Recent applications of rare-earth metal(III) triflates in cycloaddition and cyclization reactions

Rare-earth metal(III) triflates are extremely mild, efficient and water-tolerable Lewis acid catalysts for a wide range of organic transformations. Rare-earth metal triflates retain activity even in the presence of multiple Lewis bases containing oxygen, nitrogen, sulfur and phosphorus atoms


Introduction
In the last two decades, the application of lanthanide triflates Ln(OTf)3 (Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu; OTf = CF3SO3 -) in organic synthesis has experienced immense growth.Lanthanide(III) triflates, together with chemically similar triflates of pseudolanthanides Sc(III) and Y(III), have proven to be mild, stable Lewis acids that are known for their oxophilicity 1 and stability in the presence of water 2 , making them water-compatible Lewis acids particularly suitable for green chemistry applications.These rare-earth metal(III) triflates [M(OTf)3] remain active in the presence of a wide variety of Lewis bases, thereby providing exceptional functional group tolerance and in many cases obviating the need for protecting groups.M(OTf)3 have demonstrated high chemo-and regioselectivity, and exceptional conversions for a number of challenging synthetic transformations.Moreover, unlike traditional Lewis acids such as BF3, AlCl3, TiCl4, etc., catalytic usage, recovery and reuse are possible for M(OTf)3 reagents.Their low toxicity, environmentally benign character, moderate cost and ease of availability make these reagents attractive for the synthetic community.Intriguingly, a recent report demonstrated that lanthanides are an essential cofactor for methanol dehydrogenase in a volcanic methanotropic bacterium, thereby underscoring that lanthanides' superior catalytic properties are used in biological systems. 3are-earth elements(III) triflates are readily prepared from the corresponding oxides (M2O3) or chlorides (MCl3) in an aqueous trifluoromethanesulfonic acid. 4,51][12][13][14][15] Therefore, the purpose of the present review is not to summarize all the efforts in the area comprehensively, but instead highlight a select number of important applications of rare-earth metal triflates in cyclization and cycloaddition reactions reported over the last five years, up to the first three quarters of 2013.

Cycloadditions and Cyclizations
Cycloaddition and cyclization processes, exemplified by Diels-Alder (DA), hetero-Diels-Alder (HDA) reactions and Huisgen cycloaddition, are of great importance in organic chemistry, since they provide distinct reactivity and selectivity patterns, and offer rapid entries into complex cyclic structures bearing multiple stereocenters. 16,17Lewis acids, including lanthanide(III) triflates, were shown to effectively catalyze cycloaddition reactions in general, allowing for lower reaction temperatures, faster times and cleaner conversions. 18Apart from possessing high oxophilicity and moisture tolerability, the uniqueness of rare-earth metal(III) triflates with regards to cycloaddition reactions consists of their ability to offer exceptionally high coordination numbers, allowing for extremely organized transitions states, and consequently providing excellent stereoselectivities. 19,20 In this review, interesting examples of strategic utilization of rare-earth metal triflates for cycloaddition/cyclization reactions published in recent years will be highlighted, with the emphasis on advantages over conventional Lewis acids.A comprehensive treatment of all recently recorded cyclizations/cycloadditions utilizing rare-earth metal triflates is beyond the scope of this review.However, the author has attempted to provide broad coverage of diverse cyclization reaction types with the hope of reinforcing significant research activity in the area of M(III) Lewis acid catalysis.The review is organized into six main portions: carbon Diels-Alder reactions, hetero-Diels-Alder reactions, [3+2], [3+3] and [4+3] cycloadditions, hydride shift/ring closure sequences, radical cyclization processes and miscellaneous cyclization reactions.

Carbon Diels-Alder Reactions
M(OTf) 3 have been shown to be effective catalysts for Diels-Alder reactions of various sensitive dienes and dienophiles, [21][22][23] and first chiral Sc(III) and Yb(III)-based catalytic systems for DA reactions were disclosed by Kobayashi and co-workers in the 1990s. 24,25One interesting example of asymmetric DA reaction involving Danishefsky-type dienes 1 was reported by Nishida's group. 26,27Specifically, complexes of Yb(OTf) 3 , axially chiral ligands BINAMIDE and BINUREA and an amine catalyzed the DA reaction in a highly diastereo-and enantio-selective manner to provide densely functionalized chiral cyclohexenes 3. Notably, utilization of a lanthanide triflate was the key in promoting the desired reaction without any appreciable decomposition of either substrate 2 or the reaction product 3.The reaction is quite general, and can tolerate a variety of substituents on dienophile 2, including aryl, alkenyl, halogens and ester moieties.The yield/enantioselectivity was lower in the case of sterically hindered dienophiles 2 bearing bulky groups (Scheme 1).

Scheme 1. Asymmetric Diels-Alder reaction catalyzed by Yb(III) complexes.
This operationally convenient and robust protocol was subsequently employed as a key step in the asymmetric total synthesis of (+)-and (-)-platyphyllide. 28As a result, the absolute configuration of the natural (-)-form was revised to be the (6S,7S)-enantiomer.
A similar bis-thiourea 6-based asymmetric catalytic system disclosed by the same research group three year later in 2013 utilizes holmium(III) Lewis acid instead of the ytterbium(III) protocol described above.The reported [4+2]-cycloaddition of silyloxyvinylindoles 4 provides an expedient stereoselective entry into hydrocarbazoles 7 (Scheme 2), as well as hydroindoles and hydrobenzofurans. 29The obtained chiral cycloadducts could serve as potential synthetic intermediates for Strychnos alkaloids.It has been demonstrated that Sc(OTf)3 can catalyze generation and successive aromatization of isobenzofuran from o-dicarbonylbenzenes 8 to yield the corresponding naphthalene derivatives 10 (Scheme 3). 30Sc(OTf)3 catalyzed both hydrosilylation and Scheme 3. Preparation of naphthalene derivatives 10.
dehydration of an intermediate Diels-Alder adduct, and Sc/Amberlyst-15 recyclable catalyst was shown to be efficient for the reaction.The nature of R 1 and R 2 groups affected the yield of the reaction.In correlation with the hydrosilylation propensity, acetyl derivatives were less reactive, while formyl and aroyl/heteroaroyl groups provided good conversions.
Enantioselective Yb(OTf)3/Pybox-catalyzed Diels-Alder reactions with enhanced exo selectivity were studied by Sibi and co-workers. 31The nature of a pyrazolidinone auxiliary and a Pybox ligand greatly affected the yield of exo-adduct 13 (Scheme 4).It is noteworthy that the Sc(OTf)3-catalyzed reaction, as opposed to employing Yb(OTf)3 or Y(OTf)3, led to endoselective cycloadditions.An interesting Sc(OTf)3-mediated Diels-Alder reaction between biomass-derived 2,5dimethylfuran 14 and acrolein 15 to produce p-xylene 17 was reported by Toste et al. in 2011 (Scheme 5). 32The described route, although not being immediately practical, demonstrated the possibility of realizing a completely bio-renewable approach to PET precursor p-xylene utilizing Sc(III) Lewis acid.Scheme 5. Bio-renewable approach to p-xylene 17 using Sc(OTf)3.

Hetero-Diels-Alder reactions
The hetero-Diels-Alder reaction has attracted significant attention over the past decades as a unique method for the assembly of complex heterocycles in a convergent and regioselective fashion, generally from simple, readily available building blocks. 33,34Among various synthetic methodologies available, asymmetric hetero-Diels-Alder has emerged as one of the most powerful tools for the construction of complex six-membered heterocyclic systems found in the plethora of natural products and active pharmaceutical ingredients. 35,361][12][13][14][15] Below are notable examples of M(OTf)3-catalyzed HDA reactions published in the last five years.
It is worth mentioning that only two endo diastereomers were observed during this hetero-Diels-Alder reaction, despite the fact that three to four stereogenic centers were formed.The sense of asymmetric induction could be rationalized by assuming the formation of octahedral Yb(III)-diene complex 25 (Figure 1).The bulky tert-butyl group from the amine ligand 23 effectively shields the Re face of the enamine, and enone approaches from the Si face, to afford the product with the observed absolute configuration. 38An unprecedented Er(OTf)3-mediated hetero-Diels-Alder reaction of -unsaturated acid chlorides 26 with aromatic and heteroaromatic aldehydes 27 to give synthetically useful lactones 29 was developed by Peters and co-workers. 39Er(OTf)3 was selected due to its considerably lower cost compared to other lanthanide triflates, and relatively small ionic radius favoring highly organized transition states.The generality of this cooperative bifunctional Lewis acid-Lewis base catalytic approach was demonstrated on a variety of substrates bearing methoxy-, trifluoromethyl-, halo-, and nitroaryl, as well as heteroaryl moieties (Scheme 7).It should be noted that electron-donating groups on aryl aldehydes 27 resulted in lower yields, while electron-withdrawing groups enhanced the reactivity.Another application of Er(OTf)3 for a highly enantioselective synthesis of 3,4-dihydro-2Hpyrans 33 featuring remarkably low catalyst loading (0.5-0.075 mol%) was reported by Feng and co-workers in 2011. 40This protocol utilizes the highly efficient N,N′-dioxide ligand 32, which putatively forms the [(32)2Er(OTf)3] complex as suggested by a positive non-linear effect.Initial metal salts screen revealed that traditional Lewis acids like Fe(III) and Cu(II) gave poor results, while Ln(III) triflates-Er(OTf)3 being the most efficient-provided favorable conversion and enantioselectivity.A broad range of functional groups on -unsaturated -ketoesters 30 is tolerated.The reaction proceeds in DCM at 0 C, providing target products 33 in excellent chemical yields, as well as enantio-and diastereomeric excess, and could be scaled up to gram quantities with the same outstanding results (Scheme 8).
As was mentioned above, M(III)-based Lewis acids have exceptional affinities to carbonyl oxygens and carboxylates, thus allowing for extremely organized transition states for substrates bearing these moieties.This fact was utilized by Chi et al. in the course of developing highly enantioselective condensation of enals 34 with trifluoroketones 35 under N-heterocyclic carbene (NHC) catalysis (Scheme 9). 41The usage of Sc(OTf)3 as a Lewis acid co-catalyst resulted in a remarkable amplification of an otherwise weak chiral induction by enantiopure NHC 36.Scheme 8. Enantioselective HDA reaction of DHF 31 and -unsaturated -ketoesters 30.Scheme 9. Sc(OTf)3-NHC cooperative catalysis.
In another report, Doyle and his group disclosed a Sc(OTf)3-catalyzed method for the preparation of tetrahydroquinolines and benzazepines via a Povarov reaction. 42,43Upon treatment with Rh2(OAc)4, enoldiazoacetates 38 undergo dinitrogen extrusion, and the generated donoracceptor cyclopropenes react with imine counterparts 39 to afford target tetrahydroquinolines 40 in a highly regio-and stereoselective fashion (Scheme 10). 44Surveying a variety of Lewis and Brønsted acid catalysts identified Sc(OTf)3 as the catalyst of choice for this transformation.The reaction is quite general and provides excellent yields of Povarov products for both electrondonating and moderately electron-accepting groups on imine 39, as well as heteroaryl imines.However, in the case of a strongly electron-withdrawing nitro group the transformation proceeded with diminished efficiency.The obtained fused cyclopropane tetrahydroquinolines 40 upon treatment with TBAF could be further elaborated into 1H-benzazepine privileged structures 41 (Scheme 10).Scheme 10.Sc(OTf)3-promoted Povarov reaction and benzazepines synthesis.
The scope of the aforementioned Nd(III)-catalyzed reaction is rather broad, and a wide range of substituents were tolerated on both oxazoles 45 and dienophile 46 components (Scheme 11).It should be noted that small substituents at position 5 of the oxazole 45 afforded target pyridines 47 in lower yield, presumably due to partial hydrolysis of the unstable intermediate cycloadduct.The reaction was applied towards highly functionalized furopyridine derivatives possessing MEK kinase inhibitory activity. 46Scheme 11.Scope of Nd(III)-catalyzed Kondrat'eva reaction.

Scheme 13. Enantioselective Yb(III)-catalyzed aza-Diels-Alder reaction with Brassard's diene.
A structurally related L-ramipril-acid-derived N,N′-dioxide 58 ligand was successfully employed in a Sc(OTf)3-catalyzed three-component inverse electron-demand aza-Diels-Alder reaction (IEDDA) to yield ring-fused tetrahydroquinolines 59 with high enantio-and diastereoselectivities. 49 Feng et al. demonstrated that Sc(OTf) 3 was a superior co-catalyst for the reaction, and the reaction tolerated a wide range of electronically and sterically diverse aldehydes 55 (Scheme 14).The reaction was successfully performed on gram scale without any loss of selectivity, and the obtained material was structurally elaborated further to tetrahydroquinoline derivatives of potential medicinal importance.Scheme 14. Asymmetric Sc(OTf)3-catalyzed IEDDA reaction.
The generation of reactive carbonyl yildes via mild Yb(OTf)3-catalyzed C-C heterolysis of the respective oxiranes 68 was disclosed by Zhang et al. 56 Among Lewis acids tested to effect the transformation, conventional Lewis acids such as Sn(OTf)2, Bi(OTf)3, Fe(OTf)3, and Mg(OTf)2 resulted in either low efficiency or no catalytic activity.On the other hand, Sc(OTf)3, Y(OTf)3 and Yb(OTf)3 effected smooth reaction.The latter catalyst was marginally better for carbonyl ylide generation, and subsequent [3+2] cycloaddition of the generated carbonyl ylides with a range of aldehydes afforded synthetically useful cis-1,3-disubstituted 1,3-dioxolanes 70 in excellent yields (Scheme 17).A mechanism for the aforementioned transformation, featuring direct oxiranes 68 C-C bond heterolysis, followed by a reaction of Yb-coordinated ylide with aldehydes 69 and final ring closure, was postulated.In a subsequent publication, the same research group disclosed a highly regioselective Sc(OTf)3-catalyzed 1,3-dipolar cycloaddition of alkynes with azomethine ylides providing highly substituted 3-pyrrolines 73 (Scheme 18). 57Analogous to a previous transformation, Ln(OTf)3 was a key reagent to effect facile generation of azomethine ylides from N-Tos aziridines 71 via C-C heterolysis.Preliminary investigations revealed that moderate enantioselectivity can be achieved with a PyBox ligand.

Wang et al. developed an intramolecular [3+2] cross-cycloaddition of donor-acceptor cyclopropanes with aldehydes or ketones for construction of bridged oxa-[n.2.1.] skeletons 81 (Scheme 21)
. 60 The reaction is promoted by Sc(OTf)3, proceeds in a stereoselective manner and can also be applied successfully towards imines to yield aza-[n.2.1.]systems.The reported methodology was showcased in the course of a platensimycin formal synthesis and a (±)bruguierol A total synthesis. 61,62The same Sc(OTf)3 methodology subsequently was utilized to expediently construct bridged [n.2.1] carbocyclic systems via a novel intramolecular [3+2] process involving alkenes and donor-acceptor cyclopropanes. 63The strategy was successfully applied to the total synthesis of tetracyclic diterpenoids phyllocladanol and phyllocladene.

Scheme 24. Preparation of dihydrobenzopyrans 88.
In an effort to develop intramolecular redox C-H functionalization to access tetrahydroquinolines, Seidel and his research group studied [1,5]-hydride shift/ring closure of N-arylamines 89 under various reaction conditions (Table 3). 71Among the Lewis acids tested, Sc(OTf)3 and La(OTf)3 served as effective reaction promoters.Further, gadolinium triflate showed remarkable rate acceleration in the series of tested catalysts (entries 13 and 16) and was ultimately selected as a catalyst of choice for the reaction.The aforementioned cyclization protocol showed wide reaction scope with respect to both the amine donor moiety and the acceptor residue, allowing rapid access to complex tetrahydroquinolines 92 (Scheme 25). 71The transformation is rather general, with the exception of dinitrile derivatives 91 (Z, Z′ = CN), which could be explained by the limited propensity of CN groups to engage in chelating interactions.Preliminary results indicated that the reaction could be performed in an enantioselective fashion utilizing a Box ligand.Scheme 25.Efficient Gd(III)-catalyzed cyclization.

Radical cyclizations
In the past 20 years, free radical reactions have received much attention, and a wide variety of synthetic methods has been developed in the field. 72The use of Lewis acids in radical reactions to control reactivity as well as regio-and stereoselectivity was likewise a subject of numerous research publications in the past two decades. 73][12][13][14][15] Yang and co-workers have disclosed Yb(OTf)3-promoted 5-/6-exo-trig radical cyclization of -phenylseleno amido esters 93 under UV irradiation to give rise to mono-and bicyclic nitogen heterocycles 94 (Scheme 26). 74It was suggested that Yb(OTf)3 played a two-fold role in promoting the radical process: increased electrophilicity of the -radical intermediate via 1,3dicarbonyl moiety chelation and accelerated PhSe group transfer.Scheme 26.Yb(OTf)3-promoted radical cyclization.
In 2011, Yoon et al. reported a photocatalytic intramolecular cyclization of alkenyl cyclopropyl ketones 95, which is accomplished using a system comprised of La(OTf)3, Ru(bpy)3 2+ and TMEDA (Scheme 27). 75The cyclization involves generation of a distonic radical anion, which upon sequential radical cyclization, and loss of electrons produces cyclopentanecontaining frameworks 96 in a rapid diastereoselective fashion.La(OTf) 3 was critical to the efficiency of the reaction and was presumably activating substrate 95 towards one-electron reduction via chelation.Scheme 27.Scope of photocatalytic intramolecular cyclization.
Sc(OTf)3 can be successfully used as a promoter for intramolecular condensations of ynol ether-acetals.Specifically, Minehan and his group have disclosed a facile procedure to access 5-, 6-and 7-membered alkoxycycloalkane carboxylates 98 in good to excellent yields under mild reaction conditions (Scheme 28). 76The obtained compounds 98 may serve as useful intermediates for natural product synthesis.

Scheme 28. Synthesis of alkoxycycloalkene carboxylates 98.
In contrast to employing strong acids and harsh reaction conditions for classical Prins cyclization, Subba Reddy and co-workers reported that the intramolecular Prins cyclization was efficiently promoted by Sc(OTf)3 in DCE under mild heating (Scheme 29). 77The reaction represents an entirely new approach for synthesizing heterobicycles 101 from aldehydes 99 and bis-homoallyl derivatives 100 in a convenient one-pot operation.9][80][81] Sc(OTf)3 appeared to be a highly active catalyst for the transformation, with the catalyst loadings as low as 0.5 mol% on reaction scales up to 5 mmol. 81It deserves mentioning that during the initial attempt to identify suitable catalysts for the transformation, various aluminum-and boron-based Lewis acids were screened unsuccessfully. 78he enantioselective version of this protocol was reported, allowing access to medium ring 2aryl cyclic ketones 104 from the respective cyclic ketones 103 in one step in virtually quantitative yields and in up to 96% ee (Scheme 30). 80Scheme 30.Enantioselective Sc-catalyzed C-insertion.
Highly substituted 1,4-dihydropyridines 108 and fused bicyclic tetrahydropyridines 109 can be prepared via a novel Sc(OTf)3-catalyzed three-component coupling reaction of arylamines 105, -unsaturated -ketoesters 106, and 1,3-dicarbonyl compounds 107 (Scheme 31). 82otably, Cu(OTf)2 did not affect the cyclization, and Zn(OTf)2, Y(OTf)3 and Yb(OTf)3 were less efficient for this reaction, resulting in lower conversion.Prolonged reaction times did not show substantial yield improvement.On the other hand, addition of pyridine-based ligands resulted in increased conversion, presumably due to stabilization of metal complex intermediates.In a preliminary experiment, an asymmetric version of this transformation with (3aR,8aR)-indane-Pybox ligand lead to low enantioselectivity and moderate yield. 82pplication of dysprosium(III)-based Lewis acids in organic synthesis has been a subject of long-standing research interest of Read de Alaniz and his research group. 835][86] A 2013 paper from the above-mentioned group disclosed an unprecedented Piancatelli rearrangement involving alcohols as nucleophiles. 87The operationally simple reaction is catalyzed by Dy(OTf)3 and proceeds in PhMe at 80 C, affording structurally unique transsubstituted spirocyclic ether motif 111 (Scheme 32).It should be noted that the transformation effects simultaneous construction of a fully substituted carbon center and a spirocycle, thus achieving exceptional atom economy in a single step.During the development of a Lewis acid-catalyzed variant of the Trofimov reaction, 88 it was shown that among lanthanide(III) salts screened Eu(OTf)3 offered superior catalytic activity and provided an efficient method for accessing polyfunctionalized pyrroles 114 (Scheme 33). 89The Eu(OTf)3-promoted Trofimov pyrrole synthesis exhibited broad reaction scope with a wide range of aromatic, heteroaromatic and aliphatic side-chains tolerated.
An efficient and practical approach for the preparation of densely functionalized racemic and enantiopure 4,5-dihydropyrroles 117 was developed by Ghorai and co-workers. 90Thus, Nactivated aziridines 115 reacted with malononitrile 116 in the presence of Sc(OTf)3 via a novel domino ring-opening cyclization (Scheme 34).Markedly, Sc(OTf)3 additive was crucial for the activation of sulfonyl aziridine component 115 via a chelation process.The proposed mechanism proceeds via an SN2-type pathway, followed by intramolecular cyclization.

Conclusions
This contribution has highlighted diverse features and unique efficiency of rare earth metal triflates for a vast number of cyclization and cycloaddition reactions.The great advantages of M(OTf)3 reagents-their superior catalytic activity even in a presence of Lewis bases, low toxicity, easy handling, moisture and air stability, and possibility of recycling/reuse-have led to their widespread use in organic synthesis.This review will hopefully stimulate further application of rare-earth metal(III) triflates in synthesis, and the discovery of novel transformations catalyzed by these compounds will undoubtedly serve as the basis for a multitude of new and improved synthetic strategies and protocols.

Acknowledgements
The author is grateful to Dr. W. Rick Ewing and Dr. Peter W. Glunz for fruitful discussions and valuable suggestions during the preparation of this manuscript.

Table 1 .
Lewis acid catalysis of asymmetric aza-Diels-Alder reaction a

Table 2 .
Survey of Lewis acids for the synthesis of 3-hydroxypyridines a Yield determined by 1H-NMR of the crude reaction mixture relative to 42. b Isolated yield using 40 mol% of Nd(OTf)3.

Table 3 .
Screening of Lewis acid catalysts a