxides with (aminomethyl)phosphonates for the synthesis of new {[(2-hydroxyethyl)amino]methyl}-phosphonates was developed by Kaboudin and Sorbiun,103a which proceeded at 70–90 °C. Ring opening, as expected, occurred at the sterically less hindered position of the epoxide (Scheme 36). However, the ring opening of styrene oxide with (aminomethyl)phosphonates occurred at both sterically less and more hindered positions of the epoxide ring.

Scheme 36.

Ring opening of epoxides with [amino(aryl)methyl]phosphonates under SF–CF conditions.

Yet another efficient method for the synthesis of α-amino phosphonates, under SF–CF conditions, was developed by Katla and co-workers103b using aromatic aldehydes, amines, and trimethyl/triethyl phosphite. The method involves mild reaction conditions (80–85 °C), easy workup, and clean reaction profiles with the formation of the products in good-to-excellent yields (80–93 %).

A one-pot reaction of nitriles, hydroxylamine, and anthranilic acids for the preparation of 2-aryl/alkyl-4(3 H)-quinazolinones has been reported recently.104 The products were obtained in high yields (85–93 %) using fairly short reaction times, under neutral conditions, and did not require purification by column chromatography (Scheme 37). In the case of amines, however, a complex mixture was obtained. The higher nucleophilicity of hydroxylamine explains the observed reactivity.

Scheme 37.

Synthesis of 2-aryl/alkyl-4(3 H)-quinazolinones under SF–CF conditions.

Rao et al.105 developed an efficient protocol for the pivaloylation of alcohols under neat conditions to afford the corresponding pivaloyl esters in excellent yields. Although all attempts to pivaloylate phenols failed, protection of napthols was successfully achieved by increasing the reaction time. The authors could show selectivity between primary alcohols versus secondary alcohols and aliphatic alcohols versus aromatic alcohols. Interestingly, the conversion of a tert-butyl silyl (TBS)-protected alcohol to pivaloyl (Piv) protection occurred in one pot under neat and closed-vessel conditions.

A cost effective and environmentally friendly method for the synthesis of amide derivatives of N-protected amino acids and various amines was demonstrated under mild reaction conditions.106 This methodology using the same reaction condition was applicable to various other inactive esters commonly deployed as protecting groups. N-protecting groups - including tert-butyloxycarbonyl (Boc) and carboxybenzyl (Cbz) were found to be compatible under these experimental conditions.

Chakravarty and Swamy107 reported the synthesis of useful sulfanyl-substituted allylphosphonate intermediates for Horner–Wadsworth–Emmons reactions (Scheme 38). The products were obtained in 15 min under catalyst-free, base-free, and solvent-free conditions using MW irradiation. The vinyl-to-allyl phosphonate ratio obtained depended on the substituents present on the allene as well as on the thiol.

Scheme 38.

Synthesis of allyl phosphonates under SF–CF conditions.

In a recent study, Alonso et al.4g have shown that the addition of phosphanes to alkenes (styrenes, N- and S-vinyl compounds, as well as activated alkenes) occurs readily; tertiary phosphanes were obtained in moderate-to-high isolated yields (70–91 %) at 70 °C or room temperature. The authors also investigated the hydrophosphanation of phenylacetylene and found that the reaction followed an anti-Markovnikov mechanism with high regio- and stereoselectivity (Z/E=90:10).

The Betti reaction represents a useful process to obtain amidoalkyl naphthols and their derivatives,108 which are useful precursors for the synthesis of bioactive 1-aminomethyl-2-naphthols; their bradycardiac and hypotensive effects have been evaluated in humans.109 Furthermore, they are attractive compounds as chiral ligands in enantioselective reactions.110

Mohammadpoor-Baltork et al. synthesized new bis-Betti bases through a condensation reaction between aryl aldehydes and 3-amino-5-methylisoxazole in a one-pot procedure (Scheme 39).111 Although the reaction can be performed in a range of solvents such as water, ethanol, PEG-400, acetonitrile, and toluene for a period of 3 h at 80 °C, the best results were obtained under solvent-free conditions.

Scheme 39.

Synthesis of bis-Betti bases through a pseudo-five-component reaction under SF–CF conditions.

N-Nucleophiles such as imidazoles, triazoles, pyrroles, and indoles have become increasingly important building blocks in organic synthesis, pharmaceutics, and material science.112 Generally, these types of syntheses are performed through cross-coupling reactions of 6-halopurines with heteroaryl organometallic reagents in the presence of Pd or Ni catalysts. These are efficient routes for the synthesis of 6-heteroarylpurine derivatives through C[BOND]N coupling protocols.113 However, the popularity of this method is limited by the fairly harsh reaction conditions and the reduced stability/accessibility of the corresponding organometallic species.

Recently, Guo and Qu et al. prepared C6-azolyl purine nucleosides114 through a C[BOND]N coupling reaction of unprotected 6-chloropurine nucleosides and N-heterocycles under SF–CF conditions (Scheme 40) in excellent yield and short reaction time; this protocol can be extended to the reaction between 1-H-triazole and various 6-chloropurines (reactions schemes not shown).

Scheme 40.

Reactions of 6-chloropurine nucleosides with N-nucleophiles under SF–CF conditions.

In addition to oxygen, H2O2 is one of the “greenest” oxidants.1g, 115 The oxidation protocol often uses a 30 % aqueous solution of H2O2, which is a nontoxic, environmentally friendly, and inexpensive oxidant. Jereb116 reported the oxidation of sulfides to sulfones under SF–CF reaction conditions using a 30 % aqueous solution of H2O2 at 75 °C (Scheme 41).

Scheme 41.

Oxidation of sulfides to sulfones under catalyst-free conditions.

Structurally diverse sulfides were converted to sulfones irrespective of the aggregate state and the electronic nature of the substituents. In spite of the heterogeneous reaction mixtures throughout the work, no problems with stirring and reaction progress were observed. In various cases, only 10 mol % excess of H2O2 was used, contributing considerably to a high atom economy of the process. It is important to note that some solid substrates required a variable excess of H2O2; however, the reactions were performed strictly with no organic solvents. The transformation was demonstrated to be responsive for scale-up with both liquid and solid sulfides. In addition, isolation and purification of the crude products could be simply accomplished through simple filtration and crystallization. This protocol is an alternative to the one reported in the previous section using ball-milling (see Scheme 32).

Liu and coworkers reported benzoyl and ferrocenoyl 3,4-dihydropyrimidin-2(1 H)-ones (-thiones) (DHPMs) under SF–CF Biginelli condensation of 1-ferrocenylbutane-1,3-dione 1-phenylbutane-1,3-dione, hydroxyl benzaldehyde, and urea or thiourea117 (Scheme 42).

Scheme 42.

Dihydropyrimidine synthesis.

The radical-scavenging abilities of the obtained DHPMs were investigated by reacting DHPMs with the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS.+), the galvinoxyl radical, and the 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), respectively. The benzoyl and ferrocenoyl DHPMs were able to quench ABTS.+, the galvinoxyl radical, and DPPH. It is important to note that phenolic hydroxylic substituent is important for DHPMs to quench ABTS.+ and that the presence of the ferrocene moiety converted DHPMs into ABTS.+ scavengers even without a phenolic hydroxyl group attached. This interesting concept, hopefully applicable to other important multicomponent reactions, will avoid expensive catalysts/regents and solvents.

Organophosphorus compounds have been broadly used in various important drug-intermediate, agrochemical, and pharmaceutical productions.118 In recent years, increasing focus has also been dedicated for the design of metal-phosphane complexes with anticancer activity and as potential substitutes of the current platinum drugs.119 There are various important processes reported for the hydrophosphanation of alkenes catalyzed by Pd and Ni complexes.120

The process was high yielding although it suffered from some lack of atom economy under rather harsh reaction conditions, involving 5 mol % Ni[P(OEt)3]4 and 1 equiv of Et3N in benzene at high temperature. Other reported protocols also suffered drawbacks, such as expensive and toxic and harsh reactions conditions.121

Alonso et al.4g investigated the hydrophosphanation of alkenes in the absence of a catalyst, with no solvent, and in regioselectively. First, the effect of solvent was investigated for the model reaction between diphenylphosphine and styrene at 70 °C under an Ar atmosphere (to prevent the in situ oxidation of diphenylphosphine to the resultant phosphine oxide). Notably CH2Cl2, MeCN, and EtOH were found not to be suitable solvents, as low conversion to the product was obtained in THF, DMSO/DMF, and toluene (Table 1). It is important to note that a no-solvent condition was preferable to obtain excellent yields of the corresponding product. The applicability of further substrates was explored under optimized conditions and is depicted in Scheme 43.

Table 1. Optimization of reaction conditions.inline image



Conversion [%]























No Solvent


Scheme 43.

Hydrophosphanation of alkenes.

7. Conclusions and Future Aspects

Synthetic organic protocols using greener and more efficient methodologies are crucial for the development of more sustainable processes. This contribution has been aimed to highlight the importance of SF–CF methodologies in organic synthesis, with the inclusion of a comprehensive range of examples and reactions that illustrate the significant strides made in the research field over the past few years. Major developments have mainly focused on solving typical issues of organic reactions including insolubility of reagents/products, long reaction times, low yields, and selectivity issues in nonconventional solvents or in the absence of catalysts. However, many different alternatives to further advancements in the field of greener synthetic processes remain largely unexplored. Promising examples of these include laser-assisted reactions at room temperature, new media for synthetic organic processes (e.g., continuous flow reactions and process intensification), and related innovative protocols that are at the core of some scientific and technological advances expected in years to come. In the light of these premises, it is evident that the partnership between new reaction conditions with SF–CF processes can offer several advantages in the design of future synthetic protocols and it can also pave the way to advancing the field, leading to a more sustainable future society.

List of abbreviations


2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical




solvent- and catalyst-free


covalent organic framework




2,2′-diphenyl-1-picrylhydrazyl radical


deep eutectic mixtures


high speed ball milling


human cervical carcinoma


human hepatocellular carcinoma


Lawesson’s reagent




polyethylene glycol


tert-butyldimethylsilyl chloride


This work has been supported by Fundação para a Ciência e a Tecnologia through grant PEst-C/EQB/LA0006/2011. M.B.G. thanks the PRAXIS program for the award of research fellowship SFRH/BPD/64934/2009. We thank Ms. Lauren Drees for proof-reading and revising the manuscript.

Biographical Information

Manoj B. Gawande received his Ph.D. degree in Chemistry in 2008 from the Institute of Chemical Technology, Matunga, Mumbai, India, under the supervision of Prof. R. V. Jayaram. After several research stays in Germany, South Korea, and Portugal, he was recently a Visiting Professor at Nanyang Technological University, Singapore. Currently, he is working as a Senior Researcher at the Regional Centre of Advanced Technologies and Materials at Palacky University, Czech Republic. His research interests include nanocatalysis, design of nanocatalysts and their applications in green organic syntheses.

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Biographical Information

Vasco D. B. Bonifácio received his Ph.D. in Chemistry (Organic Chemistry) in 2006, from Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Portugal. After two years at Wuppertal, Germany, he was appointed Assistant Reseacher at the Massachusetts Institute of Technology (MIT) Portugal Program in 2008, where he started working on supercritical CO2 polymerizations. In 2012, he was a visiting researcher at MIT, Boston, USA. His main interests are nanomedicine (polymer therapeutics) and molecular electronics (chemical and biochemical sensors). Currently, his research is focused in the synthesis of complex 3D polymer architectures using clean technologies.

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Biographical Information

Rafael Luque [Ph.D. 2005 from Universidad de Cordoba (UCO), Spain] has obtained significant experience with biomass and waste valorization practices with regard to materials, fuels, and chemicals over the past 10 years after spending three years at the Green Chemistry Centre of Excellence at the University of York. Since 2009, he is Ramon y Cajal Fellow at UCO. He has recently been awarded the Marie Curie Prize from Instituto Andaluz de Quimica Fina in Spain (2011), the Green Talents award from the Federal Ministry of Education and Research in Germany (2011), the TR35 Spain 2012 from Technology Review-MIT and recently honoured as HKUST Distinguished Engineering Fellow 2013.

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Biographical Information

Paula Sério Branco was born in 1963 in Angola and grew up in Portugal. After a licentiateship in Chemistry at Faculdade de Ciências, UL, she joined Faculdade de Ciências e Tecnologia, UNL, in 1987 as a Teaching Assistant, where she obtained her Ph.D. (organic chemistry) in 1992 on the synthesis of heterocyclic compounds under the supervision of Prof. Sundaresan Prabhakar. Since 1992 until present, she is an Assistant Professor, and the main subject of her lectures is organic chemistry. Her research interest focuses mainly on organic chemistry involving the development of new methods for the synthesis of heterocycles alongside the study of chemical reactions mechanisms.

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Biographical Information

Rajender S. Varma was born in India (Ph.D., Delhi University 1976). After postdoctoral research in UK, he was a faculty member at US Universities prior to joining the Sustainable Technology Division, US Environmental Protection Agency (EPA), in 1999. His diverse experience ranges from natural products to environmentally friendlier alternatives for synthesis using microwaves, ultrasound, and mechanochemical mixing; recently, he focused on the green synthesis of nanomaterials and applications of magnetically retrievable nanocatalysts in benign media. He received the ‘Visionary of the Year Award’, CT, 2009 and the Silver Medal, EPA National Honor Awards 2013, for his leadership in Green Chemistry.

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