Fluorinated Imines in Tandem and Cycloaddition Reactions

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza‐Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p‐tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson‐Khand reaction, [2+2+2]‐cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N‐sulfinyl imines and their derivatives as starting materials.


Introduction
The importance of fluorine chemistry in industrial fields, such as energy, food, and healthcare has experienced rapid growth in the last decades. Of particular importance is the critical role of fluorine in the development of state-of-the-art pharmaceuticals. It is worth mentioning that more than 40 % of smallmolecule drugs approved by FDA in 2019 and 2020 contains fluorine atom(s). [1] Furthermore, 53 % of agrochemicals that have been assigned a new ISO common name over the past two decades also contain a fluorine atom in their structure. [2] The reason for this blossoming is the fact that the introduction of fluorine generally enhances lipophilicity, membrane permeability, bioactivity, and metabolic stability of pharmaceuticals. Taking into account the benefits of incorporating fluorine atoms in pharmaceuticals, fluorination methods and synthetic approaches for the functionalization of unsaturated bonds with trifluoromethyl group and other fluorinated substituents is currently a flourishing field in synthetic organic chemistry. [3,4] It is not surprising that the presence of fluorine atoms in pharmaceuticals is increasingly growing as evidenced by the approval of new fluorinated drugs in the treatment of COVID-19, such as Paxlovid (Pfizer), Favipiravir (Toyoma), Mefloquine (Tokyo University of Science), Proxalutamide or Sofosbuvir. [5,6] The construction of complex organic molecules has fascinated organic synthetic chemists along the past decades. [7] Nitrogen heterocycles are amongst the most common structural components of pharmaceuticals. In this sense, the synthesis of complex organic molecules containing a nitrogen heterocycle remains field of interest in modern organic chemistry. [8] Imines are well established starting materials for the synthesis of functionalized amines and nitrogen-containing heterocycles. [9] With the emergence of fluorine-containing dugs that had been overlooked until very recently, the versatile reactivity of fluorinated substrates has been investigated in a plethora of cycloaddition reactions, including tandem reactions, Pauson-Khand reactions -in both inter and intramolecular version-, [2 + 2 + 2]-cycloadditions, among others. The scope of this account is, therefore, to highlight the intrinsic potential of fluorinated imines in tandem and cycloaddition reactions and encourage chemists to better exploit the reactivity of fluorinated derivatives.

Tandem Reactions
Tandem reactions are processes in which multiple reactions are combined into one synthetic operation. They are atom-and step-economic, and environmentally more benign than the corresponding step-by-step operations and, therefore, the development of tandem reactions should have significant ramifications for efficient synthetic strategies and green chemistry. [10] These processes are mainly classified into: a) cascade or domino reactions; b) consecutive tandem reactions, and c) sequential tandem reactions.
Among the latter, the term "tandem catalysis", which has been used to describe synthetic strategies that involve sequential catalytic reactions with a minimum of work-up or change in reaction conditions, is even more important. In this review, we have chosen to focus primarily on tandem sequences developed in our laboratories in the last decade as part of our effort towards the synthesis and reactivity of carbocycles and heterocycles with fluorinated groups in their structure.

Tandem Nucleophilic Addition-Intramolecular Aza-Michael Reactions
Although non-fluorinated isoindolines are substructures of importance, present in many natural products and pharmaceuticals, [11] only a few reports were published until 2010 for the asymmetric synthesis of enantiomerically enriched substituted isoindolines. In this context, Enders et al. reported in 2008 one of the first tandem diastereo-and enantioselective organocatalyzed syntheses of non-fluorinated 1,3-disubstituted isoindolines in a one-pot, two-step method consisting of a chiral Brønsted acid catalyzed aza-Friedel-Crafts reaction followed by a base-catalyzed intramolecular aza-Michael reaction (IMAMR) (Scheme 1). [12] IMAMRs are of great interest as, through this methodology enantiomerically enriched heterocycles with nitrogen-substituted stereocenters can be easily obtained. [13] Indoles and N-tosyliminoenoates were selected as nucleophilic and electrophilic components for this process. The best results (er up to 95 : 5 and yields of 71-99 %) were obtained by using BINOL-derived N-triflyl phosphoramides A as organocatalyst, DCM as solvent, room temperature, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) as base and short reaction times. The IMAMR was cis-selective and (S,S)configured isoindolines were formed under these conditions (Scheme 1).
Two years later, Sasai et al. reported a new strategy for preparing non-fluorinated 1,3-disubstituted isoindolines based on a new tandem process, which implies the use of enones and N-tosylimines as starting materials. An organocatalyzed process took place by an initial aza-Morita-Baylis-Hillman (aza-MBH) reaction and a subsequent intramolecular aza-Michael domino reaction mediated by a bifunctional Brønsted acid and Lewis base organocatalyst. [14] After testing a variety of organocatalysts, the authors found that the best results in terms of chemical yield (up to 98 %), solvent (CHCl 3 ) and enantioselectivity (up to 92 %) were obtained by using (S)-2diphenylphosphanyl-[1,1']binaphthalenyl-2-ol (B) as organocatalyst. The authors also found that the aza-MBH/intramolecular aza-Michael domino reaction was found to be cis-Jorge Escorihuela received his PhD in Chemistry at Universitat Jaume I (Castellon, Spain) in 2009. After a postdoctoral stay at the Institute of Molecular Recognition and Technological Development (IDM), he worked at Wageningen University and did research ( selective and (R,S)-configured isoindolines were synthesized (Scheme 2).
In the synthesis of this kind of heterocyles the selective incorporation of fluorine atoms or fluorinated functional groups in their structure has provided an important tool of optimization and modulation of many biological properties. [15] On the other hand, since their introduction more than four decades ago, chiral sulfinyl imines have played an important role in the asymmetric synthesis of a wide variety of nitrogen molecules. [16] The addition of fluorinated nucleophiles to sulfinylimines represents a very efficient method for the direct preparation of fluorinated amines. In 2001, Prakash, Olah et al. described the first example of the addition of a CF 3 group to N-tertbutylsulfinyl imines. They also observed that the Ruppert-Prakash reagent (TMSCF 3 ) in the presence of a stoichiometric amount of tetrabutylammonium difluorophenylsilicate (TBAT) was an effective method for synthesizing trifluoromethylated N-tert-butylsulfinyl amines in good yields and diastereoselectivity (Scheme 3a). [17] This methodology was later extended to α,β-unsaturated N-tert-butylsulfinyl aldimines. In the presence of TBAT or TMAF (tetramethyl ammonium fluoride) as activators, the 1,2-addition took place exclusively, generating the corresponding chiral trifluoromethyl allylamines with good yields and diastereoselectivity (Scheme 3b). [18] In recent years, one of the areas of interest of our research group has been the use of ortho-substituted aromatic tertbutylsulfinyl imines as building blocks to obtain structural diversity through a diversity-oriented synthesis strategy (DOS). In the last decades, DOS has been developed to satisfy the need for designing small molecule collections that exhibit a range of bioactivities, by applying a diverse variety of reaction conditions. [19] In this way, it has been possible to access asymmetrically a variety of fluorinated and non-fluorinated benzofused carbo-and heterocycles, some of which such as isoindolines, isoquinolines, isoindolinones, indanones and other derivatives of synthetic and pharmacological interest, depicted in Scheme 4.
Concerning the reactivity of aryl-substituted Ellman aldimines in tandem processes, our group described in 2010 one of the first examples of a tandem diastereoselective nucleophilic addition (A N ) of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by an intramolecular aza-Michael reaction (IMAMR) process, providing a simple and effective strategy for the preparation of a great variety of fluorinated 1,3-disubstituted isoindolines, which can, in fact, be considered precursors of fluorinated β-amino acid derivatives. [20] The global process is included in the methodology which uses a chiral auxiliary attached to one of the starting materials. Among the available chiral auxiliaries, Ellman's (R)-N-(tert-butanesulfinyl)imines were chosen due to their versatility and commercial availability. The Ellman imine was incorporated in the appropriate aromatic ortho-substituted derivative. Concerning the fluorinated nucleophile, the Ruppert-Prakash reagent [21] was initially considered as the fluori-nated nucleophile of choice in this approach and TBAT also proved to be the best activating agent for the addition of this nucleophile onto sulfinylimines. Thus, substrates 1, obtained in two-steps from ortho-substituted aldehydes, [20] reacted with 2 equivalents of both TMSCF 3 and TBAT in THF at À 55°C for approximately 1 hour, providing, after allowing the reaction to reach room temperature, the target products 2 in good yields and excellent diastereoselectivity, indicating that the N-sulfinyl imine is more reactive than the carbonyl group of the α,β-unsaturated ester (Scheme 5). The scope of the tandem reaction was studied by using a variety of substituted arene rings as well as some heavier analogues of the Ruppert-Prakash reagent (TMSC 2 F 5 and TMSC 3 F 7 ) and some partially fluorinated nucleophiles such as CFH 2 and CHF 2 . In the latter two cases, fluoro-alkylating nucleophilic agents such as PhSO 2 CFXH (X=F, H) [22] were used as starting materials. The corresponding products were obtained in moderate to good chemical yields and excellent syn diastereoselectivity.
Finally, the chiral tert-butanesulfinyl group was removed with 4 M HCl in dioxane yielding the corresponding free amines 3 after basification. In the case of substrates 2 (R F =CFXSO 2 Ph, X=H, F), the desulfonylation step was carried out by treatment with Na(Hg) in MeOH (Scheme 6).
Three years later, the same strategy was applied by our group to the synthesis of new chiral 1,3-disubstituted isoindolines using a variety of non-fluorinated nucleophiles, which increased the utility and versatility of this methodology in the synthesis of this kind of heterocycles. To this purpose and starting from the Ellman's imines 1, we selected representative non-fluorinated nucleophiles such as allyl, propargyl, cyanide, enolates and trichloromethyl groups. [23] The result of this study was that, given the diversity of the structures, the reaction conditions for the initial 1,2-addition had to be independently optimized for each case. Thus, for example, in the case of allyl derivatives the best conditions involved the use of allyl zinc bromide in THF at À 40°C, while for propargyl derivatives the best results were obtained by using allenyl boronic derivatives in the presence of zinc salts, in THF at rt. The trichloromethylation reaction was carried out by using a freshly sublimed chlorinated analogue of the Ruppert-Prakash reagent (TMSCCl 3 ) and an appropriate fluoride source such as TBAT in THF at À 78°C. In the case of the addition of enolates to imines 1 a Reformastky reagent derived from ethyl bromo acetate in THF at 0°C was used. The process took place with high yield and excellent diastereoselectivity. The Strecker reaction was also studied. In this case, the best results were obtained with TMSCN as nucleophile in the presence of Sc(OTf) 3 as catalyst. The corresponding addition product was obtained in moderate yield along with a small amount of a 1,3-disubstituted isoindoline resulting from a tandem process.
Next, the intramolecular aza-Michael reaction was studied under different conditions. Thus, the cyclization with an inorganic base such as tetrabutylammonium fluoride (TBAF) afforded the cis products 4 in good yields and as single diastereoisomers, in most cases. However, in the case of trimethylsilyl cyanide decomposition was observed, with the starting material (arising from a retro-Strecker reaction) being the only identifiable product (Scheme 7).
Subsequently, and to avoid the formation of meso products after the elimination of the chiral auxiliary, particularly for the Reformatsky reaction, we decided to evaluate the use of other bases to obtain a trans stereodivergent cyclization. [24] It was observed that the use of DBU at room temperature produced the trans isomer with good yield and complete diastereoselectivity (Scheme 8). Other studies demonstrating the stereodivergence of the process and the thermodynamic/kinetic origin of cis and trans stereoisomers were carried out.
Recently, Shibata et al. in collaboration with our group studied the same process [25] but using a very inexpensive and commercially available trifluoromethylating agent such as the Scheme 5. Tandem reaction using R F TMS/TBAT as the fluorinated nucleophiles.

Scheme 6.
Removal of the tert-butanesulfinyl group and desulfonylation step. . Compared to other trifluoromethylation agents, for example the Rupert-Prakash reagent and its derivatives, fluoroform (HFC-23), an industrial byproduct in the synthesis of polytetrafluoroethylene (PTFE), represents due to its low price and availability, one of the most interesting and simple agents for the incorporation of the trifluoromethyl group in a variety of organic molecules of synthetic and industrial interest. However, this reagent has hitherto been very poorly developed [26] probably due to its undesirable physicochemical properties (À 82°C at pKa 27). In the published reports, it has been indicated that the nature of the counterion is of crucial importance. Thus, for example, in their studies of the stereodivergent trifluoromethylation with N-sulfinylimines, Shibata's group found that the unstable trifluoromethyl anion (CF 3 À ) generated from HFC-23 can be stabilized as ion pairing with highly sterically demanding cations, such as the polyaminophosphazene superbase P 4 -tBu. [27] In this context, the use of HFC-23 in a tandem nucleophilic addition/intramolecular aza-Michael sequence to obtain enantioenriched trifluoromethylated isoindolines was investigated (Scheme 9). After testing different reaction conditions, particularly solvents and bases, the best results were achieved by reacting tert-butyl esters of aldimines 1 with an excess of fluoroform in toluene and in the presence of P 4 -tBu as superbase, obtaining good to excellent chemical yields and diastereoselectivity (dr up to > 99 : 1). However, other bases such as KHMDS or t-BuOK provided less efficient results. It should be noted that the obtained results in this process are comparable, in chemical yield and selectivity, with those reported using the traditional Rupert-Prakash reagent (Schemes 5 and 9). [20] In the same report, Shibata et al. also published a simple strategy for preparing enantioenriched vicinal α-trifluoromethyl diamines [28] in a stereodivergent manner depending on the base and using HCF-23 as nucleophilic reagent (Scheme 10a). When the reaction was carried out in the presence of P 4 -tBu diamine (R s ,S)-5 a nonchelated transition state could explain the results, whereas the use of KHMDS provided trifluoromethylated N-sulfinamides (R s ,R)-5 explicable by a chelated transition state. The vicinal diamines could also be selectively deprotected in two steps furnishing free diamines (S,S)-6 in good yields (Scheme 10b). [29] In 2011, the behavior of N-tert-butylsulfinyl ketimines 7 bearing a Michael acceptor at the ortho position in tandem reactions was studied with the purpose of increasing the versatility of this kind of processes to obtain 1,3-disubstituted isoindolines 8 with a quaternary center in their structure. [30] To this end, the Ruppert-Prakash reagent was used as nucleophilic reagent under the same reaction conditions as for the corresponding aldimines (see, Scheme 5).
Ketimines 7 were subjected to the optimized conditions used for the tandem A N /IMAMR with aldimines, but the formation of the expected isoindolines 8 was not observed. Instead, the only isolated product, obtained with good yield and as single diastereoisomer, was the indanone derivative 9 arising from an intramolecular asymmetric Michael reaction through the imine α-position without incorporation of the CF 3 moiety (Scheme 11). In this case, the CF 3 À anion formed by the combination of the Ruppert-Prakash reagent with a fluorine source acts as a base (CÀ C) instead of a nucleophile CÀ N). The difference in reactivity between aldimines and ketimines toward nucleophiles such as TMSCF 3 might explain this different behavior. After testing different bases, temperatures and solvents, the best results were obtained by using TMSCF 3 /TBAT in THF at low temperature. Other common bases, e. g. LDA or LiHMDS, were not efficient in term of yield although the use of TBAF alone provided comparable results (Scheme 11).
Additionally, the hydrolysis of the imino group afforded asymmetric 3-substituted indanones 10, a common structural motif in natural products and synthetic drugs. In the same way, the chemoselective reduction of the imino group using NaBH 4 in THF at À 78°C followed by deprotection of the chiral auxiliary gave rise to syn δ-amino acid derivatives 11 as the hydrochloride salt with good yield and excellent diastereoselectivity (Scheme 12).
In 2013, our group published a new strategy for the synthesis via an intramolecular hydroamination reaction catalyzed by gold complexes of new enantiomerically enriched fluorinated isoindolines 12 and dihydroisoquinolines 13, which are privileged structures for drug-discovery and in medicinal chemistry research. The synthetic sequence designed to prepare these compounds is based on a diastereoselective addition of fluorinated nucleophiles through the initial addition of the Ruppert-Prakash reagent and derivatives to Ellman's N-(tert-butanesulfinyl)imines 14 followed by a sequence of Sonogashira cross coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate 17. [31] However, the cycloisomerization did not take place in the presence of the tert-butanesulfinyl group. Therefore, the conversion of t-BuSO into another nitrogen-protecting group compatible with the intramolecular hydroamination was required. After testing different protecting groups and gold(I) catalysts, the best results were obtained with a tert-butyloxycarbonyl (Boc) group and AuSPhosNTf 2 as gold catalyst (Scheme 13).
In contrast to published results, it was observed that the gradual introduction of fluorine atoms at the α-position (CH 3 < CH 2 F < CHF 2 , CF 3 , C 2 F 5 ) promotes the 5-exo-dig mechanism, leading to isoindolines 12 as a major product under the optimized conditions. Therefore, the regioselectivity of the hydroamination reaction will be largely conditioned by the nature and position of the substituent R 2 as well as the fluorinated group in the α position with respect to the nitrogen atom mainly due to an electronic effect of the fluorinated grouping. In this context, it should be mentioned that most cycloisomerizations catalyzed by a transition metal (i. e. Ag, Cu, In, and partially by gold complexes), [32] lead to the formation of the isoquinoline skeleton as a result of a favored 6-endo-dig cyclization, contrasting with the results obtained in this study. [33] Finally, the diastereoselective hydrogenation of the generated double bond followed by Boc deprotection afforded the free NH isoindoline 18 and tetrahydroisoquinoline 19 in good yields (Scheme 14).
The isoindolinone heterocycle constitutes an important scaffold found in numerous bioactive molecules, natural products and pharmaceuticals. [34] However, despite its interest, only a few enantioselective approaches have been described, [35] the synthesis of racemic and chiral fluorinated isoindolinones being almost testimonial. [36] Following a strategy based on DOS, our group reported in 2015 the first asymmetric synthesis of fluorinated isoindolinones 20 by a palladium-catalyzed aminocarbonylation reaction starting from the corresponding chiral ortho-iodofluoroalkyl benzylamines (Scheme 15). [37] The starting materials 15 Scheme 12. Asymmetric synthesis of indanones and δ-amino acid derivatives.

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were prepared following previously described methodologies (see, Scheme 13).
In a preliminary study, it was found that when unprotected ortho-iodo derivatives were subjected to the carbonylation protocol, the desired isoindolinones 20 were provided in good yields but with partial erosion of optical purity (Scheme 16). To avoid this inconvenience, the influence of the base, solvent, temperature, Pd-catalytic systems, and CO pressure was evaluated. After testing different reaction conditions, CO (1 atm), [Pd(PPh 3 ) 4 ] (10 mol%), 90°C, toluene, and Et 3 N (4 equiv) as base were selected as the most appropriate. However, unfortunately, an important loss of optical purity was observed in all cases during the carbonylation step, being particularly important in the case of substrates bearing electron-withdrawing groups such as F (20 c), or CF 3 (20 d).
On the contrary, in the case of non-fluorinated substrates 20 e not racemization was found under the same conditions. In view of these results, the use of other N-protected groups was later considered, and it was found that the tert-butoxycarbonyl (Boc) and the benzyloxycarbonyl (Cbz) allowed the cyclization with no racemization with some exceptions such as substrates containing strong electron withdrawing groups (e. g. CF 3 ) at the aromatic ring.
Additionally, a few experiments were carried out to shed light on the origin of this racemization. It was suggested that this partial racemization takes place by reversible β-hydride elimination (β-HE)/hydropalladation (HP) on one of the intermediates (I) after oxidative addition. Finally, a correlation between the pK a of the base and the er of the final products was observed. Thus, it was observed the weaker the base, e. g. AcONa, the higher the optical purity of the product, including substrates with strong electron-withdrawing groups such as 20 d, which was finally converted into the target molecule 21 in good yield and excellent enantioselectivity by deprotection with TFA in DCM at rt (Scheme 17).
Diversity Oriented Synthesis (DOS) is a synthetic strategy to obtain structural diversity in a rapid and efficient highthroughput manner from a common intermediate. In this context, our group reported in 2016 the synthesis of chiral benzofused mono fluorinated derivatives 22 as well as chiral benzofused derivatives bearing a trifluoromethyl group and other fluoroalkyl substituents in their structure 23 starting from ortho-halo benzaldehydes as a common precursor (Scheme 18).
This study was initiated by describing a practical method for the synthesis of an array of fluorinated benzo-fused homoallylic amines using fluorinated building blocks 24 as key intermediates, which after a three-step sequence implying first incorporation of the chiral auxiliary, followed by asymmetric allylation of the corresponding tert-butylsulfinyl imines and exchange of the protecting group, afforded enantioenriched

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homoallylic amines 25 in moderate to good yields with good to complete diastereoselectivity. [38] During the exchange of the protecting group from the N-sulfinyl group to tert-butyloxycarbonyl (Boc) or acetyl (Ac) no decay of the optical purity of 25 was observed. The final step involved a ring closing metathesis (RCM) of the obtained homoallylic amines 26 (R F =CF 3 , C 2 F 5 , CF 2 SO 2 Ph) in the presence of either second Generation Grubbs catalyst [Ru-II] (5 mol%) (PG=Boc), or Hoveyda-Grubbs II catalyst (PG=Ac) (5 mol%) in toluene at 100°C. In this way, enantiomerically enriched fluorinated benzo-fused bicyclic homoallylic amines 23 were obtained in moderate to good yields (Scheme 19).
Although this methodology has mainly been studied for the trifluoromethyl groups, other non-fluorinated 2-vinylbenzaldehyde derivatives 25 [R=Me, CO 2 Et] were also considered in order to assess the influence of fluoroalkyl groups directly attached to a vinyl moiety on their reactivity in olefin metathesis reactions. The result was that α-fluoroalkylated styrenes are much less reactive than the corresponding nonfluorinated α-substituted ones and this deactivation is much more pronounced than for common electron-withdrawing groups such as esters. , [38] [39] The starting α-trifluoromethylstyrene derivatives 24 were synthesized via a palladium catalyzed coupling reaction of ortho-bromobenzaldehydes with trifluoromethylated tosylhydrazone 27 following a modification of the procedure described in 2014 by Valdes and co-workers. [40] In our case, we used lower temperatures, THF as solvent and microwave irradiation. Compounds 24 were used immediately in the next reaction step due to their instability (Scheme 20).
In a separate study, our group also applied the same methodology to substrates with an ortho-(α-fluoro)vinyl group. [41] In this context, the asymmetric synthesis of fluorine containing 1-amino-4-fluoro-1,2-dihydronaphthelene derivatives 22 via two complementary synthetic strategies was reported. The first of the two makes use of the N-acetylated bicyclic substrate 28 obtained in five-steps starting from 2vinylbenzaldehyde (Scheme 21). Bromofluorination of the double bond using the conditions developed by Olah et al.
(HF/py, NBS) [42] provided intermediate 29 in moderate yield and complete diasteroselectivity. The use of t-BuOK in THF afforded the target vinyl fluoride 22 with HBr elimination in moderate yield.
In order to explain if the elimination of HBr requires anchimeric assistance by participation of the neighboring amine protecting group, several experiments using a variety of starting compounds with different protecting groups were carried out. The best results were obtained with the trifluoroacetyl protecting group and the use of 1 equiv. of NaH in DMF as base. The COCF 3 group was selected due to its easy removal (K 2 CO 3 in MeOH/H 2 O) and its participation in other anchimerically assisted reaction pathways. In this way, the tricyclic compounds 30 were obtained in high chemical yield from the corresponding bromofluoro intermediates 29. Furthermore, it was found that the use of an excess of 4 equiv. of base afforded the target fluorinated dihydronaphtalenes 22 [43] in one step and in high yields. Additionally, it was observed that the treatment of 30 with TFA in wet THF provided all-cis fluorinated 1,3-amino alcohols 31 in quantitative yields and complete stereoselectivity (Scheme 22). The exchange of the protecting group was essential given that the tert-butylsulfinyl group was incompatible with the reaction conditions (HF · Py) (Scheme 22).
In the second strategy, 2-vinylbenzaldehyde was treated with HF · Py/NBS affording the corresponding 1,2-bromofluoro compound 32 in just 1 min in moderate yield. Next, a three-step/one purification procedure, which implies an initial condensation with the chiral auxiliary on the bromofluoro intermediates, followed by elimination, asymmetric allylation and simply exchanging the protective group at the nitrogen for acetyl afforded good yields and excellent diastereoselectivities of substrates 33. Finally, a RCM reaction of 33 in the presence of the Hoveyda-Grubbs catalyst (30 mol %) in toluene at

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100°C provided high yields of the target molecules 22 (Scheme 23). Previously, we had studied a quite simple protocol for the one-pot asymmetric synthesis of cyclic benzo-fused homoallylic amines [44] involving an allylation/ring closing metathesis (RCM) sequence starting from ortho-substituted aromatic tertbutylsulfinyl imines, which, in turn, were easily obtained from 2-halobenzaldehydes. [45] Thus, sulfinimines reacted first in a stepwise manner and then in a one-pot procedure with allylzinc bromide in THF at À 40°C, followed by an RCM reaction in the presence of [Ru-II] (5 mol %) in DCM at rt achieving the desired products 35 in good yields and diastereoselectivity. The one-pot procedure starting from aldehyde 34 and the synthesis of seven-membered analogues were also successfully studied. Final deprotection under standard conditions afforded the corresponding chlorohydrates 36 in excellent yields (Scheme 24).
A formal synthesis of the antidepressant sertraline [46] and the epimeric norsertraline was also described. The final steps implied a dibromination/debromination of 28 to achieve the intermediate 37. The bromoolefin undergoes a cross-coupling reaction under microwave irradiation for the introduction of the 3,4-dichlorophenyl group to obtain 38. Heterogeneous hydrogenation of the double bond gives rise to 39, an intermediate in the total synthesis of sertraline 40 (Scheme 25).
A representative example of the applicability of the diversity oriented synthesis (DOS) [47] is the use of 8iodonaphthalene-1-carbaldehyde 41 as versatile building block in this kind of processes. Once converted into the corresponding Ellman's imine, it was subjected to a variety of transformations that allowed the selective introduction of different functionalities for the generation of carbo-and heterocycles of 5 to 7-membered rings. [48] Thus, for example reactions of intramolecular aminocarbonylation, Buchwald-Hartwig aminations, an intramolecular Heck reaction, intermolecular crosscoupling Sonogashira and Suzuki reactions alone or in combination with ring-closing metathesis (RCM), gold catalyzed hydroaminations, and finally ring-closing enyne metathesis (RCEYM) and intramolecular Pauson À Khand reaction (PKR) were studied to obtain different kinds of fluorinated and non-fluorinated derivatives. In summary, a library of 19 polycyclic carbo-and heterocyclic compounds containing this versatile common naphthalene framework were prepared (Scheme 26).

Asymmetric Tandem Reactions Involving a ptolylsulfinyl Group as Chiral Inducer
In 2008, and in collaboration with Garcia Ruano's group, we developed a simple methodology for the preparation of enantiomerically fluorinated indolines starting from diaryl substituted sulfoxides and fluorinated aldimines or ketimines. The process represents a new asymmetric tandem reaction,

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which implies a nucleophilic addition (A N ) followed by an intramolecular aromatic substitution (S N Ar) (Scheme 27). [49] The p-tolylsulfinyl-phenyl group behaves in this process both as chiral inducer and chiral auxiliary.
Indolines are an interesting class of compounds both from a synthetic point of view and also because of the range of biological properties associated to them. [50] However, although their chemistry has received a great deal of attention, almost no examples of the corresponding fluorinated indolines have been reported.
The reaction of benzyl carbanions derived from the sulfoxide (S)-42 with fluorinated aldimines 43 (R 2 = H) at À 78°C in THF and LDA as base, followed by protonation at the same temperature provided a mixture of two easily separable diastereoisomers anti-44 and syn-44 (Scheme 27). The diastereoselectivity, however, was highly dependent on the nature of the starting carbanions. Thus, when R 1 is a hydrogen, a 7 : 3 epimeric mixture of the anti(major):syn adducts was obtained. On the contrary, when R 1 ¼ 6 H the process is highly selective in favour of the anti-adduct 44 (> 98 : 2). The use of fluorinated ketimines (R 2 ¼ 6 H) as electrophiles afforded exclusively the anti diastereoisomer 44 (> 98 : 2), with the complete stereoselective control of the quaternary centers being observed in the reactions with ketimines significant (Scheme 27A).
Next, the transformation of these substrates into indolines 45 was carried out in the presence of a base. After trying different bases (e. g. LDA, LiHMDS, NaHMDS) and temperatures, it was found that the best reaction conditions for the transformation of the addition product anti-44 into the target molecules involved the use of KHMDS in THF at 0°C. The cyclization worked well for both aldimines and ketimines affording the corresponding fluorinated indolines in good yields. The formation of the indolines 45 can be explained by an initial nucleophilic addition with CÀ C bond formation, followed by an unusual intramolecular nucleophilic substitution with CÀ N bond formation (Scheme 27B).
Finally, the tandem process starting from sulfoxides and fluorinated imines without isolation of the addition products was evaluated. After testing different reaction conditions (bases and temperatures, it was found that when the initial reaction mixture was allowed to reach room temperature in the presence of LDA (before protonation), the intramolecular cyclization took place smoothly in about one hour to give indolines 45, as single compounds and in a completely stereoselective manner, with moderate to good yields (Scheme 28).
The reactivity of anti-46, also prepared with an alternative method described by García Ruano in 2007, [52] in the presence of different bases (e. g. LDA, LHMDS, KHMDS) was studied. The optimal results were obtained with KHMDS. With the latter, the reactivity increased substantially, especially when 18crown-6-ether was added, obtaining non-fluorinated trans-47 indolines in good yields (Scheme 29).Using the same strategy, non-fluorinated indolines 47 were prepared [51] by reacting sulfoxides 42 with N-protected benzylideneimines 48 (see, also Scheme 30) in the presence of LDA at low temperatures, followed by protonation at the same temperature. In this way, an isolated mixture of syn/anti diastereoisomers was obtained.
Moreover, the tandem reaction was applied to the preparation of the non-fluorinated indolines 47, following the same strategy as in the case of the corresponding fluorinated After carrying out different experiments (NMR, X-ray studies and MM3 calculations) in order to clarify the origin of the stereoselectivity, a double π,π-stacking donor-acceptor interaction between the four aromatic rings that stabilizes the transition states that lead to the desired indolines was proposed (Figure 1).
In 2009, an application of this methodology related to the synthesis of optically pure anti-β-fluoroalkyl β-amino acid derivatives 49 was reported. [53] Optically pure β-amino acids constitute interesting building blocks for peptidomimetics and a great variety of pharmaceutically important compounds. Although many strategies have been developed for the synthesis of these derivatives, very little was known about the chemistry and biological activity of the corresponding fluorine derivatives. In this context, our group previously reported two different strategies for the diastereo-and enantioselective synthesis of syn fluorinated β-amino acids, using 8-phenylmenthol as chiral auxiliary [54] and an organocatalytic reaction in the presence of proline as catalyst. [55] The products resulting from the reaction of 2-p-tolylsulfinyl benzyl carbanions (S)-42, considered as synthetic equivalents of ester enolates, with fluorinated imines were converted into anti fluorinated β-amino acids 49 by a two-step sequence that implies an initial desulfinylation followed by oxidation of the phenyl ring.
Removal of the sulfoxide group was achieved by treatment with Ni-Raney, which afforded the desulfurated products 50 in good yields after several hours at room temperature. The transformation of the phenyl ring into the carboxylic acid requires the previous conversion of the PMP (p-methoxyphenyl) group into other protecting groups such as acetyl or N-Boc groups compatible with the oxidation step. Therefore, amines 50 were treated first with cerium ammoniun nitrate (CAN) and then acylated with acetic anhydride or (Boc) 2 O under standard conditions. Final oxidation of the amide 51 with "ruthenium oxide" (RuCl 3 /NaIO 4 ), followed by esterification of the carboxylic acid with trimethylsilyl diazomethane provided the targeted anti amino acids 49 with different substitution patterns in good yields (Scheme 31).
Another interesting application of this methodology was the diastereodivergent synthesis of fluorinated cyclic β 3 -amino acid derivatives 55 [56] by reaction of sulfoxides 51 with fluorinated imines in a three-steps sequence, which implies an initial deprotonation of sulfoxide (S)-42 (R 1 = allyl) with LDA at À 78°C to obtain 52, followed by a cross-metathesis reaction (CM) with ethyl acrylate, which renders esters 53 as separable mixtures of E/Z diastereoisomers, and an intramolecular aza-Michael reaction (Scheme 32). The IMAMR reaction was studied under different reaction conditions, the best results being achieved with the use of TBAF as base in THF at rt. Under these conditions (Method A), pyrrolidines anti-54 were obtained in good yields and moderate diaster-

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eoisomeric ratio. The IMAMR was also evaluated in the presence of a Lewis acid and it was observed that when compounds 53 were treated with BF 3 .OEt 2 , the exclusive formation of the syn-54 isomer took place (Method B) (Scheme 32). These results indicated that it was possible to perform a diastereodivergent synthesis of both syn/anti isomers by a simply change of the reaction conditions. The removal of the chiral auxiliary was carried out by treatment of syn/anti-54 isomers with Ni-Raney in THF for 15 minutes providing the derivatives 55 in good yields as single isomers (Scheme 33).
In order to evaluate the role of the sulfoxide moiety in the process, an additional experiment was performed (Scheme 34). Thus, the removal of the chiral auxiliary (t-BuLi, THF, À 78°C) in 52 (R F =CF 3 , R=Me) was carried out in the first step, followed by a CM reaction and treatment of the intermediate in acidic conditions (see, Method B). The result was the preparation of the target compound 55 in good yield but with a 9 : 1 mixture of diastereoisomers only. This drop of selectivity (from > 99 : 1 to 9 : 1) indicates the crucial role of the sulfoxide in the process with an additional coordination site to the Lewis acid (Scheme 34).

Asymmetric Vinylogous Reactions with Ellman's Fluorinated Aldimines
Vinylogous reactions have been recognized for many years as a powerful and attractive tool for stereoselective carbon-carbon bond formation. Among the different classes of vinylogous reactions, the aldol reactions, the Mannich reactions, organocascade reactions, organocatalytic asymmetric Michael reactions and Mukaiyama aldol reactions stand out for their significance and importance in organic synthesis. [57] In this regard, our group reported in 2018 one of the first asymmetric vinylogous Mannich reactions (AVMR) by reacting α,α-dicyanoalkenes with α-fluoroalkyl sulfinyl imines under basic conditions, which gives access to a family of chiral α-fluoroalkyl amines with an excellent level of stereocontrol. [58] Moreover, α,α-dicyanoalkenes, readily prepared through the condensation of carbonyl compounds and malononitrile, have emerged in the last decade as versatile vinylogous donors acting as nucleophiles through the γ-position, [59] although the combination of dicyanoalkenes and fluorinated imines had until then been unprecedented. In fact, only two examples, reported by Qing's group, involving an AVMR with fluorinated aldimines had been described. The first consists of a TMSOTf-catalyzed reaction with silyl dienolates (Scheme 35), [60] and the second entails the reaction with 3alkenyl-2-oxoindoles. [61] Thus, sulfinyl imines 56 were treated at room temperature with dicyanoalkenes 57 in the presence of several bases in order to find suitable conditions for the attainment of vinylogous addition product. After testing different inorganic and organic bases and solvents the best results were obtained with 1 equiv. of t-BuOK as base and DCM or DCE as solvent, affording the vinylogous adducts 58 in high yield and complete selectivity (> 99 : 1). Under these optimized conditions an array of bicyclic and monocyclic dicyanoolefins as well as imines bearing fluoralkyl substituents other than the trifluoromethyl group renders the corresponding fluorinated adducts 58 in good yields as single diastereoisomers (Scheme 36). The addition products were finally converted into valuable synthetic intermediates such as fluorinated βamino ketones 59. Taking into account that the dicyanometh-

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ylene group can be considered a masked ketone, the double bond was initially oxidized with KMnO 4 , but a mixture of ketones containing both the sulfonyl and sulfinyl moieties was obtained. Therefore, the oxidation of the sulfoxide group with m-CPBA was carried out before the double bond cleavage. Finally, the removal of the chiral sulfoxide auxiliary to obtain the free trifluoromethylamine 60 was carried out (Scheme 36).
A chelated transition state model is invoked to rationalize the observed diastereoselectivity allowing the nucleophile to attack the Re face of the electrophilic imine (Scheme 37). The selectivity found in our protocol is reverse compared to that encountered in analogous examples previously reported for which a non-chelated transition state model was proposed. [60] One year later, we described a simple strategy for the preparation of chiral γ-monosubstituted and γ,γ-disubstituted butenolides 61 and butyrolactams 62 by reaction of heterocyclic silyloxy dienes 63 and fluorinated Ellman's aldimines 56 through a process that implies an asymmetric vinylogous Mukaiyama-Mannich-type reaction (VMMnR) as the key step. [62] Although this kind of processes had been quite well studied in the case of non-fluorinated aldimines, [63] only a few examples of the use of fluorinated aldimines in VMMnR had been described for the asymmetric preparation of the corresponding fluorinated butenolides.
In this regard, Shi et al. reported, [64] in a quite complex study, that the combination of three components such as a chiral phosphine-oxazoline ligand, a silver(I)complex as catalyst along with the additional incorporation of a second chiral auxiliary at the nitrogen of the starting imine was necessary to achieve the synthesis of fluorinated butenolides in good yield and selectivity (> 95 % ee). This study showed the difficulties involved in the obtention of the target butenolides in an easy manner. In our case, we initially selected siloxy furan 63 (X=O, R 2 = TMS) and imine 56 (R F =CF 3 ) as model substrates to study their reaction in the presence of various catalysts and solvents. After testing different reaction conditions, we found that the best results were obtained by use of TMSOTf (1 equiv) as Lewis acid in dichloromethane as solvent. Under these conditions, a high chemical yield (67-91 %) and dr (up to 96 : 4) were obtained when the reaction was conducted at À 78°C for 2 hours (Scheme 38). Additionally, γ-substituted siloxy furans 63 (R 1 = Me, R 2 = TMS) were tested obtaining anti-butenolides 61 bearing a quaternary chiral center at the γposition, in general, with good yields (47-89 %) and excellent diastereoselectivity (> 99 : 1). Moreover, the VMMn reaction was extended to the pyrrole-based siloxy dienes 63 (X=NBoc) with the purpose of obtaining fluorinated anti-butyrolactam derivatives 62. In these cases, however, the reactivity was lower than in the case of the furan dienes (e. g. 5-7 h vs 2 h for the furan) obtaining the target molecules with moderate yields but high diastereoselectivity (dr up to 98 : 2). The absolute anticonfiguration of the adducts was determined by X-ray diffraction analysis in all cases. Finally, the removal of the chiral auxiliary was carried out by treating the obtained antiadducts 61 with HCl in dioxane at 0°C affording the free amines 64 without loss of the optical purity (Scheme 38).
A plausible explanation for the obtained anti-selectivity could be given by the transition states TS1, TS2 and TS3 where an ul approach (re face of the dienolate vs si face of the imine) take place due to the favorable stereoelectronic requirements ( Figure 2). The lk approach is less favored due to the interaction existing between the methyl group and the O-AL

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grouping [see, e. g. TS3 (dr > 95 % anti) vs TS4 (dr > 5 % syn) in Figure 2].

Cycloaddition Reactions
Cycloaddition reactions represent straightforward routes for the construction an array of complex cyclic skeletons, many of which are found in natural products, biologically active substances, and functionalized materials. The preparation of complex chiral fluorinated cyclic structures applying current synthetic methodology based on transition metal catalyzed reactions such as Pauson-Khand reactions, [2 + 2 + 2]-cycloadditions, ring-closing and cross enyne metathesis represent efficient routes to synthesize a variety of enantioenriched carbo-and heterocycles.

Pauson-Khand Reactions
Metal-mediated reactions play a crucial role in the construction of complex organic molecules. [65,66] Among these reactions, the Pauson-Khand reaction (PKR) constitutes an effective strategy for the construction of cyclopentenonecontaining moieties. [67,68] The PKR can be classified as a formal [2 + 2 + 1] cycloaddition in which three CÀ C bonds are sequentially formed yielding polycyclic molecules with a cyclopentenone motif. [69] Its efficiency and atom-economy make this reaction very attractive and the cyclopentenones derivatives formed after the cycloaddition constitute highly important scaffolds to be used in the construction of natural products. [70] Since its discovery more than 40 years ago by Pauson and Khand, [71,72] different transition metals have been applied with Co being the most widely used. However, other metals such as Mo, Rh, Ru, Ir, Ti, Fe and Ni have also been effectively used in mediating this cycloaddition reaction. [73] In general, carbon monoxide (CO), which is a toxic and odorless gas, is used as CO source. However, other most sustainable CO sources have been efficiently used, including aldehydes and alcohols. The use of Co 2 (CO) 8 complex was firstly reported by Pagenkopf and Livinghouse in 1996, [74] and since then it has become a popular choice in Co-mediated PKR. Most of the Co-mediated PKRs require high temperatures and long reaction times to reach good yields. Interest-ingly, the reaction rate can be accelerated by the addition of promoters, such as N-methylmorpholine oxide (NMO), which acts oxidizing CO into CO 2 on the enyne/Co 2 (CO) 6 complex, and favoring the coordination to the olefin through the newly generated vacant orbital. [75] The use of NMO as a reaction promoter has allowed the performance of PKR under remarkably mild conditions. Other alternative amine N-oxides trimethylamine N-oxide, TMANO), sulfides (butyl methyl sulfide, n-BuSMe) [76] and sulfoxides (dimethyl sulfoxide, DMSO) and cyclohexylamine [77] have been found to accelerate PKRs leading to excellent yields. Other ways of labializing CO ligands are based on the use of ultraviolet light and ultrasound irradiation, which have allowed elevated reaction efficiencies in reduced reaction times. [78,79]

Intermolecular Pauson-Khand Reactions
The intermolecular PKR has an appreciably wide tolerance regarding substrate structure and functional groups. In relation to the alkyne counterpart, acetylene and terminal alkynes generally react more effectively in comparison with internal alkynes. A look at the other reaction partner, i. e., the alkene, shows that strained cyclic derivatives tend to give good yields in PKR, whereas sterics around the olefin decrease the reaction yield.
The study of intermolecular PKR reactions of fluorinated substrates has been limited by the poor reactivity and selectivity of simple alkenes. It is not surprising that most examples have been restricted to the use of ethylene or strained alkenes such as cyclopropene, norbornene, norbornadiene, (E)cyclooctene, or bicyclo[3.2.0]hept-6-ene. [80,81] The first example of an Pauson-Khand intermolecular version of fluorinated compounds was reported by our group in collaboration with Riera's group in 2010. [82] In this seminal study, four model fluorinated alkyne precursors 65 were synthesized (Scheme 39). The amide derivatives were easily prepared from bromodifluoroacetylenes [83] and the ethyl 4,4,4-trifluorobutynoate was commercially available. The alkynes reacted next with Co 2 (CO) 8 at rt, followed by addition of an excess of norbornadiene (10 equiv) at 70°C. The PK adducts 66 were obtained in moderate to excellent yields and complete regioselectivity, the fluorinated moiety being located surprisingly in all cases at the α-position of the enone. The reactivity

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of the PKR adducts 66 in conjugated additions with different nucleophiles was also explored. The result was that the conjugated addition of nitromethane or cyanide in the presence of TBAF provided a new and unexpected derivative 67 with concomitant loss of the CF 3 group (Scheme 40). One of the main problems found in the intermolecular PKR is the control of the regiochemistry. Thus, while in the case of terminal alkynes only the α-substituted cyclopentenone 68 is formed (Scheme 41A), with internal nonsymmetrical alkynes the final regiochemistry strongly depends on a difficult to predict combination of steric and electronic effects. In this context, Riera, Fustero and co-workers in 2013 generalized the use of trifluoromethylalkynes 69 as substrates for the PKR. [84] The copper-catalyzed trifluoromethylation of terminal alkynes described by Qing et al. allowed the efficient preparation of a small library of substrates bearing aryl, alkyl, and alkenyl substituents. [85] These were isolated after complexation with Co 2 (CO) 8 as the corresponding adducts, due to difficulties in their isolation. Subsequent reaction with norbornadiene in toluene at 70°C yielded the corresponding cyclopentenone products 70 in good to excellent yields and complete regioselectivity, with the PK adduct with the CF 3 group being the only regioisomer observed in the α-position (Scheme 41B). In this way, and after a carefully study of the reaction conditions to remove the trifluoromethyl group of the adducts 70 a new procedure to prepare the unknown β-substituted PK adducts of type 71 (71 vs 68) was reported (Scheme 42).
The elimination of the trifluoromethyl group was carried out by treatment of the obtained cyclopentenone derivatives 70 with 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in nitro-methane and a small amount of water under reflux (Scheme 42). Under these conditions, the conjugate addition/ detrifluoromethylation product 71 was formed in moderate to good yields. A mechanism in which after the initial conjugate addition of nitromethane, followed by elimination of fluoride would release a difluoroenone intermediate 72 was proposed. Next, a conjugate addition of water, followed by a retro-aldol reaction would form an intermediate enol derivative 73. Finally, after a retro-Michael reaction of nitromethane, the desired cyclopentenone 71 was formed releasing a nitromethane molecule (Scheme 42).
The essential role of the nitromethane as solvent and the small amounts of water were confirmed by several experiments, e. g. the reaction did not take place in toluene or in dioxane among others, and also the complete removal by using dry nitromethane led to a dramatic decrease of the conversion, which was consistent with the observation that the loss of fluoride occurred after the Michael addition of the nitromethane to the enone.
The synthetic utility of this methodology was demonstrated with the formal synthesis of a member of the cuparene family, the bicyclic sesquiterpene α-cuparenone.
In a later study, the influence of the olefin counterpart on the regioselectivity of the PKR was extended using internal trifluoromethyl alkynes and norbornene and ethylene as olefinic counterparts. [86] When evaluating the reaction with norbornene using stoichiometric amounts of Co 2 (CO) 8 in anhydrous toluene at 80°C, the corresponding adducts 74 were formed in good to moderate yields and in a 6 : 1 mixture of isomers, with regioselectivities in agreement with other results found for similar substrates. Likewise, a PKR with ethylene (6 bars) were carried out using stoichiometric amounts of Co 2 (CO) 8 in anhydrous toluene and heating at

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80-85°C. The use of ethylene allowed the obtention of αtrifluoromethyl cyclopentenones 75 in low to moderate yields, but in high regioselectivity (Scheme 43).

Intramolecular Pauson-Khand Reactions
Fluorinated imines have been used as starting materials for the construction of more complex building blocks, such as enynes, capable of undergoing intramolecular Pauson-Khand reactions. The intramolecular version of the PKR has recently gained a great deal of attention as it gives straightforward access to the synthesis of cyclopentenone-fused ring systems, which are generally not easy to synthesize. Compared with the intermolecular PKR, the intramolecular version has attracted more interest in the organic chemistry community, as bicyclic enones can be obtained in a single step and the formation of regioisomers can be avoided. For this metal-mediated cycloaddition, 1,6-or 1,7-enyne derivatives have been widely used as substrates yielding bicyclo [3.3.0] or [4.3.0] enone derivatives after the PKR. [87] However, the intramolecular Pauson-Khand reaction involving fluorinated substrates has remained less explored. [88] In this sense, our group described in 2014 a quite simple strategy for the preparation of fluorinated and non-fluorinated polycyclic amines 78 using ortho-iodobenzaldehydes 14 as starting materials. In this process, a sequence involving an asymmetric allylation of 2-iodo-sulfinylimines, followed by a Sonogashira coupling reaction and a diastereoselective intramolecular Pauson-Khand reaction of the initially prepared fluorinated 1,7-enynes 76 appear as key steps of the process. Examples of intramolecular PKRs starting from fluorinated enynes including an example of a CF 3 -containing enyne, having the trifluoromethylethynyl group at the ortho position, have been reported (Scheme 44). [89] One of the key steps in the preparation of the starting enynes was the highly diastereoselective allylation reaction of chiral Ellman's sulfinylimines 15 (see, Scheme 13). Based on this strategy, a family of chiral fluorinated and non-fluorinated 1,7-enynes 76 were prepared, following a three-step sequence including a Sonogashira crosscoupling from sulfinylimines derived from o-iodobenzaldehydes 14. A variety of fluorinated compounds bearing aromatic rings, fluoroalkyl groups attached to the aryl moieties and a trifluoromethyl grouping were efficiently prepared in good yields. The preparation of the CF 3 enyne 76 (R F =CF 3 ), having the trifluoromethylethynyl group at the ortho position, and obtained in 30 % yield from the corresponding TMS derivative 76 (R 1 = TMS) by cooper catalyzed electrophilic trifluorination using Togni's reagent is noteworthy. In this work, 1,7-enynes 76 showed to be reactive in the Co-mediated intramolecular PKR using stoichiometric amounts of Co 2 (CO) 8 and NMO as a promoter in CH 2 Cl 2 at room temperature. These fluorinated substrates yielded the corresponding [4.3.0] enone derivatives 77 in good to moderate yields and high diastereoselectivity. Removal of the chiral auxiliary was carried out in the presence of one equivalent of HCl in dioxane/MeOH at 0°C, rendering the free amines 78 as hydrochlorides (Scheme 44). This methodology has also been applied to the first de novo synthesis of aminosteroid derivatives.
Concerning the intramolecular PKR with fluorine atoms or fluorinated groupings at the vinylic position, very few examples have been described to date. Ichikawa et al. explored in 2010 the reactivity of enynes bearing a trifluoromethyl group at the vinylic position in the intramolecular PKR, affording the desired CF 3 -adducts in good yield and diastereoselectivity [90] In this context, our group recently explored the reactivity of 1,n-enynes bearing a vinyl fluoride moiety as the olefin counterpart in the intramolecular PKR. [91] The 1,6-enynes 79 were evaluated in the Co-mediated intramolecular PKRs considering both the scope and limitations of this reaction, always using stoichiometric amounts of Co 2 (CO) 8 under different reaction conditions. The synthesis of the starting enynes 79 was carried out through two different strategies. The first one implies a metal-free approach starting from the corresponding fluoroalcohol allyl derivatives 81. The second approach makes use of an initial metal catalyzed fluorination of terminal alkynes 80, followed by a propargylation reaction (Scheme 45). [92] Then, the nature of the

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promoting agent was considered. Thus, when the promoter was the most classical NMO, the expected cycloaddition adduct was not detected, obtaining instead the defluorinated derivative 83 in moderate yield. [93] Therefore, an optimization of the reaction conditions (promoter, solvent and temperature) was necessary, avoiding the use of NMO. After testing different promoters, the use of DMSO in DCM at room temperature was the most efficient, providing an array of the Pauson-Khand adducts 82, including some biorelevant examples, in moderate to good yields (Scheme 45). Different substituents at the alkyne were also tested and bicyclic [3.3.0] enone derivatives 82 were formed in moderate to good yields from enynes having aryl substituents at the propargyl moiety.
In the case of alkyl substituted derivatives, a slight decrease in the yield was observed but the TMS substituted derivative was obtained in a significantly lower yield. The nature of the linker was also considered and heteroatoms such as ether (Z=O) or N-tosylamine (Z=NTs) were well tolerated in the Co-mediated intramolecular PKR, [94] affording the corresponding monofluorinated cyclopentenone derivatives 82 in good yields. On the contrary, the use of a sulfur-based tethering units such as thioether and sulfone-based linkers was unsuccessful, and the PKR product was not detected, recovering the starting materials.
The work was also extended to the use of the chiral enyne 79 to study the effect of chirality on the PKR (Scheme 46). This chiral ether-linkage enyne underwent the Co-mediated PKR to deliver the corresponding cyclopentenone derivative 82 in moderate yield (50 %) and complete diastereoselectivity (dr > 20 : 1, as determined by 19

F NMR).
This regioselective PKR of 1,6-enynes containing a vinyl fluoride moiety was theoretically studied by means of DFT calculations using the M11 functional with the 6-311 + G(d,p) basis set and SDD for the Co atoms. [95] The theoretical study indicated that the rate-and stereoselectivity-determining step was the alkene insertion, as observed for similar PKRs. The reaction rate was found to be affected by the substituents at the alkyne and also in the tethering unit. In this recent work, the alkene insertion step was found to proceed via the Re-face or the Si-face of the alkene, favoring the formation of the cyclic intermediate with the R configuration at C3 (Figure 3). These theoretical results are consistent with the reported high diastereoselectivity (dr > 20 : 1).
As a comparison, we also explored the reactivity of the corresponding chloro-and bromo-enynes 84 as olefinic counterparts for the intramolecular PKR. Disappointingly, the formation of corresponding PKR adducts could not be ascertained in the crude reaction mixtures as a dimerized product 85 was formed. The presence of the cyclopentenone core in the final product allowed us to envision that the PKR adduct would indeed be formed as a radical intermediate

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end, Ellman's tert-butane sulfinyl imines 88 would be suitable starting materials, as they can be used as electrophiles in many diastereoselective addition reactions with a variety of nucleophiles. The synthesis of the target molecules begins with the diastereoselective addition of propargyl magnesium bromide to Ellman's tert-butane sulfinyl imines, which enables the obtention of a variety of sulfinylamide derivatives 89 in high yields and diastereoselectivity. [96] However, the direct alkylation of the sulfinylamides resulted in unsatisfactory yields (< 20 %), which could be increased after oxidation towards the corresponding sulfonamides 90 with m-CPBA and subsequent N-allylation of with 2-fluoroallyl mesylate in DMF and in the presence of NaH as base. With this strategy, a family of Ntethered fluorinated enynes 87, direct precursors of the of the PK adducts, was synthesized in good to high yields. These building blocks were next used in the Co-mediated Pauson À Khand reaction, allowing the stereoselective introduction of a fluorine atom in an otherwise synthetically challenging bridgehead quaternary stereocenter. After a reaction time of 24-48 hours using DMSO as promoter, DCE as solvent at 65°C and one equivalent of Co 2 (CO) 8 , the corresponding bicyclic cyclopentenones 91 were obtained in moderate to good yields and high diastereoselectivity (dr > 20 : 1). The removal of the tert-butylsulfonyl group (BUS) was carried out by treatment of the PK adducts 91 with a mixture of trifluoromethylsulfonic acid (TfOH) and anisole, with the results of free amine 92 being isolated as the hydrochloride salt (Scheme 48). Our group has also studied the intramolecular PKR of chiral fluorine-containing N-tethered 1,7-enynes. [97] In this reaction, bicyclic [4.3.0] enone derivatives, containing a fluorinated group in the bridge position could be obtained with high diastereoselectivity. To this end, and following a well-established methodology, chiral sulfonamides 95 were prepared in two-steps from fluorinated tert-butanesulfinylimines 93, [98] by a controlled diastereoselective addition of propargylmagnesium bromide, [99] followed by oxidation using m-CPBA of the initially obtained sulfinylamides towards sulfonamides 95 in nearly quantitative yields. However, in the case of the substituted propargylmagnesium bromides (R ¼ 6 H, e. g. phenylpropargyl magnesium bromide) a mixture of the corresponding propargyl and allenyl derivatives was obtained. Therefore, an alternative procedure was necessary for obtaining the fluorinated sulfonyl amides 95 and enyne derivatives 94. Substitution at the triple bond with aryl groups was carried out via a Sonogashira cross-coupling reaction from homopropargylic sulfonamides 95. On the other hand, alkyl-substituted enynes were synthesized by direct alkylation of the triple bond in 94 (R=H) with an alkyl halide (e. g. MeI) and HMDSLi as base (Scheme 49, B). The allylation of the homopropargyl sulfonamides 96 with the corresponding bromide (Scheme 49, A) in basic conditions at room temperature gives the Ntethered 1,7-enynes 94 (R=Ar) in good yields. Finally, the chiral fluorine-containing N-tethered 1,7-enynes 94 were evaluated in the Co-mediated intramolecular PKR using stoichiometric amounts of Co 2 (CO) 8 and NMO as promoter in CH 2 Cl 2 at room temperature. Thus, the corresponding bicyclic cyclopentenones 97 were obtained as single diastereoisomers in moderate to good yields. The study of the

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reaction scope revealed a good tolerance of mono-and disubstituted olefins; however, trisubstituted olefins remained unreactive and 1,7-enyne was recovered, in accordance with previously studied systems. Fluorine-containing N-tethered 1,7-enynes bearing a vinyl fluoride moiety yielded the cyclopentenone derivative 98 in lower yields but maintaining the high diastereoselectivity. The catalytic PKR was studied on a biphasic system of 15 % v/v of ethylene glycol in toluene (Scheme 49). The reaction mechanism of the Co 2 (CO) 8 -mediated PKR reaction of chiral fluorine-containing N-tethered 1,7-enynes was recently examined in a theoretical study by means of DFT calculations using the M11 functional with the 6-311 + G(d,p) basis set and SDD for the Co atoms ( Figure 4). [100] The mechanism starts with the complexation with Co 2 (CO) 8 of the N-tethered enyne through the alkyne forming the cobaltacetylenic complex INT-A and releasing two molecules of CO.  6 . The stereoselectivity-determining step of the PKR reaction was found to be the intramolecular alkene insertion into the carbon-cobalt bond. Theoretical calculations showed a preference for the alkene insertion through the Re-face over the Si-face insertion, which displayed unfavourable steric N-BusÀ CF 3 interactions. The incorporation of a trifluoromethylated group at the asymmetric carbon of the enyne was found to be beneficial for the alkene insertion, showing that the presence of a fluorinated group decreased the activation barrier for this step. However, the introduction of fluorine or fluorinated groups on the alkene or alkyne had the opposite effect and higher barriers were computed.
The presence of a fluorinated group at different positions of the chiral N-tethered 1,7-enynes was evaluated. The presence of a methylfluorinated group at the chiral carbon of the enyne had a positive effect accelerating the alkene insertion, as reflected in the lower Gibbs energy barrier compared to the 1,7-enyne with a methyl group at the same

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position. The introduction of fluorine at the alkene moiety had a negative effect on the barrier of the TS for the alkene insertion, whereas a fluorinated group at the alkyne moiety had the opposite effect, lowering the barrier for this step ( Figure 5).

Rh-Catalyzed Reactions
Cycloaddition reactions play a significant role in the synthesis of polycyclic compounds although, in most cases, a metallic catalyst is required. Transition-metals have been shown to be efficient catalysts in cycloaddition reactions allowing the reaction to take place with high yield and selectivity, and with a wide functional group tolerance. Among these transformations, transition-metal catalyzed [2 + 2 + 2]-cycloadditions constitute a reliable method to access sophisticated ring structures and useful intermediates in the synthesis of a variety of N-heterocyclic compounds. Metals such as Rh, Co, Ru, Ir, Pd and Pt among others, have been used to this purpose. Recently, our group reported the synthesis of new linear chiral N-tethered-1,7,13-triynes starting from chiral homopropargyl amides. [101] For the preparation of the required triynes 99, a previously reported approach based on the diastereoselective 1,2-addition of propargylmagnesium bromide to a different substituted Ellman's sulfinylimines 88 was followed (see, also Scheme 48). In this way, the corresponding chiral homopropargyl amides 100 were obtained in good to high yield and diastereoselectivity (dr > 95 : 5). Then, the desulfinylation of 100 with HCl/MeOH followed by N-tosylation with TsCl in Et 3 N yielded p-tosylamide derivatives 101. The desired chiral triynes 99 were finally obtained after deprotonation of the corresponding p-tosylamide 101 with Cs 2 CO 3 in CH 3 CN followed by a reaction with the 2-butyn-1,4-ditosylate at 80°C. Linear triynes bearing a methyl-or bromosubstituent at the terminal triple bond 102 could be synthesized by treatment of the triynes 99 with n-BuLi or HMDSLi and subsequent reaction with either MeI or by treatment with AgNO 3 and N-bromosuccinimide (NBS), respectively (Scheme 50).
Linear 1,7-triynes (S,S)-99 and (S,S)-102 underwent a rhodium-catalyzed intramolecular [2 + 2 + 2]-cycloaddition reaction under the optimized conditions i. e. RhCl(PPh 3 ) 3 (10 mol%), toluene as solvent, at reflux for 14 h, in which three sigma bonds were simultaneously created affording the corresponding tricyclic compounds in moderate to good yields. In order to find the optimized reaction conditions, Rh, Co, Ru and Ir complexes were tested as catalysts, with the Wilkinson complex being the most effective for the intramolecular [2 + 2 + 2]-cycloaddition. Using this strategy, tricyclic compounds with a benzene embedded in two chiral piperazines 103 were obtained in moderate to good yields (Scheme 51).

Ruthenium Reactions
Since the pioneering work of Grubbs describing rutheniumcatalyzed metathesis cascade reactions, [102] a few variants of metathesis reactions have been developed and efficiently applied in the field of total synthesis of natural products. [103] In this regard, metathesis reactions have become, since their discovery, some the most important strategies for the carboncarbon bond formation, with the ring-closing metathesis (RCM) being an excellent strategy in modern organic synthetic chemistry. Another interesting variant of this reaction is the ring-closing enyne metathesis (RCEYM), a powerful tool for the synthesis of heterocycles, which under mild conditions is capable of generating 1,3-conjugated cyclic dienes with an exocyclic double bond in its structure and widely used in the synthesis of medium-and large-sized rings capable of undergoing further synthetic transformations. [104] In this context, our group reported quite recently the use of the ruthenium-catalyzed ring-closing enyne metathesis (RCEYM) and cross enyne metathesis/ring-closing metathesis (CEYM/RCM) reactions of chiral fluorinated and nonfluorinated nitrogen-containing 1,7-enynes for the preparation of a variety of enantioenriched tetrahydropyridine derivatives. [105] The synthesis of the chiral N-tethered 1,7-enynes 94 was carried out in good yields following a previously reported fourstep synthetic sequence. [97] The ring closing enyne metathesis reaction (RCEYM) of 94, using 1,7-octadiene as an in situ source of ethylene, was tested next with different catalysts, solvents and temperatures and it was found that the Hoveyda-Grubbs catalyst HG2 (3 mol%), DCM or DCE as solvent and rt or 60°C were the optimal reactions conditions. Thus, a series of chiral 1,7-enynes 104 with different aromatic, heteroaromatic, aliphatic and fluorinated substituents at the stereogenic carbon center were obtained in good yields (Scheme 52A). It is noteworthy that when the reaction was performed in the absence of 1,7-octadiene, the formation of 104 was not observed. [106] Moreover, in the ruthenium-catalyzed domino cross enyne metathesis/ring closing metathesis (CEYM/RCM) of enynes 94 and different aromatic and aliphatic olefins, a mixture of enantioenriched tetrahydropyridines 104 and 105, easily separable by flash chromatography, was observed (Scheme 52B).
The reactivity of several chiral 1,3-dienes (104 and/or 105) was also evaluated through a Diels-Alder reaction with readily available carbo-and heterodienophiles, such as tetracyanoethylene (TCNE) and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). In all cases, the process took place efficiently to give cycloadducts 106 in high yields and diastereoselectivity (dr > 20 : 1). The absolute stereochemistry of adducts 106 was determined to be (S,S) according to X-ray crystallography analysis and a gram scale with no loss of yield was carried out for some of them (Scheme 53).

Conclusions and Outlook
In this personal account, the recent advances achieved in the use of fluorinated imines in tandem reactions as well as in transition metal-mediated cycloaddition reactions such as the Pauson-Khand reaction, rhodium-catalyzed intramolecular [2 + 2 + 2]-cycloaddition and metathesis reactions have been presented and discussed. Fluorinated imines have been efficiently used as starting materials in the preparation of more complex scaffolds having fluorine or fluorinated groups in their structure. To obtain these more sophisticated structures, cycloaddition reactions involving an intermolecular or intramolecular [2 + 2 + 1]-cycloaddition, in the case of the Pauson-Khand reaction, or a [2 + 2 + 2]-cycloaddition, in the case of rhodium-catalyzed cycloadditions have been employed affording the desired compounds with high enantio-or diastereoselectivity. These elegant cycloadditions and other tandem reactions described in this personal account have provided organic chemists with new synthetic tools to construct complex molecules in a concise fashion. Our group has made several important contributions to this field, and we have used fluorinated imines to synthesize various fluorinated products of interest.

P e r s o n a l A c c o u n t T H E C H E M I C A L R E C O R D
devoted to investigating their reactivity in transition metalmediated cycloaddition reactions.