An Ideal Reagent for Green Chemistry? - American Chemical Society

Review pubs.acs.org/OPRD

Cp2TiCl: An Ideal Reagent for Green Chemistry? María Castro Rodríguez,† Ignacio Rodríguez García,‡ Roman Nicolay Rodríguez Maecker,§ Laura Pozo Morales,† J. Enrique Oltra,∥ and Antonio Rosales Martínez*,†,§,⊥ †

Department of Chemical Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain Organic Chemistry, ceiA3, University of Almería, 04120 Almería, Spain § Petrochemical Engineering, Universidad de las Fuerzas Armadas-ESPE, 050150 Latacunga, Ecuador ∥ Department of Organic Chemistry, Faculty of Science, University of Granada, 18071 Granada, Spain ‡

ABSTRACT: The development of Green Chemistry inevitably involves the development of green reagents. In this review, we highlight that Cp2TiCl is a reagent widely used in radical and organometallic chemistry, which shows, if not all, at least some of the 12 principles summarized for Green Chemistry, such as waste minimization, catalysis, safer solvents, toxicity, energy efficiency, and atom economy. Also, this complex has proved to be an ideal reagent for green C−C and C−O bond forming reactions, green reduction, isomerization, and deoxygenation reactions of several functional organic groups as we demonstrate throughout the review.

1. INTRODUCTION Green Chemistry, also called sustainable chemistry, is a term coined in the early 1990s by Anastas et al.1 of the US Environmental Protection Agency (EPA). It is an area of chemical engineering and chemistry centered on the chemical methodologies and design of components that minimize the use and formation of hazardous substances. The 12 principles of Green Chemistry reported by Anastas et al.1 are listed in Scheme 1. This new concept allowed change from the traditional concepts of reaction efficiency and selectivity focused on chemical yield, to one that assigns value, among others, waste prevention, atom economy, and elimination of hazardous and/ or substances. For decades in the area of chemical synthesis, great efforts were made to develop newer methodologies and reagents without considering the sustainability of chemical processes. The development of Green Chemistry inevitably involves the development of new methodologies and green reagents which have experienced significant growth over the past two decades while contributing to the development of sustainable chemistry. Many of these reagents largely comply with the principles set for Green Chemistry. Some examples of these reagents were reported by P. Tundo and V. Esposito2 and have involved the design of new synthetic pathways which allow chemical methodologies to be performed in a very controlled way, so as to minimize drastically, or even eliminate, all the environmental impact. In this context, new green reagents are of paramount importance in the development of alternative methodologies in chemical synthesis that catalyze several efficient transformations, under mild reaction conditions, with simple experimental procedures, safer solvents, and avoiding toxic wastes. In this way, after the seminal works reported by Nugent and Rajanbabu in the radical opening of epoxides,3 titanocene monochloride (Cp2TiCl) has proved to be a mild single-electron transfer (SET) which has found wide use in organometallic and radical4 chemistry, which include, if not all, © 2017 American Chemical Society

at least some of the 12 principles reported for Green Chemistry. In this review, we highlight that Cp2TiCl can be considered an ideal reagent for green C−C and C−O bond forming reactions, green reduction, isomerization, and deoxygenation reactions of several functional organic groups. The content of the review aims to demonstrate that Cp2TiCl is a reagent which evaluates the chemical yield, selectivity, solvents, catalysis, toxicity, and efficiency according to the atoms economy principle established by Trost.5

2. Cp2TiCl AS A GREEN CHEMISTRY REAGENT 2.1. Synthesis and Properties of Cp2TiCl. Cp2TiCl is a single-electron-transfer (SET) complex that can be easily prepared from commercial and nontoxic Cp2TiCl2 (Scheme 2) by using economic and nontoxic reductants such as Mn or Zn.6a,b In solution, Cp2TiCl is in an equilibrium between mononuclear and dinuclear species (Scheme 2).7 It has recently been reported that the stoichiometric metal reductant can be replaced by an organic reducing agent.6c The structures of these species of titanium(III) show an unpaired d electron, giving them mild electron-reducing character (E°= −0.8 vs Fc+/Fc).8 This reducing character together with the presence of a vacant site allows the coordination of a heteroatom with free valence electrons, thus initiating the monoeletronic transfer through an innersphere mechanism.9 In the seminal works reported by Nugent and Rajanbabu,3 it was observed that Cp2TiCl was a novel single-electron transfer species capable of generating a radical from an epoxide, which under different experimental conditions could give cyclization reactions, intermolecular additions, reductions, and deoxygenation reactions. From this moment, this SET was widely used in Received: March 15, 2017 Published: June 12, 2017 911

DOI: 10.1021/acs.oprd.7b00098 Org. Process Res. Dev. 2017, 21, 911−923

Organic Process Research & Development

Review

Scheme 1. Principles of Green Chemistry

Scheme 2. Equilibrium of species in the preparation of Cp2TiCl from Cp2TiCl2

Scheme 3. Stoichiometric Opening of Epoxides with Cp2TiCl

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chemical synthesis,10 meeting if not all, at least many of the 12 principles reported for Green Chemistry. Although Cp2TiCl is not a renewable feedstock, it is important to say that this SET is a good alternative to them because it is obtained from nonhazardous materials and also because titanium is one of the most abundant and safe transition metals on Earth.11 2.2. Catalysis and Waste Minimization. As we have already discussed, Nugent and Rajanbabu introduced Cp2TiCl as an efficient stoichiometric reagent for single-electron-transfer capable of generating a radical from an epoxide. The subsequent functionalization of the β-titanoxyl carbon radical 1 (Scheme 3) is used in C−C bond forming reactions, reduction, deoxygenation reactions, and the disproportionation process. The opening of the epoxide leads to the more stable βtitanoxyl radical, which in the presence of a hydrogen-atom donor such as 1,4-cyclohexadiene (CHD) or water is reduced (path 1) to give the less substituted alcohol. In the absence of a hydrogen-atom donor the β-titanoxyl radical can be trapped by a second equivalent of Cp2TiCl (path 2) to generate an organometallic alkyl-TiIV complex 2 (Scheme 3), which, after βelimination, gives a deoxygenated product (alkene) or undergoes a disproportionation process to give an allylic alcohol. Also, the β-titanoxyl radical can react with olefins conjugated with electron deficient groups (path 3) such as esters or nitriles to create a new C−C bond. The use of stoichiometric amounts of Cp2TiCl was an important drawback to include Cp2TiCl as a green chemistry reagent, because as is it noted in the principles of Green Chemistry, catalytic reagents are superior to stoichiometric reagents. The first catalytic system for such an epoxide-opening making use of in situ generated Cp2TiCl was developed by Gansäuer et al.,12 who found that the TiIV-alkoxy species generated during the epoxide opening can be protonated by hydrochloride-substituted pyridines (collidine hydrochloride) to provide the corresponding alcohols and Cp2TiCl2. This Cp2TiCl2 complex can be reduced in situ with Zn or Mn to regenerate Cp2TiIIICl, thus closing the catalytic cycle (Scheme 4). In addition, an economic and environmental improvement was achieved when it was discovered that water13a,b can act as a hydrogen atom donor to the radicals formed in the Cp2TiCl

mediated process, as in this way the use of toxic hydrogen atoms donors such us 1,4-cyclohexadiene is avoided. Another way to perform the reaction using catalytic amounts of the titanium species and in the absence of hydrogen atoms donors (like 1,4-cyclohexadiene) was developed by our research group and is summarized in the catalytic cycle presented in Scheme 5. The addition of 2,4,6-trimethyl-1Scheme 5. Ti-Catalyzed Nonreductive Epoxide Opening Reactions

trimethylsilylpyridinium chloride [Coll/TMSCl] allows not only the regeneration of the TiIV-alkoxy species but also the formation of Cp2TiCl2 from Cp2Ti(Cl)H, acetoxy-titanium derivatives, or derivatives with “TiIV−O−TiIV” bonds,14 which are formed under nonreductant conditions. Depending on the nature of the epoxide, the initially formed radical would undergo a disproportionation process or form a C−Ti bond followed by β-elimination of “O−Ti”. In both cases, the titanium derivatives species formed are transformed into Cp2TiCl2 by [Coll/TMSCl]. Both catalytic cycles previously described allow for the synthesis of alcohols, alkenes, and allylic alcohols from epoxides and catalytic amounts of Cp2TiCl. Also, in both cases, the yields of reactions are high (see section 2) being that the amount of Cp2TiCl used ranges from 5 to 20 mol %. The use of catalytic procedures eludes one of the major sources of waste in chemical manufacture. Although Mn or Zn is used as a stoichiometric reducing reagent to obtain the active TiIII-complex, the excess of the stoichiometric (2−8 equiv) reducing agent can be conveniently removed by filtration. Also, an economically attractive feature of these catalytic procedures is that collidine can be easily recovered during the reaction workup by simple acid−base extraction.15 These catalytic cycles are also applicable when other functional groups such as ozonides, oxetanes, carbonyl groups, α,β-unsaturated carbonyl derivatives, activated halides, imines, and α-halo esters are used as functional targets of the Cp2TiCl (see section 3).10h 2.3. Safer Solvents. The solvent used in the reaction is another major source of waste. It can be recycled by distillation, although this involves a 10% loss. From the point of view of the Green Chemistry, the solvent should not have deleterious environmental effects or unacceptable toxicity. Only solvents

Scheme 4. Ti-Catalyzed Reductive Epoxide Opening Reactions

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with low toxicity and low risk to human health can be used,16 such as alcohols, esters, ketones, or ethers.17 In the practical guide of solvents for medicinal chemists that was reported by Pfizer scientists,18 the solvents are classified into three categories: undesirable, usable, and preferred. Under these criteria, toluene and THF, two of the solvents used to generate Cp2TiCl from Cp2TiCl2 and Mn or Zn, are considered usable solvents, minimizing the effect of the solvent in reactions catalyzed by Cp2TiCl. Some of us reported in 200213a,b that Cp2TiCl can be generated in situ by stirring Cp2TiCl2 and Mn in THF or toluene until the mixture turned lime green (when THF is used) or green-brown (when toluene is used) (Table 1). Some

conditions, that is, in the absence of a donor source of hydrogen atoms), and several stereogenic centers. So, we can say that this radical cyclization catalyzed by TiIII mimics the biosynthesis of natural terpenes. Later, in the section of the C−C bond forming reaction, we will describe some of the most important synthesis of natural compounds using Cp2TiCl as the key step in the radical cyclizations of epoxipolyprenes. Excellent reviews on the applications of Cp2TiCl for preparation of natural compounds were reported by Oltra et al.,10b,c Barrero et al.,10e Gansäuer et al.,10f,d and Cuerva et al.10f,g 2.5. Minimization of Energy Consumption and Reduction of Derivatives. Another important feature of Cp2TiCl is that the reactions catalyzed by Cp2TiCl are conducted at room temperature and atmospheric pressure, contributing to the energy efficiency of the process. In this way, the catalytic cycles previously described operate with minimum energy requirements and with reaction times ranging from 30 min to 6 h. On the other hand, as is described in the next section, this SET reagent is able to catalyze a range of transformations that are very useful in organic synthesis such as C−C and C−O bond forming reactions, reduction, isomerization, and deoxygenation reactions under mild conditions, which are compatible with several functional groups including esters, silanes, ethers, fluorinated, and acetoxy derivatives, among others. So, in many transformations catalyzed by Cp2TiCl there is no need for blocking functional groups through protection/deprotection techniques and/or temporary modification, thus saving synthetic steps. Finally, it is worth mentioning that the functional targets of the Cp2TiCl are functional groups with heteroatoms bearing free valence electrons, such as epoxides, oxetanes, ozonides, alcohols, carbonyl groups, peroxides, activated halides, imines, and Michael acceptors (Scheme 7). These functional groups can experience monoelectronic transfers if the process is energetically favorable. The remaining Green Chemistry principles, reported by Anastas et al.,1 are principles which mainly focus on the characteristics that must have the manufactured product and its process of synthesis from a global point of view and not in stages. Note that the green reagents are one of the different strategies necessary in the development of innovative sustainable technology platforms.1

Table 1. Solvents Used in Radical and/or Organometallic Chemistry Catalyzed by Cp2TiCl solvent THF toluene chlorinated hydrocarbon (CCl4, CH2Cl2) a

solvent categorya

Cp2TiCl from Cp2TiCl2/Mn

solution color of Cp2TiCl

usable usable undesirable

formed formed not formed

lime green green-brown −

Based on the guide of Pfizer scientist for medicinal chemistry.17

attempts in other solvents,13 such as chlorinated hydrocarbon and DMF, were unsuccessful. So, this single-electron-transfer reagent (Cp2TiCl) is environmentally friendly since the solvent is THF or toluene and not chlorinated hydrocarbons. 2.4. Atom Economy. A green reagent paves the way for the development of synthetic methodologies that maximize the selectivity and atom and step economy. This concept has a decisive influence on the strategies employed by chemists. In this context, Cp2TiCl has actively contributed to the development of highly selective and efficient synthetic procedures. One of the most important is the Cp2TiCl-catalyzed cascade cyclization of epoxypolyprenes, which is a useful procedure for the synthesis of C10, C15, C20, and C30 terpenoids, including monocyclic, bicyclic, and tricyclic natural compounds (Scheme 6).19 The cyclization in all cases proceeds with high regio- and stereoselectivity and allows yields which can generally be regarded as satisfactory if we bear in mind that this Cp2TiClcatalyzed cyclization selectively affords compounds containing several fused rings, an exocyclic alkene (under nonreducing

Scheme 6. Synthesis of Terpenes through Cp2TiCl Cascade Cyclizations of Acyclic Monoepoxy-polyprenes

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Scheme 7. Functional Targets of Cp2TiCl

3. REACTIVITY OF Cp2TiCl IN ORGANIC SYNTHESIS As we have described, Cp2TiCl is a single-electron transfer prepared in situ by reduction of nontoxic Cp2TiCl2. This reagent of Ti(IV) is a quite common reagent that is readily available from any major supplier. Cp2TiCl2 can be easily obtained in large scale from TiCl4 following the original synthesis described by Wilkinson and Birmingan6d or using freshly distilled cyclopentadiene (Scheme 8).6e

these carbon-centered radicals progress depends upon the reaction conditions. Normally, in the absence of a good hydrogen-atom donor, such as water, and in the presence of electron-withdrawing groups, the radicals formed can originate a new C−C or C−O bond, either inter- or intramolecularly. In the presence of a good hydrogen-atom donor such as water,13a,b,20a reduction products are formed. On the other hand, in the absence of electron-withdrawing functional groups, the carbon-centered radical is usually transformed into alkenes by a mixed disproportionation process.13b,21 As a general trend, when the radical is on a trisubstituted carbon, a hydrogen atom is removed from the α-position leading to the formation of Cp2TiCl(H) and a C−C double bond13b,21 (isomerization process; see section 3.3). In the case of radicals on disubstituted carbons, an alkene is usually formed4,13b,21 (deoxygenation process, see section 3.4). That is, the carboncentered radical can be trapped by a second Cp2TiCl species to form a bimetallic intermediate that originates an alkene (the corresponding deoxygenation product) and titanocene(IV) oxide. In this section, we report the reactivity of Cp2TiCl in C−C and C−O bond forming reactions. C−C bond forming reactions are one of the most useful transformations in synthetic organic chemistry. In this context, catalytic amounts of Cp2TiCl have actively contributed by allowing the formation of carbon radicals from functional groups such as epoxides, ozonides, oxetanes, activated halides, carbonyl groups, and carbonyl derivatives under green conditions. These radicals can be trapped by electronic acceptors or by a second molecule of Cp2TiCl to generate an organometallic compound that can be added to electrophilic carbons. In both cases, the result is the formation of a new C− C bond either inter- or intramolecularly.10,22,23 In this way, epoxides and unsaturated epoxides were the first functional groups used as substrates in Cp2TiCl-catalyzed C−C bond forming reactions, either inter- or intramolecularly, under sustainable and environmentally friendly conditions (Scheme 10). This radical opening of epoxides using Cp2TiCl is a complementary methodology to anti-Markovnikov traditional methods. Several examples of this green methodology of C−C bond forming reactions using catalytic amounts of Cp2TiCl and epoxides have been reported in literature (Scheme 11).23,24 The C−C bond forming reaction catalyzed by Cp2TiCl has its highest expression in the synthesis of natural terpenes from cyclizations of monoepoxides of acyclic polyprenes and catalytic amounts of Cp2TiCl. These radical cyclizations are an important example of a step-economy reaction. Compared with carbocationic cyclizations, these cyclizations are highly efficient and diastereoselective. This useful methodology was

Scheme 8. Synthesis of Cp2TiCl2

In this section, we summarize the main reactions of this green reagent in radical and/or organometallic chemistry with emphasis on the research published in recent years. Only the reactions catalyzed by Cp2TiCl which are performed under green reaction conditions are reported. There are many other examples of chemical reactivity of this complex that are carried out under noncatalytic conditions.10h 3.1. Reactivity of Cp2TiCl in C−C and C−O Bond Forming Reactions. The Cp2TiCl complex can interact with epoxides, ozonides, oxetanes, allylic and propargylic halides, saturated ketones, imines, α-haloketones, unactivated alkyl halides, and α,β-unsaturated and aromatic aldehydes and ketones10 to yield the corresponding carbon-centered radicals (Scheme 9). As we have already mentioned, the way in which Scheme 9. General Reactivity of Cp2TiCl

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Cp2TiCl(cat.) could be taken to be an efficient artificial cyclase26 and therefore a remarkable green reagent (Scheme 6). Natural terpenes with important biological activities have been synthesized using catalytic amounts of Cp2TiCl as a green reagent in the key step of the synthesis (Scheme 12). Excellent reviews on the applications of Cp2TiCl in the synthesis of natural products have been reported in literature.10a−h The radical transannular cyclization of epoxygermacrolides using substoichiometric amounts of Cp2TiCl is also an important example of a C−C bond forming reaction using this reagent. Several natural eudesmanolides were obtained in high yields and with excellent selectivities (Scheme 13)13a,b,14,35 using Cp2TiCl in the key step of these cyclizations. The experimental results obtained in these transannular cyclizations allowed development of two of the most important concepts13b discovered in the chemistry of Cp2TiCl. On one side, a catalytic cycle was able to generate Cp2TiCl2 from Cp2Ti(Cl)H and alkoxy-titanium derivatives (obtained when the reaction does not finish under reducing conditions) (see section 2.2). On the other, experimental proof was obtained that in Ti(III)-mediated free-radical chemistry water can act in a reductive way, working as a hydrogen atom donor.13a Therefore, we believe that the generally accepted passivity of water in free-radical chemistry should be carefully revised, especially in the presence of Ti(III) and other “metal-centered free radicals”. These concepts have allowed Cp2TiCl to become a new and efficient green reagent. Other functional groups used by Cp2TiCl in C−C bond forming reactions are oxetanes36 and ozonides.37 In both cases, carbon radical precursors are obtained and are suitable to form C−C bonds via either homo- or cross-coupling processes (Scheme 14). In the case of ozonides the weak O−O bond38 offers a starting point to initiate reagent-controlled free-radical processes under mild conditions. In addition, other functional groups such as α-haloketones have been used to obtain radical precursors for C−C bond forming reactions in processes catalyzed by Cp2TiCl. This catalytic reaction between α-haloesters and aldehydes in the presence of Cp2TiCl was reported by Oltra et al.39 to obtain βhydroxy esters. In this case, the halide is removed by Cp2TiCl, via SET, to generate a radical carbon that is reduced by another molecule of Cp2TiCl resulting in the formation of an enolate, which can be trapped by an aldehyde leading to the synthesis of β-hydroxy esters (after workup), under mild and neutral conditions (Scheme 15).6c These Reformatsky reactions were carried out using a metal reducing reagent6c (Scheme 15, pathway A) or an organosilicon reducing reagent6c (Scheme 15, pathway B) giving the corresponding β-hydroxy esters in excellent yields and avoiding reductant-derived metal waste. More recently, Streuff40 reported that Cp2TiCl can catalyze C−C bond forming reactions through a redox umpolung process in the presence of a metal reducing agent40a or with an organosilicon reducing reagent.40b In this context, the reaction between enones and acrylonitriles generates 1,6-difunctionalized ketonitriles. In this reaction, the interaction of Cp2TiCl with the enone provides an allylic radical, which adds to acrylonitrile at the β position generating a second radical intermediate. A second molecule of Cp2TiCl and the catalyst regenerator Et3N·HCl transform this radical into a [Ti]IV enolate which is converted into a silyl enol ether by the chlorotrimethylsilane present in the reaction medium (Scheme 16).

Scheme 10. Inter- and Intramolecular Cp2TiCl Catalyzed C−C Bond Forming Reactions from Epoxides

Scheme 11. Examples of C−C Bond Forming Reactions from Epoxides and Catalytic Cp2TiCl

reported in 2001 by Barrero et al.25 using stoichiometric amounts of Cp2TiCl. The catalytic system developed by Gansäuer12 and also that reported in our research group14 revalued this general methodology of synthesis of terpenoids by diastereoselective homolytic opening of monoepoxides of acyclic polyprenes. If the reaction is performed in the absence of a good hydrogen atom donor, the final radical evolves by the action of Cp2TiCl into an alkene, thus mimicking a cationic process. In this sense, 916



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Scheme 12. Cp2TiCl-Catalyzed Synthesis of Terpenoids

Scheme 13. Synthesis of Natural Eudesmanolides Using Cp2TiCl(cat.)

Scheme 14. C−C Bond Forming Reactions Using Ozonides and Oxetanes

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Scheme 15. Cp2TiCl-Catalyzed Reformatsky Additions

group also activated by a second molecule of Cp2TiCl generating a new C−C bond. In this same line, the reductive radical cyclization of ketonitriles catalyzed by Cp2TiCl to give the corresponding derivative amino alcohol via stereoselective cyclization41c and the intermolecular ketone-nitrile couplings has also been reported.41a Activated halides have also been used in C−C bond forming reactions using catalytic amounts of Cp2TiCl. These Barbiertype reactions between carbonyl derivatives and activated halides constitute an excellent green methodology for the preparation of, in one step, homoallyl, homopropargyl, and allenyl alcohols at room temperature, under mild conditions, chemioselectively and in very high yields. Homoallyl or homopropargyl alcohols are obtained when the reaction is performed between a carbonyl compound and unsubstituted allyl or propargyl halides using Cp2TiCl as a catalyst.43 In these cases, an alkyl or allenyl titanium intermediate is formed, which, in turn, attacks the aldehyde or ketone to provide a homoallylic or homopropargylic alcohol (Scheme 18).

Scheme 16. C−C Bond Forming Reaction between Enones and Acrylonitriles Catalyzed by Cp2TiCl

Scheme 18. Barbier-Type Reactions Catalyzed by Cp2TiCl

The same author41a,b,42 reported a green cross-coupling reaction of imines, chromanes, or quinolones and nitriles for the direct formation of α-aminoketones using substoichiometric amounts of Cp2TiCl (Scheme 17). These reactions involve the coordination of Cp2TiCl to a ketone or an imine to form a radical, which attack a nitrile

On the other hand, when Cp2TiCl reacts with substituted propargyl halides an equilibrium mixture of propargyl-titanium and allenyl-titanium intermediate is formed. In this way, ketones afford mainly internal homopropargylic alcohols while aldehydes afford mainly α-hydroxy-allenes (Scheme 19).44 This green methodology was used for the straightforward synthesis of exocyclic allenes,45 as the intramolecular Barbiertype reaction of substituted propargyl halides only yields exocyclic allenes (Scheme 19). Allylic carbonates and carboxylates have also been used as substrates of some nice Barbier-type reactions catalyzed by multimetallic systems (Cp2TiCl and palladium or nickel complex).46 However, in this case, the additional use of other transition metals decreases its appeal as green methodology for C−C bond forming reactions. Usually, the carbon-centered radicals formed using substoichiometric amounts of Cp2TiCl and the above-described functional groups undergo homocoupling reactions in the absence of hydrogen atom donors or electronic acceptors and when the deoxygenation and disproportionation processes are not favored,36,37,47 resulting in the formation of a new C−C

Scheme 17. Intramolecular Coupling of Nitriles and Imines or Chromanes Catalyzed by Cp2TiCl

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Finally, a C−O bond forming reaction was reported by Gansäuer49a−c (catalytic Cp2TiCl was used) and Trost49d (stoichiometric Cp2TiCl was used) using the stable radicals formed in the Cp2TiCl-mediated opening of hindered epoxides. The greater steric hindrance shown by stabilized radicals that are tertiary, secondary or benzylic prevents the formation of alkyl titanium species allowing the radical to attack the Ti−O bond formed in the radical opening of the epoxide by Cp2TiCl yielding a cis-THF ring (Scheme 22). This observed stereoselectivity can be easily explained considering that although from the thermodynamic point of view the trans radical intermediate is preferred, the formation of the cis-THF ring is kinetically favored according to the Beckwith−Houk rules.50 3.2. Reactivity of Cp2TiCl in Reduction Reactions. The carbon-centered radicals and/or alkyl-titanium species, formed when the target functional groups are treated with Cp2TiCl, suffer reduction in the presence of H2O, which acts as a hydrogen-atom donor to give a C−H bond (Scheme 23). The reduction can proceed either through a hydrogen-atom transfer process (HAT) or by hydrolysis of an organometallic alkyl-TiIV intermediate. In the case of the titanaoxirane species,51 H2O can promote the hydrolysis to generate the reduced compound. Unprecedented HAT from H2O to radicals was reported for the first time in the transannular radical cyclizations of epoxygermacrolides using Cp 2 TiCl and water.13a,b This phenomenon was later explained considering that the coordination of H2O to Cp2TiCl might weaken the strength of the O−H bond.20 Theoretical calculations indicated a homolytic bond-dissociation energy (BDE) for the Cp2TiCl− H2O complex of 49.4 kcal/mol. This value is somewhat 60 kcal/mol lower than the calculated BDE of water. From the comparison of several experimental results, it can be stated that hindered radicals are reduced via HAT from H2O in a process catalyzed by Cp2TiCl while primary and not hindered radicals are normally reduced via hydrolysis of an alkyl-TiIV species.20b Apart from mechanistic considerations, the Cp2TiCl/Mn/ H2O is an excellent green reagent in the promotion of reductions,52 environmentally friendly, sustainable, and efficient (Scheme 24). 3.3. Reactivity of Cp2TiCl in Isomerization Reactions. The isomerization of organic compounds has a played a crucial role in the preparation of compounds of high added value. Although a number of methods are known, chemists and chemical engineers are still struggling for low cost catalytic reagents in order to replace those which are expensive and not environmentally friendly. In this way, the development of methodologies of isomerization respectful of the environment has provoked great interest due to the high impact that these processes present in the chemical industry. In this context, Cp2TiCl also has contributed to the development of sustainable and respectful processes of isomerization with the environment, concretely, in the synthesis of a C−C double bond without deoxygenation from epoxides.21,13b In this way, when an epoxide is treated with catalytic amounts of Cp2TiCl under anhydrous conditions, allylic alcohols are obtained if the radical intermediate formed in the opening of the epoxide is trisubstituted or sterically hindered. In this case, the radicals are not trapped by the bulky Cp2TiCl and the abstraction of hydrogen atoms mediated by Cp2TiCl gives the corresponding C−C double bond. In this way, the experimental results can be explained on the basis of an intermolecular mixed disproportionation process, which

Scheme 19. Synthesis of Internal Homopropargylic Alcohols and α-Hydroxy-allenes Catalyzed by Cp2TiCl

bond. In this way, several green coupling reactions have been described using Cp2TiCl as the catalyst under mild conditions of reaction (Scheme 20). Scheme 20. Homocoupling Reactions Catalyzed by Cp2TiCl

It is also worth mentioning that Cp2TiCl has been used for the polymeric formation of C−C bonds. Asandei48 investigated epoxides, peroxides, aldehydes, and halides as initiators in the Cp2TiCl-catalyzed radical polymerization of styrene. The radicals initially formed start the styrene polymerization. The termination step can be performed by a second molecule of Cp2TiCl (Scheme 21). This method of polymerization is safe, prevents pollution, and is efficient in the use of energy, so it can be considered a green polymerization method. 919



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Scheme 21. Polymeric Formation of C−C Bonds Catalyzed by Cp2TiCl

Scheme 22. C−O Bond Reactions Catalyzed by Cp2TiCl

Scheme 23. Formation of C−H Bonds Using Catalytic Amounts of Cp2TiCl and H2O

Scheme 24. Green Reductions Using Cp2TiCl(cat.)/Mn/ H2O

Scheme 25. Synthesis of a C−C Double Bond without Deoxygenation from Epoxides

leads to the formation of a C−C double bond without deoxygenation (Scheme 25).21,13b There are many reported examples of isomerization reactions using substoichiometric amounts of Cp2TiCl under mild, neutral conditions and compatible with many functional groups (Scheme 26).13b,14,19,21

3.4. Reactivity of Cp2TiCl in Deoxygenation Reactions. Another important transformation in organic chemistry is the deoxygenation reaction. Despite its importance in chemical processes, there has been little progress in the search for a green reagent capable of catalyzing these transformations. In this context, the deoxygenation of epoxides, alcohols, and 1,2diols can be performed using catalytic amounts of Cp2TiCl under mild, efficient, and environmentally respectful conditions. As was reported in the seminal works of Nugent and Rajanbabu,4 the homolytic opening of epoxides facilitates the epoxide deoxygenation under mild and anhydrous conditions. Later studies13b,21 have shown that if the steric hindrance of the epoxide is low, the β-titanoxy radical intermediate formed 920



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Scheme 26. Isomerization Reactions Catalyzed by Cp2TiCl

Scheme 28. Cp2TiCl-Catalyzed Deoxygenation of Epoxides, Alcohols, and Diols

active, and additional innovative applications are expected. In this way, the immobilization of the catalyst precursor on solid support is a common technique that will be widely used for simplifying reaction procedures and/or increasing the stability of the catalyst.

directly after radical opening of the epoxide can be trapped by a second molecule of Cp2TiCl, to give an alkyl-TiIV intermediate. This organometallic intermediate leads to the formation of an alkene by β-titanoxy elimination (Scheme 27, path A).

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AUTHOR INFORMATION

Corresponding Author

Scheme 27. Proposed Mechanism for the Deoxygenation of Epoxides and Alcohols

*E-mail: [email protected]. ORCID

Antonio Rosales Martínez: 0000-0003-0182-0548 Present Address ⊥

Department of Chemical and Environmental Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Ministerio de Economiá y Competitividad (MINECO) (Project CTQ2015-70724-R) is gratefully acknowledged. A.R. acknowledges the University of Sevilla for his position as professor.

The deoxygenation of alcohols and 1,2-diols47c involves a Ccentered radical intermediate formed after the homolysis of the corresponding C−O bond. This radical can be trapped by another molecule of Cp2TiCl, yielding an alkyl-TiIV species, which is protonated to yield an alkane (Scheme 27, path B). Several examples of deoxygenation reactions of epoxides, diols, and alcohols promoted by catalytic Cp2TiCl under anhydrous conditions are shown in Scheme 28.

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REFERENCES

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4. CONCLUSIONS Cp2TiCl has proved to be an ideal reagent for green C−C and C−O bond forming reactions, isomerization, and deoxygenation processes, being highly efficient, selective, inexpensive, and environmentally friendly. In this review, its properties have been exemplified highlighting the recently developed processes with application in organic and inorganic chemistry. Also, this manuscript highlights the potential of Cp2TiCl chemistry with regard to future applications in polymer chemistry, fine chemistry, and other fields. Research with this complex and other chiral complexes of titanocene continues to be very 921



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An Ideal Reagent for Green Chemistry? - American Chemical Society

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