Cycloadditions of Azomethine Imines - MDPI

molecules Review

Synthesis of Non-Racemic Pyrazolines and Pyrazolidines by [3+2] Cycloadditions of Azomethine Imines Franc Požgan 1 1 2

*

ID

, Hamad Al Mamari 2 , Uroš Grošelj 1 , Jurij Svete 1

ID

and Bogdan Štefane 1,2, *

ID

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Veˇcna pot 113, SI 1000 Ljubljana, Slovenia; [email protected] (F.P.); [email protected] (U.G.); [email protected] (J.S.) Department of Chemistry, College of Science, Sultan Qaboos University, P.O. Box 36, Al Khoud Muscat, Oman; [email protected] Correspondence: [email protected]

Received: 29 November 2017; Accepted: 12 December 2017; Published: 21 December 2017

Abstract: Asymmetric [3+2] cycloadditions of azomethine imines comprise a useful synthetic tool for the construction of pyrazole derivatives with a variable degree of saturation and up to three stereogenic centers. As analogues of pyrrolidines and imidazolidines that are abundant among natural products, pyrazoline and pyrazolidine derivatives represent attractive synthetic targets due to their extensive applications in the chemical and medicinal industries. Following the increased understanding of the mechanistic aspect of metal-catalyzed and organocatalyzed [3+2] cycloadditions of 1,3-dipoles gained over recent years, significant strides have been taken to design and develop new protocols that proceed efficiently under mild synthetic conditions and duly benefit from superior functional group tolerance and selectivity. In this review, we represent the current state of the art in this field and detailed methods for the synthesis of non-racemic pyrazolines and pyrazolidines via [3+2] metal and organocatalyzed transformations reported since the seminal work of Kobayashi et al. and Fu et al. in 2002 and 2003 up to the end of year 2017. Keywords: pyrazolines; pyrazolidines; metal-catalyzed cycloadditions; cycloadditions; azomethine imines; [3+2] cycloadditions

organocatalyzed

1. Introduction [3+2] Cycloadditions comprise a powerful tool for the construction of five-membered heterocycles [1–4]. Due to concertedness of the reaction mechanism [4–6], [3+2] cycloadditions are also the most straightforward way to obtain a (partially) saturated system with multiple stereogenic centers in a highly stereoselective manner [1–6]. The advent of asymmetric catalysis, which also took place in the field of [3+2] cycloaddition chemistry, nowadays enables the preparation of various types of non-racemic saturated heterocycles in a highly efficient manner. Within this context, the use of nitrile oxides, nitrones and azomethine ylides is well established [7,8], whereas asymmetric cycloadditions of azomethine imines remain much less explored [8–11]. To date, less than three dozen reports on the synthesis of non-racemic pyrazolines and pyrazolidines by [3+2] cycloaddition of azomethine imines can be found in the literature. However, the fact that all these examples have been published since 2003 points at increasing interest in this field. Azomethine imines are 1,3-dipoles of the aza-allyl type represented with iminium amide and diazonium ylide mesomeric structures [9–12]. They are easily accessible from hydrazine derivatives, diazoalkanes and azo-compounds. Although many azomethine imines are stable compounds, also the unstable dipoles are easily generated in situ from the above precursors. [3+2] Cycloadditions of azomethine imines are of broad substrate scope as the reactions can be performed with all

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common types of dipolarophiles. Accordingly, with acetylenes provide to pyrazolines, types of dipolarophiles. Accordingly, reactions reactions with acetylenes provide access to access pyrazolines, whereas types of dipolarophiles. Accordingly, reactions with acetylenes provide access to pyrazolines, whereas whereas cycloadditions to olefins are employed to obtain the fully-saturated pyrazolidines. In terms cycloadditions to olefins are employed to obtain the fully-saturated pyrazolidines. In terms of cycloadditions to olefins are employed to obtain the fully-saturated pyrazolidines. In terms of of stereochemistry, [3+2] cycloadditions of azomethine imines furnish products with up tonewlythree stereochemistry, [3+2] cycloadditions of azomethine imines furnish products with up to three stereochemistry, [3+2] cycloadditions of azomethine imines furnish products withderivatives upobtained to threeobtained newlynewly-formed stereogenic centers [9–11] (Figure 1). In addition, the pyrazolidine formed stereogenic centers [9–11] (Figure 1). In addition, the pyrazolidine derivatives through formed stereogenic centers [9–11] 1). In addition, the pyrazolidine derivatives obtained through through these annulations can readily be transformed into differently-protected 1,3-diamine derivatives these annulations can readily be(Figure transformed into differently-protected 1,3-diamine derivatives via these annulations can readily be transformed into differently-protected 1,3-diamine derivatives via via N–N bond cleavage with N–N bond cleavage with SmISmI 2. 2. N–N bond cleavage with SmI2.

Figure framework via via 1,3-dipolar 1,3-dipolarcycloadditions cycloadditions(DCs). (DCs). Figure1.1.Construction Constructionofofpyrazoline pyrazoline and and pyrazolidine pyrazolidine framework Figure 1. Construction of pyrazoline and pyrazolidine framework via 1,3-dipolar cycloadditions (DCs).

Shintani and Fu have published the first example of asymmetric [3+2] cycloadditions of azomethine Shintaniand and have published the first example of asymmetric [3+2] cycloadditions Shintani Fu Fu have published the first example ofcatalyst asymmetric [3+2] cycloadditions of azomethine imines to acetylenes in 2003. They utilized Cu(I)-based with chiral phosphaferrocene-oxazoline of azomethine imines to acetylenes in 2003. They utilized Cu(I)-based catalyst with chiral imines to acetylenes in 2003. They utilized Cu(I)-based catalyst with chiral phosphaferrocene-oxazoline ligand to obtain the desired cycloadducts regioselectively and in excellent enantioselectivity [13]. Soon phosphaferrocene-oxazoline ligand to obtain the desired cycloadducts regioselectively and in excellent ligand to obtain desired cycloadducts regioselectively in excellent enantioselectivity after, the same the catalyst was also employed in kinetic and resolution of azomethine imines[13]. by Soon [3+2] enantioselectivity [13]. Soon after, the same catalyst was also employed in kinetic resolution of after, the same catalyst was also employed in kinetic resolution of azomethine imines by [3+2] cycloaddition [14]. Besides Cu(I)-, also Ag(I)- and Cu(II)-catalysts are amenable in cycloadditions to azomethine imines by [3+2] cycloaddition [14]. Besides Cu(I)-, also andin Cu(II)-catalysts are cycloaddition [14]. Besides Cu(I)-, also Cu(II)-catalysts are Ag(I)amenable cycloadditions to acetylenes [11,15]. In the reactions of Ag(I)olefins,and however, asymmetric organocatalysts comprise the amenable in cycloadditions to acetylenes [11,15]. In the asymmetric reactions of organocatalysts olefins, however,comprise asymmetric acetylenes [11,15]. In the reactions of olefins, however, the leading approach, although examples of metal-catalysis have also been reported [8,11]. Most organocatalysts comprise the leading approach, although examples of metal-catalysis have alsoMost been leading approach, although of metal-catalysis have also beensystems, reportedas [8,11]. probably, the combination ofexamples the proven viability of different catalytic well as the reported [8,11]. Most probably, combination of theofproven viability of different systems, probably, theofcombination of the proven viability different catalytic systems,catalytic asand well as the applicability the pyrazoline scaffold in the development of drugs, agrochemicals, materials as well as theof applicability of the pyrazoline scaffold in the development of drugs, agrochemicals, and applicability the pyrazoline in interest the development of drugs, agrochemicals, and materials (Figure 2) will continue to spurscaffold increased in these reactions. materials (Figure 2) will continue to spur increased interest in these reactions. (Figure 2) will continue to spur increased interest in these reactions.

Figure 2. Pyrazolines and pyrazolidines as subunits of bioactive compounds and drugs. Figure Figure 2. 2. Pyrazolines Pyrazolines and and pyrazolidines pyrazolidines as as subunits subunits of of bioactive bioactive compounds compounds and and drugs. drugs.

This review covers the synthesis of non-racemic pyrazolines and pyrazolidines by [3+2] This review the synthesis of non-racemic pyrazolines and pyrazolidines by [3+2] cycloadditions of covers azomethine imines until September 2017. The vast majority of examples are This review covers the synthesis of non-racemic pyrazolines and pyrazolidines by [3+2] cycloadditions of azomethine imines until September 2017. The vast majority of examples are asymmetric catalyzed cycloadditions; however, the preparation non-racemic cycloadducts by cycloadditions of azomethine imines until September 2017. Theofvast majority of examples are asymmetric cycloadditions; however, the preparation of non-racemic cycloadducts by resolution ofcatalyzed stereoisomers is also included. asymmetric catalyzed cycloadditions; however, the preparation of non-racemic cycloadducts by resolution of stereoisomers is also included. resolution of stereoisomers is also included. 2. Synthesis of Pyrazolines by Metal-Catalyzed Cycloadditions 2. 2. Synthesis Synthesis of of Pyrazolines Pyrazolines by by Metal-Catalyzed Metal-Catalyzed Cycloadditions Cycloadditions Following the success of copper-catalyzed 1,3-dipolar cycloadditions of alkynes to azides [16,17], success copper-catalyzed 1,3-dipolar cycloadditions of [16,17], Following the successinof of2003, copper-catalyzed 1,3-dipolar cycloadditions of alkynes alkynes to azides [16,17], and Following to nitronesthe [18,19], Fu and co-workers extended this useful modeto ofazides reactivity to and to nitrones [18,19], in 2003, Fu and co-workers extended this useful mode of reactivity to and to nitrones [18,19], in 2003, Fu andasco-workers useful mode of reactivity N,N-cyclic N,N-cyclic azomethine imines dipoles. extended They this demonstrated that the to reaction of N,N-cyclic azomethine imines dipoles. They that at the of azomethine imines as dipoles. demonstrated that thedemonstrated reactionaccelerated of 3-oxopyrazolidin-ium-2-ides 3-oxopyrazolidin-ium-2-ides 1 They with as terminal alkynes dramatically room reaction temperature 3-oxopyrazolidin-ium-2-ides 1 with of terminal alkynes dramatically accelerated at room temperature 1inwith terminal of alkynes dramatically accelerated at room inofthe presence of catalytic the presence catalytic amount CuI, presumably via temperature the formation copper acetylide as the in the presence of catalytic amount of CuI, presumably via the formation of copper acetylide as2the amount of CuI,dipolarophile, presumably viaand the gave formation of copper acetylide as the more reactive products dipolarophile, more reactive the corresponding pyrazolo[1,2-a]pyrazole as more dipolarophile, and gave theable corresponding pyrazolo[1,2-a]pyrazole as singlereactive regioisomers (Scheme 1) [13]. To be to control the stereoselectivity of theproducts reaction, 2they single (Scheme 1) oxazolines [13]. To be as able to controlchiral the stereoselectivity of the reaction, they utilizedregioisomers enantiomerically-pure privileged ligands, since bidentate phosphines utilized enantiomerically-pure oxazolines as privileged chiral ligands, since bidentate phosphines

in the reaction of azomethine imine 1 (R = Ph) with ethyl propiolate, the level of enantioselectivity was considerably increased in the presence of P,N phosphaferrocene-oxazoline chiral ligand L2a bearing an isopropyl substituent on the oxazoline moiety (19% ee → 90% ee). Introduction of the sterically more demanding tert-butyl group (ligand L2b) or changing the planar chirality of the phosphaferrocene Molecules 2018, 23, 3 subunit as in ligand L3 resulted in a significant decrease of enantiomeric excess 3 of 31 (90% ee → 58% ee and 80% ee, respectively). This was the first asymmetric Cu(I)-catalyzed [3+2] cycloaddition of azomethine imines with alkynes. and gave corresponding products as single regioisomers (Scheme 1) [13]. Theirthe methodology waspyrazolo[1,2-a]pyrazole applicable to azomethine imines 2derived from aryl-, alkyland alkenylTo be able to control the stereoselectivity of the reaction, they utilized enantiomerically-pure oxazolines aldehydes, and thus, they prepared a series of the corresponding enantioenriched pyrazoline as privileged chiralhigh ligands, since yields bidentate catalysis While the derivatives 2 with chemical andphosphines ee values upinhibited to 98%. the With regard by to copper. the dipolarophile bis(oxazoline) ligand L1 induced only modest stereoselection in the reaction of azomethine imine coupling partner, the best yields and ee values were obtained with electron-poor alkynes having a 1 (R = Ph) with ethyl propiolate, the level of enantioselectivity was considerably increased in the carbonyl, an electron-deficient aromatic or heteroaromatic group. Simple aryl- or alkyl-acetylenes presence of P,N phosphaferrocene-oxazoline chiral ligand L2a bearing L2a an isopropyl on the also reacted in the presence of the Cu(I)-phosphaferrocene-oxazoline catalytic substituent system, although oxazoline moiety (19% ee → 90% ee). Introduction of the sterically more demanding tert-butyl group they required gentle heating for a reasonable reaction rate, which consequently resulted in erosion of (ligand L2b) or changing the protocol planar chirality of the subunit as in ligand L3 resulted regioselectivity (~6:1). This tolerates alsophosphaferrocene substituents in the pyrazolidinone ring of an in a significant decrease of enantiomeric excess (90% ee → 58%products ee and 80% ee, respectively). This was azomethine imine yielding sterically more congested bicyclic 3 and 4 with excellent yields the first asymmetric Cu(I)-catalyzed [3+2] cycloaddition of azomethine imines with alkynes. and enantioselectivities. O N 1

O

N

CuI (5 mol%), L2a (5.5 mol%)

R1

+

(1.2 equiv.)

R

N

Cy2NMe, CH2Cl2, r.t.

R 2 R1 Me

Me

Me O

O

L1

O

O

P

N

P Fe

Me

i-Pr

Me Me Me

Me

N

N i-Pr

R2

Me

Me

O

a: R = Ph (99%, 90% ee) b: R = o-FC6H4 (99%, 81% ee) c: R = m-BrC6H4 (99%, 86% ee) N N d: R = p-CF3C6H4 (99%, 95% ee) e: R = m-BrC6H4 (99%, 86% ee) CO2Et f: R = 1-cyclohexyl (98%, 94% ee) R g: R = n-pentyl (92%, 82 ee) h: R = Cy (94%, 96 ee) O N

N Fe

Me Me

N

CO2Et Ph 3: 99%, 98% ee

Me

i-Pr

Me

Me L2a: R2 = i-Pr, L2b: R2 = t-Bu

Me Me

N

Me L3

i: R1 = CO2Et (98%, 90% ee) j: R1 = COMe (98%, 90% ee) k: R1 = CONMePh (100%, 94% ee) N N l: R1 = p-EtO2CC6H4 (77%, 88% ee) m: R1 = p-CF3C6H4 (90%, 86% ee) Ph R1 n: R1 = 2-pyridyl (100%, 84% ee) o: R1 = Ph (73%, 88% ee) p: R1 = n-pentyl (63%, 74 ee) Me O Me O

N

N

CO2Et Ph 4: 100%, 96% ee

Scheme The Cu(I)-catalyzed asymmetric cycloaddition of imines azomethine iminesalkynes. with Scheme 1.1.The firstfirst Cu(I)-catalyzed asymmetric cycloaddition of azomethine with terminal terminal alkynes.

Their on, methodology was applicable to azomethine imines derived from aryl-, alkyl- and Later the same research group extended the above-mentioned asymmetric Cu(I)-catalyzed alkenyl-aldehydes, and thus, they prepared a series of the corresponding enantioenriched pyrazoline cycloaddition for the efficient preparation of enantiomerically-enriched C5-substituted azomethine derivatives 2 withkinetic high chemical andracemic ee values up to 98%. With2)regard to the dipolarophile imines 5 through resolutionyields of their mixtures (Scheme [14]. The catalytic reaction coupling partner, the best yields and ee values were obtained with electron-poor alkynes of racemic azomethine imines 5 with ethyl propiolate in the presence of the previously usedhaving chiral a carbonyl, an electron-deficient aromatic or heteroaromatic group. Simple arylor alkyl-acetylenes phosphaferrocene-oxazoline ligand L2a was less efficient in kinetic resolution than the reaction also reactedwith in the the Cu(I)-phosphaferrocene-oxazoline L2a catalytic although performed thepresence catalytic of system comprising CuI and ligand L4 bearing a bigger system, phenyl group on they required gentle heating for a reasonable reaction rate, which consequently resulted in erosion the oxazoline moiety. The employment of ligand L4 furnished a two-times higher selectivity factor s of regioselectivity (~6:1). This protocol tolerates also substituents in the pyrazolidinone ring of (s = rate of fast-reacting enantiomer/rate of slow-reacting enantiomer) than of ligand L2a (49 vs. 27) an azomethine sterically more congested bicyclic and 4 C4-substituted with excellent yields and allowed theimine use ofyielding even lower catalyst loading (1 mol % vs. products 5 mol %).3While (e.g., and enantioselectivities. Later on, the same research group extended the above-mentioned asymmetric Cu(I)-catalyzed cycloaddition for the efficient preparation of enantiomerically-enriched C5-substituted azomethine imines 5 through kinetic resolution of their racemic mixtures (Scheme 2) [14]. The catalytic reaction of racemic azomethine imines 5 with ethyl propiolate in the presence of the previously used chiral phosphaferrocene-oxazoline ligand L2a was less efficient in kinetic resolution than the reaction

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performed with the catalytic system comprising CuI and ligand L4 bearing a bigger phenyl group on the oxazoline moiety. The employment of ligand L4 furnished a two-times higher selectivity factor s (s = rate of fast-reacting enantiomer/rate of slow-reacting enantiomer) than of ligand L2a Molecules 2018, 23, 3 4 of 30 (49 vs. 27) and allowed the use of even lower catalyst loading (1 mol % vs. 5 mol %). While (e.g., R = cyclohexyl) azomethine provided low selectivity < 2) in RC4-substituted = cyclohexyl) azomethine imine provided very lowimine selectivity (s < 2)very in kinetic resolution,(s a variety kinetic resolution,dipoles a variety of be C5-substituted dipoles by canCu/L4-catalyzed be effectively resolved by Cu/L4-catalyzed of C5-substituted can effectively resolved cycloadditions with estercycloadditions with esteror amide-substituted alkyne. With this new catalyst system, they succeeded or amide-substituted alkyne. With this new catalyst system, they succeeded in preparing highly in preparing highlyazomethine enanatio-enriched up have to 99%), which have aabenzylidene, enanatio-enriched imines azomethine (ee’s up to imines 99%), (ee’s which a benzylidene, heteroaryl a heteroaryl an methylidene, anoralkenylidene or a cycloalkylidene at the5.N1 of the dipole 5. methylidene, alkenylidene a cycloalkylidene substituent at thesubstituent N1 of the dipole EnantiomericallyEnantiomerically-pure azomethine imines 5 prepared in these kinetic resolutions served precursors pure azomethine imines 5 prepared in these kinetic resolutions served as precursors for theas synthesis of for thepyrazolidinone synthesis of useful pyrazolidinone 6, 7 and 8. useful derivatives 6, 7 and derivatives 8. O R

O

N

N rac-5

CuI (1 mol%), L4 (1.1 mol%)

+

Cy2NMe, CH2Cl2 or CHCl3, r.t. R2 (0.5-0.6 equiv.)

R1

R

N 5

R1 (R = Ph, R2 = CO2Et) s ee of the dipole 5 (%) R (R1 = Ph) Ph

53 O

Me

99

95

96

Me N

Cy

27

99

35

95

15

91

O t-Bu

N Ph

S

N

N CONMePh

6 (95 : 5 dr)

7

N

R

R1 s

N

R2

ee of the dipole 5 (%)

99

2-thienyl (R2 = CO2Et)

15

98

i-Pr (R2 = CONMePh)

76

97

t-Bu (R2 = CONMePh)

51

93

O

NH

NH

Ph i-Pr

N

Me Ph

O

Me P

N Me

Ph

8 ( 97 : 3 dr)

N

R1

3-BrC6H4 (R2 = CONMePh) 54

O

Ph

O

Fe

Me

Me Me

Me L4

Scheme 2. Kinetic resolution of racemic azomethine imines via asymmetric 1,3-dipolar cycloaddition. Scheme 2. Kinetic resolution of racemic azomethine imines via asymmetric 1,3-dipolar cycloaddition.

Arai et al. developed a chiral (S,S,S,S)-bis(imidazolidine)pyridine ligand L5 (Py-Bidine) and al. catalytic developedasymmetric a chiral (S,S,S,S)-bis(imidazolidine)pyridine ligand L5 imines (Py-Bidine) andalkyl used used Arai it inetthe cycloaddition of cyclic aryl-azomethine 9 with it in the catalytic asymmetric cycloaddition of cyclic aryl-azomethine imines 9 with alkyl propiolates propiolates (Scheme 3) [20]. The best catalytic system, in terms of activity and enantioselectivity, (Scheme 3) [20]. catalytic system, in terms of activity and enantioselectivity, turned out to turned out to beThe thebest combination of L5 and CuOAc as a source of Cu+ ions, which provided + be the combination L5 and as a source(R)-cycloadduct of Cu ions, which provided quantitative yield andof60% ee ofCuOAc the corresponding 10 (Ar = Ph, R =quantitative Et, R1 = H) inyield the 1 = H) in the reaction of and 60% ee of the corresponding (R)-cycloadduct 10 (Ar = Ph, R = Et, R reaction of 2-benzylidene-5-oxopyrazolidin-2-ium-1-ide with ethyl propiolate at room temperature. 2-benzylidene-5-oxopyrazolidin-2-ium-1-ide with propiolate at room temperature. Lowering Lowering the reaction temperature (r.t. → –20 °C) andethyl the addition of base N,N-diisopropylethylamine ◦ C) and the addition of base N,N-diisopropylethylamine (DIPEA) the reaction temperature (r.t. → –20 (DIPEA) significantly improved enantioselectivity in CH2Cl2 (60% ee → 74% ee). Examination of significantly improved enantioselectivity in CH ee → 74% ee). THF, Examination of different 2 Claprotic 2 (60% (PhMe, different solvents, from nonpolar to polar protic and EtOH, 1,4-dioxane, MeCN, solvents, from nonpolar to polar protic and aprotic (PhMe, EtOH, THF, 1,4-dioxane, MeCN, CH 2 Cl2a), CH2Cl2), revealed only a slight solvent effect on the reaction with the exception of MeCN, in which revealed only a slight solvent effect on the reaction with the exception of MeCN, in which a low low chemical yield of the product was obtained. Interestingly, while the use of Cu(I) salts is believed chemical yield of the product was obtained. Interestingly, while the use of Cu(I) salts is believed to to be crucial for the formation of copper acetylide as a reactive dipolarophile, Cu(II) salts also be crucialsignificant for the formation acetylide as a reactive Cu(II) salts also exhibited exhibited activityof in copper the presence of ligand L5. Thedipolarophile, authors also proposed a mode of action significant activity in the presence of ligand L5. The authors also proposed a mode of actionThe of the of the catalyst Cu(I)-L5 responsible for assuring an asymmetric [3+2] cycloaddition reaction. in situ generated copper acetylide first coordinates to the (S,S,S,S)-Py-Bidine ligand to which (Z)-azomethine imine 9 approaches from an upper-side. Because the enantio-faces of the azomethine imine are differentiated on the molecular surface of the (S,S,S,S)-(Py-Bidine)–Cu complex, a suitable combination of catalyst and substrate is necessary for a high efficiency. Consequently, the azomethine imine 9 approaches in such a way as to minimize the non-bonded repulsion between the phenyl ring of the

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catalyst Cu(I)-L5 responsible for assuring an asymmetric [3+2] cycloaddition reaction. The in situ generated copper acetylide first coordinates to the (S,S,S,S)-Py-Bidine ligand to which (Z)-azomethine imine 9 approaches from an upper-side. Because the enantio-faces of the azomethine imine are differentiated on the molecular surface of the (S,S,S,S)-(Py-Bidine)–Cu complex, a suitable combination of catalyst and substrate is necessary for a high efficiency. Consequently, the azomethine imine 9 approaches in such a way as to minimize the non-bonded repulsion between the phenyl ring of the Molecules and 2018, 23, 5 of 30 10 Py-Bidine the3 aromatic ring of the azomethine imine (model A) resulting in bicyclic product withMolecules R configuration. On the other hand, as presented in model B, steric repulsion between5 phenyl 2018, 23, 3 of 30 with R configuration. On the other hand, as presented in model B, steric repulsion between phenyl groups prevents the formation of the opposite (S)-enantiomer. Although the enantiomeric excesses groups prevents the formation of the opposite (S)-enantiomer. Although the enantiomeric excesses with R configuration. On the other hand, as presented in model B, steric repulsion between phenyl of the bicyclic pyrazolo[1,2-a]pyrazolone 10 were were moderate (32–74%), this newly-designed of the bicyclic pyrazolo[1,2-a]pyrazoloneproducts products 10 moderate (32–74%), this newly-designed groups prevents the formation of the opposite (S)-enantiomer. Although the enantiomeric excesses ligand L5 L5 hashas high potential of chiral chiralligands ligandstotopromote promote asymmetric [3+2] ligand high potentialfor forfurther furtherdevelopment development of asymmetric [3+2] of the bicyclic pyrazolo[1,2-a]pyrazolone products 10 were moderate (32–74%), this newly-designed cycloaddition reactions. cycloaddition reactions. ligand L5 has high potential for further development of chiral ligands to promote asymmetric [3+2] cycloaddition reactions. Ph

Ph Ph O R1

Ph

NO

+ CO2R N Ar (1.2 equiv.) + 1 R 9N CO2R N

R11 R

Ar

9

Ph Ph

Ph Ph HN N Bn Ph N N N Bn L5 (5.5 mol%)Bn

N NH Bn

N

CuOAc mol% ) L5(5 (5.5 mol%) 0.5 equiv. DIPEA, CH2Cl2 CuOAc (5 mol% ) 0.5 equiv. Ph DIPEA, CH2Cl2

(1.2 equiv.)

Bn N

Ph

HN

NH

N

O N Bn N N N O N N Cu N N N N Cu

O Ar = Ph, 4-I-C6H4, 3-Cl-C6H4 R1 N Ar1 = 4-I-C6H4, R = Ph, H, Me R1 N 3-Cl-C 6HEt 4 R = Me, N 1 Ar CO R 2 R R1 = H, Me 10 (32-74% ee) Ar CO2R R = Me, Et 10 (32-74% ee) Ph

R1

NO

O

Ph NBn Ph NBn Ph

N N Ph BnN N N N Ph N

steric repulsion

Ph NBn Ph NBn Ph

N

BnN O

N

N Cu

N

Cu

RO2C

steric repulsion A: FAVORED

RO2C

B: DISFAVORED

RO2C

A: FAVORED

RO2C

B: DISFAVORED

Scheme 3. Chiral Py-Bidineligand ligandin inCuOAc-catalyzed CuOAc-catalyzed cycloaddition imines with Scheme 3. Chiral Py-Bidine cycloadditionofofazomethine azomethine imines with alkyl propiolates. alkyl propiolates. Scheme 3. Chiral Py-Bidine ligand in CuOAc-catalyzed cycloaddition of azomethine imines with alkyl propiolates.

To further explore the versatility of tridentate chiral pyridine ligands in asymmetric catalysis, Tofive-membered further explore the versatility ofin tridentate chiral pyridine ligands in asymmetric catalysis, the imidazolidine rings L5 were replaced by differently substituted oxazolidines, To further explore the versatility of tridentate chiral pyridine ligands in asymmetric catalysis, the which five-membered imidazolidine rings in L5 were replaced by differently substituted oxazolidines, can easily beimidazolidine constructed inrings highinoptical purity fromby L-amino acid-derived alcohols 11 and the five-membered L5 were replaced differently substituted oxazolidines, which can easily be constructed in high optical purity from L-amino acid-derived alcohols 11 and symmetric pyridine(dicarboxaldehyde) [21]. The circular dichroism-high throughput screening which can easily be constructed in high optical purity from L-amino acid-derived alcohols 11 and approach was utilized to find the most efficient catalyst prepared from the in situ generated chiral symmetric pyridine(dicarboxaldehyde) [21]. The circular dichroism-high throughput screening symmetric pyridine(dicarboxaldehyde) [21]. The circular dichroism-high throughput screening polymer-supported bis(oxazolidine)pyridine ligands (Py-Bodine) and copper (Scheme 4). chiral approach was utilized totofind catalyst prepared from theinsalts in situ generated chiral approach was utilized findthe themost mostefficient efficient catalyst prepared from the situ generated

polymer-supported bis(oxazolidine)pyridine andcopper coppersalts salts (Scheme polymer-supported bis(oxazolidine)pyridineligands ligands (Py-Bodine) (Py-Bodine) and (Scheme 4). 4). Ph

Ph

OHC

N

CHO

H2N Ph OH Ala Ph

OHC

N

CHO

H2N

O O O i-Pr O i-Pr

OH AlaPh

x

Ph

x

H2N Ph OH Ile Ph

i-Pr

H2N Ph OH Ile Ph

i-Pr

H2N Ph OH Val Ph

Si Si

H2N

Val

OH

Ph Ph OH N Ph H Pro Ph OH N H Pro Ph Ph

H2N Ph OH Leu Ph H2N Ph OH Ph Leu Ph Ph OH HPh 2N Ph PhGly H N OH 11 2 PhGly

CuOAc x

CuOAc Cu(OAc)2

x

Cu(OAc)2 CuI CuI

Scheme 4. Preparation of chiral polymer-supported Py-Bodine–Cu catalysts. 11 Scheme Preparationof ofchiral chiral polymer-supported polymer-supported Py-Bodine –Cu catalysts. Scheme 4. 4. Preparation Py-Bodine–Cu Using this custom-made approach, the best candidate in the reaction ofcatalysts. azomethine imine 12 Ph) this withcustom-made ethyl propiolate was established as Py-Bodine(Ala)–Cu(OAc) 2 furnishing the (R1 =Using approach, the best candidate in the reaction of azomethine imine 12 (R)-isomer of the cycloadduct 13 with high chemical yield (99%) and excellent enantioselectivity (R1 = Ph) with ethyl propiolate was established as Py-Bodine(Ala)–Cu(OAc)2 furnishing the (94% ee). Interestingly, the Py-Bodine ligand prepared from proline-derived gave the (R)-isomer of the cycloadduct 13 with high chemical yield (99%) and excellent alcohol enantioselectivity (S)-isomer, but with significantly lower enantioselectivity (76% ee) for the same reaction. The complex (94% ee). Interestingly, the Py-Bodine ligand prepared from proline-derived alcohol gave the of Py-Bodine(Ala) ligand L6 and Cu(OAc)2 effectively catalyzed the reaction of various azomethine (S)-isomer, but with significantly lower enantioselectivity (76% ee) for the same reaction. The complex imines 12 bearing aryl or alkyl R1 groups with alkyl propiolates providing the corresponding bicyclic of Py-Bodine(Ala) ligand L6 and Cu(OAc) 2 effectively catalyzed the reaction of various azomethine

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Using this custom-made approach, the best candidate in the reaction of azomethine imine 12 (R1 = Ph) with ethyl propiolate was established as Py-Bodine(Ala)–Cu(OAc)2 furnishing the (R)-isomer of the cycloadduct 13 with high chemical yield (99%) and excellent enantioselectivity (94% ee). Interestingly, the Py-Bodine ligand prepared from proline-derived alcohol gave the (S)-isomer, but with significantly lower enantioselectivity (76% ee) for the same reaction. The complex of Py-Bodine(Ala) ligand L6 and Cu(OAc)2 effectively catalyzed the reaction of various azomethine imines 12 bearing aryl Molecules 2018, 23, 3 6 of 30 or alkyl R1 groups with alkyl propiolates providing the corresponding bicyclic pyrazoline products 13 in apyrazoline highly enantioselective (ee’s up to 98%) and with nearly quantitative chemical yields in products 13 inmanner a highly enantioselective manner (ee’s up to 98%) and with nearly most cases (Scheme 5). quantitative chemical yields in most cases (Scheme 5).

O

N

N

Cu(OAc)2(10 mol%), L6 (11 mol%)

CO2R2

+

MS 4Å, CH2Cl2, -40

R1

HN

NH O

N

N

N

R1

CO2R2 13: 11 examples 77-99% yield

12

Ph Ph

O

oC

O

L6: Py-Bodine(Ala)

Ph Ph

O

N

R

N

O

N

CO2Et R = H, Me, F, I, MeO (89-94% ee) O

N

N

Ph

CO2tBu (80% ee)

N

O

N

Cl

CO2Et (94% ee)

O

N

N

CO2Et (88% ee)

N

Ph

CO2Me (98% ee)

O

N

N

CO2Et (95% ee)

Scheme 5. Py-Bodine(Ala)–Cu(OAC)2 as a superior catalyst in [3+2] cycloaddition.

Scheme 5. Py-Bodine(Ala)–Cu(OAC)2 as a superior catalyst in [3+2] cycloaddition.

Multicomponent 1,3-dipolar cycloaddition is an attractive strategy for the construction of Multicomponent 1,3-dipolar cycloaddition an attractive strategy forasthe construction pyrazolines, particularly where less stable acyclicisazomethine imines are used dipoles. In this of context, Marouka et al. where reportedless on stable the one-pot three-component asymmetric [3+2] pyrazolines, particularly acyclic azomethine imines are used ascycloaddition dipoles. In this reaction of aldehydes hydrazides terminal acetylenes 16 by employing the[3+2] catalytic system context, Marouka et al.14, reported on 15 theand one-pot three-component asymmetric cycloaddition composed of CuOAc, (R,R)-L7acetylenes and binaphthyl dicarboxylic (R)-L8system as reaction of aldehydes 14, pyridine-bisoxazoline hydrazides 15 and terminal 16 by employing theacid catalytic chiral ligands (Scheme 6) [22]. While the ligand L7 is proposed to coordinate to the copper center,asthe composed of CuOAc, pyridine-bisoxazoline (R,R)-L7 and binaphthyl dicarboxylic acid (R)-L8 chiral chiral Brønsted acid L8 could interact with the azomethine imine via hydrogen bonding [23]. The ligands (Scheme 6) [22]. While the ligand L7 is proposed to coordinate to the copper center, the chiral labile acyclic azomethine imines generated in situ from aldehyde 14 and hydrazide 15 effectively Brønsted acid L8 could interact with the azomethine imine via hydrogen bonding [23]. The labile coupled with the present acetylenes 16 in a highly regioselective and stereoselective manner. The acyclic azomethine imines generated in situ from aldehyde 14 and hydrazide 15 effectively coupled corresponding 3,4-disubstituted pyrazolines 17 formed under mild conditions (r.t. or 40 °C), although for with the present acetylenes 16 in a highly regioselective and stereoselective manner. The corresponding high yields, extended reaction times had to be applied (1–3 days). Notably, the use of axially-chiral ◦ C), although for high yields, 3,4-disubstituted pyrazolines 17 formed under mild conditions (r.t. or 40 dicarboxylic acid as a co-catalyst was not only beneficial to enantioselectivity, but also increased extended reaction times had to bethe applied (1–3ofdays). Notably, the use of dicarboxylic chemoselectivity by suppressing formation alkynylation by-product 18.axially-chiral The most effective acid acid as a co-catalyst was not only beneficial to enantioselectivity, but also increased chemoselectivity was found to be binaphthyl dicarboxylic acid (R)-L8 bearing 3,3′-disilyl groups. The methodology by was suppressing thewith formation ofcyclic alkynylation by-product most effective acid was found to be compatible aliphatic and acyclic, aromatic 18. andThe heteroaromatic aldehydes. Moreover, 0 binaphthyl (R)-L8 can bearing 3,3 as -disilyl groups. The methodology was compatible aromatic dicarboxylic and aliphaticacid acetylenes be used coupling partners, and various substituents on thewith aliphatic cyclic and acyclic, aromatic andalso heteroaromatic aldehydes. Moreover, aromatic hydrazide moiety are tolerated. It was found that chiral pair matching of ligands L7 and and aliphatic L8 is crucial for the efficient asymmetric induction since the combination of (S,S)-L7 and (R)-L8 led to a are acetylenes can be used as coupling partners, and various substituents on the hydrazide moiety significant drop of the ee value (from 99% to 55%) of the pyrazoline product 17 prepared from tolerated. It was also found that chiral pair matching of ligands L7 and L8 is crucial for the efficient N′-benzylbenzohydrazide, and phenylacetylene. asymmetric induction sincebenzaldehyde the combination of (S,S)-L7 and (R)-L8 led to a significant drop of the Cu(I)-catalyzed 1,3-cycloaddition of azomethine imines with alkynes to proceed via 0 -benzylbenzohydrazide, ee value (from 99% to 55%) of the pyrazoline product 17 prepared fromisNbelieved Cu-acetylide intermediate and is therefore restricted to terminal alkynes (Scheme 7, a). On the other benzaldehyde and phenylacetylene. hand, Lewis acid-catalyzed cycloaddition can be applied also to internal alkynes, which importantly Cu(I)-catalyzed 1,3-cycloaddition of azomethine imines with alkynes is believed to proceed via extends the use of 1,3-cycloaddition methodology by allowing the synthesis of densely-substituted Cu-acetylide intermediate and is therefore restricted to terminal alkynes (Scheme 7, a). On the other pyrazoline derivatives (Scheme 7, b).

hand, Lewis acid-catalyzed cycloaddition can be applied also to internal alkynes, which importantly

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extends the use of 1,3-cycloaddition methodology by allowing the synthesis of densely-substituted pyrazoline derivatives (Scheme 7, b). Molecules 2018, 23, 3 7 of 30 Molecules 2018, 23, 3

7 of 30 R3

H R3 NH 4 N NR 3 RH N15 R4 H O + 15 O + 1 R R2 16 14 1 R R2 16 14

O O Ph Ph

N N

N N

N N (R,R)-L7 (R,R)-L7 R R

3

4 R1 NR CuOAc (10 mol%), L7 (12 mol%) N R4 R1 N CuOAc(10 (10 mol%), L7 (12 mol%) (R)-L8 mol%) N R (R)-L8 (10 mol%) R2 MS 4Å, CH2Cl2, r.t. or 40 oC, 1-3 d R MS 4Å, CH2Cl2, r.t. or 40 oC, 1-3 d 17:182 examples 17:18 examples 49-98% yield 49-98%ee yield 88-99% 88-99% ee

O O Ph Ph

CO2H CO2HH CO 2 CO2H R (R)-L8 R (R)-L8 R = H, Br, SiMe2Ph, R = H,2Br, SiMe2Ph, 2,6-Me -4-t-Bu-C 6H2 2,6-Me2-4-t-Bu-C6H2

H R3 NH 4 N R3 N R 4 N R R1 R118 R2 18 R2 5-10% 5-10%

selected examples: selected examples: Bn Bn Bn NBn Bz NBn Bz Me NBn Bz BnO N N Bz N N Bz Me N N Bz BnO N N N Ph Ph Ph (49%,Ph 99 ee) Ph >99 ee) Ph >99 ee) (87%, (93%, (49%, 99 ee) (87%, >99 ee) (93%, >99 ee)

O O

Bn NBn Bz N N Bz N

Ph (92%,Ph >99 ee) (92%, >99 ee) Bn Bn NBn Bz Bn Cy Bn N N Bz NBn Bz Cy NBn Bz N NBn Bz O N N Bz N N Bz Cl N N Bz O N N Me N Cl Cl Ph MePh Ph Ph 88% ee) Cl (95%, (92%, Ph94% ee) (94%, 98% Ph ee) (93%, 99% ee) (95%, 94% ee) (92%, 88% ee) (94%, 98% ee) (93%, 99% ee) Bn Bn Bu Bn Bn Bu NBn Cbz N N Ph Cy Ph NBn Bz Cy Bz Bz N N Cbz N N Bz Ph N N Bz Ph Cy N N Bz Cy N N N N Ph EtO2C Ph Cy Ph 90% ee) (91%, EtO2C96% ee) Ph 93% ee) (82%, (94%, (91%, Cy 98% ee) (91%, 90% ee) (82%, 98% ee) (94%, 96% ee) (91%, 93% ee)

Scheme 6. Dual asymmetric induction in three-component reaction for preparation the preparation of Scheme 6. Dual asymmetric induction in three-component reaction for the of enantioScheme 6. Dual asymmetric induction in three-component reaction for the preparation of enantio-enriched 3,4-disusbtituted pyrazolines enriched 3,4-disusbtituted pyrazolines enantio-enriched 3,4-disusbtituted pyrazolines

R2

2

R O a a O N N N b R2 2 N b R R1 R1

R1 R1 R1 R2 R1 N * N * 2 [Cu] R N N + N * N* [Cu] + N N R2 O R2 2+] O [Cu O O 2+] O R1 [Cu O O R1 O R3 * N R3 R3 N N* R3 N R2 O R2 O

Scheme 7. Cu(I)- vs. Lewis acid-catalyzed 1,3-dipolar cycloaddition.

Scheme Cu(I)-vs. vs.Lewis Lewis acid-catalyzed acid-catalyzed 1,3-dipolar Scheme 7. 7.Cu(I)1,3-dipolarcycloaddition. cycloaddition. In this context, the groups of Sakakura and Ishihara reported on the asymmetric [3+2] In this context, the groups of Sakakura andwith Ishihara reported on the asymmetric [3+2] cycloaddition of N,N-cyclic azomethine imines 19 propioloylpyrazoles dipolarophiles In this context, the groups of Sakakura Ishihara reported on 20 theas [3+2] cycloaddition of N,N-cyclic azomethine imines and 19 with propioloylpyrazoles 20 asasymmetric dipolarophiles (Scheme 8) [24]. The reaction was catalyzed by the Cu(II)-complex of 3-(2-naphthyl)-L-alanine amide cycloaddition of N,N-cyclic azomethine imines 19 with propioloylpyrazoles 20 as dipolarophiles (Scheme 8)L9 [24]. reaction was catalyzed by the 3-(2-naphthyl)-Lproducts -alanine amide derivative as The chiral ligand, which enabled theCu(II)-complex preparation ofof(R)-cycloadduct 22 in (Scheme 8) [24]. reaction catalyzed Cu(II)-complex of 3-(2-naphthyl)-L-alanine derivative L9 asThe chiral ligand,was which enabled by the the preparation of (R)-cycloadduct products 22 in good-to-excellent isolated yields (70–98%) and high enantioselectivities (80–95% ee). Among Cu(II) amide derivative L9 2as chiral ligand, which enabled the preparation of (R)-cycloadduct products good-to-excellent yields and high of enantioselectivities ee). Among Cu(II) salts tested, Cu(NTfisolated )2 exhibited the(70–98%) highest reactivity the chiral catalytic(80–95% system. This methodology salts tested, Cu(NTf 2)2 isolated exhibited the highest reactivity of the chiral catalytic system. This methodology 22 in good-to-excellent yields (70–98%) and high enantioselectivities (80–95% ee). Among tolerates meta- and para-substituted phenyl groups, heteroaryl and alkenyl groups on the azomethine tolerates metaand para-substituted phenyl groups, heteroaryl and alkenyl groups on the azomethine Cu(II) tested, Cu(NTf highest reactivity of the system. 2 = H),catalytic 2 )2 exhibited iminesalts coupling partner 19. Besides terminalthe pyrazole-containing alkyne 20 (Rchiral β-substituted 2 = H), β-substituted imine coupling partner 19. Besides terminal pyrazole-containing alkyne 20 (R This methodology tolerates metaand para-substituted phenyl groups, heteroaryl and alkenyl groups propioloylpyrazoles as disubstituted acetylenes also effectively participated in the present propioloylpyrazoles as disubstituted acetylenes also effectively participated in the present on cycloaddition the azomethine imine coupling partner 19. derivatives Besides terminal pyrazole-containing alkyne 20 to give fully-substituted pyrazoline 22. The activity and enantioselectivity cycloaddition to give propioloylpyrazoles fully-substituted pyrazoline derivatives 22. activity and enantioselectivity (R2of = this H), novel β-substituted as disubstituted also effectively participated π–cation catalyst can be finely tuned by changing acetylenes the The N-alkyl R group on the ligand L9. of this novel π–cation catalyst can22beserved finely tuned by changing theprecursors N-alkyl R group on the ligand L9. The synthesized cycloadducts as optically-active for 22. the synthesis in the present cycloaddition to give fully-substituted pyrazoline derivatives The activityofand The synthesized cycloadducts 22chiral served as optically-active precursors for the synthesis of 1,3-diamines with contiguous centers, such in 23.tuned enantioselectivity of three this novel π–cation catalyst can be as finely by changing the N-alkyl R group 1,3-diamines with three contiguous chiral centers, such as in 23.

on the ligand L9. The synthesized cycloadducts 22 served as optically-active precursors for the synthesis of 1,3-diamines with three contiguous chiral centers, such as in 23.

Molecules 2018, 23, 3 Molecules 2018, 23, 3 Molecules 2018, 23, 3

8 of 31 8 of 30 8 of 30 R1 O R1 O N L9c Cu(NTf2)2 (10 mol%) N N N L9c Cu(NTf2)2o(10 mol%) N N N CH2Cl2, -40 C, MS 4Å N R2 CH2Cl2, -40 oC, MS 4Å 2 O R 22: 18 examples O 22: 18 examples 70-98% yield, 80-95 ee 70-98% yield, 80-95 ee R1 = Ph, 2-MeO-C6H4,3-MeO-C6H4, N 1 = Ph, 2-MeO-C H 3-MeO-C H O R4-MeO-C 6 24, 6 4,6H4, -C6H4, 4-Br-C 6H4, 4-NO N O 4-MeO-C 4-NO2-C 6H4,3-furyl, 6H4, 4-Br-C 6H4, 2-naphthyl, PhCH=CMe R 2-naphthyl, 3-furyl, PhCH=CMe NR MeOCH R2 = ClCH2, 2, MsOCH2,BzOCH2, 2 = ClCH MeOCH MsOCH BzOCH NH R[(CH 2, 2, 2, 2, O)2CH], PhthalNCH 2 2 H L9a: R = c-C6H11 L9d: R = c-C3H5 [(CH2O)2CH], PhthalNCH2 L9a: L9b:RR==c-C c-C L9e:RR==c-C i-Pr3H5 6H 119 L9d: 5H L9b: L9f:RR == i-Pr Me L9c:RR==c-C c-C54HH97 L9e: L9c: R = c-C4H7 L9f: R = Me

O R1 N R1 O N N NN + N N + R2 N 20 O R2 20 O19 19

Ph O Ph O N N N N NN N N O MeO O MeO

MeO2C MeO2C N N

Ph Ph

CO2Me CO2Me OMe OMe

N O NH O H de) 23 (>99 23 (>99 de)

Scheme 8. 8. Asymmetric catalyst-induced cycloaddition cycloaddition of of N,N-cyclic N,N-cyclic azomethine azomethine imines imines Scheme Asymmetric π–cation π–cation catalyst-induced Scheme 8. Asymmetric π–cation catalyst-induced cycloaddition of N,N-cyclic azomethine imines with propioloylpyrazoles. with propioloylpyrazoles. with propioloylpyrazoles.

On the basis of experimental observations and previous results [25], a transition state assembly Onthe thebasis basisof ofexperimental experimental observationsand and previousresults results[25], [25],aatransition transitionstate stateassembly assembly On for the asymmetric cycloadditionobservations of 19 and 20 was previous proposed (Scheme 9). Since the carbonyl Re face for the asymmetric cycloaddition of 19 and 20 was proposed (Scheme 9). Since the carbonyl Re of for the asymmetric cycloaddition and 20 was proposed (Scheme 9). Since the carbonyl Reface face of a coordinated alkyne is shielded by a naphthyl group through the intramolecular π–cation a coordinated alkyne is shielded by a naphthyl group through the intramolecular π–cation interaction, of a coordinated alkyne isimine shielded by a naphthyl group through the endo-TS intramolecular π–cation interaction, an azomethine approaches the Si face via more favored by avoiding steric an azomethine imine approaches the Si face via more favored endo-TS by avoiding steric repulsion interaction, an azomethine imine approaches the Si face via more favored endo-TS by avoiding steric 1 repulsion between the R group (e.g., cyclopentyl) of the amide ligand L9 and the R group (e.g., Ph) between the R group (e.g., cyclopentyl) of the amide ligand and L9 the R1 the group (e.g., Ph) ofPh) the repulsion between the R group (e.g.,the cyclopentyl) of the(R)-product amide L9 ligand R1enantiomer. group (e.g., of the azomethine imine 19 to give corresponding 22 as and the major Less azomethine imine imine 19 to give corresponding (R)-product 22 as the22major enantiomer. Less hindered of the azomethine 19 tothe give the corresponding (R)-product as the major enantiomer. Less hindered N-cycloalkyl groups are successful in avoiding steric repulsion with the ethylene group of N-cycloalkyl groups are successful in avoiding steric repulsion with the with ethylene group ofgroup 19. Thus, hindered groups aregroups successful avoiding steric repulsion the the ethylene of 19. Thus,N-cycloalkyl the most efficient R are in cyclopropyl and cyclobutyl giving (R)-product 22 1 2 = H) the1 Thus, most efficient R groups are cyclopropyl and cyclobutyl giving the (R)-product 22 (R = Ph, R 19. the most efficient R groups are cyclopropyl and cyclobutyl giving the (R)-product 22 (R = Ph, R2 = H) with 93% ee and 95% ee, respectively, while the use of cyclohexyl and sterically 1 = 93% with ee, 93% respectively, while use of cyclohexyl and similar isopropyl groups (R Ph,isopropyl Ree2 and = H)95% with 95% ee,the respectively, the sterically use of cyclohexyl and sterically similar groups ledeetoand a significant decrease of while enantioselectivity (54% ee and 60% ee). The led to a significant decrease of enantioselectivity (54% ee and 60% ee). The N-methyl group, however, similar isopropyl ledwas to a too significant decrease enantioselectivity (54%Ineethe andexo-TS, 60% ee). The N-methyl group, groups however, small for efficientofenantio-differentiation. strong was too small for however, efficient enantio-differentiation. In theenantio-differentiation. exo-TS, strong steric repulsion betweenstrong the R1 N-methyl group, was1 too small for efficient In the exo-TS, steric repulsion between the R and cyclohexyl groups disfavors the addition of an azomethine imine and cyclohexyl groups disfavors thecyclohexyl addition of an azomethine imine to a coordinated alkyne, imine which steric repulsion between R1 and groups the addition of an azomethine to a coordinated alkyne, the which would otherwise lead todisfavors the formation of (S)-enantiomeric product 22. would otherwisealkyne, lead towhich the formation of (S)-enantiomeric product 22. to a coordinated would otherwise lead to the formation of (S)-enantiomeric product 22.

N N

N N Cu2+ N N O Cu2+ 1 RO 1 R H ( )n H N N ( )n N N

O O NH NH

N N

R2 R2

n = 1: weak steric repulsion O nn==1:0:weak steric repulsion O less steric n = 0: less steric repulsion state endo-transition endo-transition state FAVORED FAVORED (R)-22 (R)-22

N N Cu2+ N N O Cu2+ R2 H O R2 H N R1 N N R1 O N O strong steric repulsion strong stericexo-transition repulsion state exo-transition state DISFAVORED DISFAVORED O O NH NH

(S)-22 (S)-22

Scheme 9. Proposed endo- and exo-transition states for the asymmetric π–cation catalyst-promoted Scheme 9.9. Proposed Scheme Proposedendoendo-and andexo-transition exo-transitionstates statesfor forthe theasymmetric asymmetricπ–cation π–cation catalyst-promoted catalyst-promoted cycloaddition. cycloaddition. cycloaddition.

Copper-catalyzed 1,3-dipolar cycloadditions of N,N-cyclic azomethine imines to terminal Copper-catalyzed cycloadditions of N,N-cyclic imines to terminal alkynes, which proceed1,3-dipolar via Cu(I)-acetylide intermediate, generallyazomethine afford 5,6-disubstituted bicyclic alkynes, which proceed via Cu(I)-acetylide intermediate, generally afford 5,6-disubstituted bicyclic

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Copper-catalyzed 1,3-dipolar cycloadditions of N,N-cyclic azomethine imines to terminal alkynes, which proceed via Cu(I)-acetylide intermediate, generally afford 5,6-disubstituted bicyclic Molecules 2018, 23, 3 9 of 30 products of type 26. In 2012, Kobayashi et al. developed a silver amide-catalyzed cycloaddition of azomethine terminal alkynes to developed exclusivelyaafford products products of imines type 26.24Inwith 2012, Kobayashi et al. silver 5,7-disubstituted amide-catalyzed bicyclic cycloaddition of 25 (Scheme 10) [26]. This was the first protocol for the synthesis of 5,7-cycloadducts with reversed azomethine imines 24 with terminal alkynes to exclusively afford 5,7-disubstituted bicyclic products regioselectivity as inThis previously cycloadditions. It was of found out that the strong basicity 25 (Scheme 10) [26]. was thereported first protocol for the synthesis 5,7-cycloadducts with reversed of AgHMDS was essential for this cyclization reaction. To efficiently suppress the formation of regioselectivity as in previously reported cycloadditions. It was found out that the strong basicity of 1,2-adduct reaction for has to be cyclization performed in the presence of molecular sieves using only a slight AgHMDS 27, wastheessential this reaction. To efficiently suppress the formation of excess of alkyne. An asymmetric version of this highly regioselective cycloaddition was achieved 1,2-adduct 27, the reaction has to be performed in the presence of molecular sieves using only a slight 0 -binaphthalene by utilizing CuHMDS in combination chiral 2,20regioselective -bis(diphenylphosphino)-1,1 excess of alkyne. An asymmetric versionwith of this highly cycloaddition was achieved by (BINAP) L10. inThe reaction tolerated electron-deficient and electron-rich aryl, alkenyl and utilizing ligand CuHMDS combination with chiral 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene alkyl R1 groups on the imine electron-deficient 24 furnishing theand products 25 in high and values (BINAP) ligand L10. Theazomethine reaction tolerated electron-rich aryl,yields alkenyl andeealkyl R1 in the range of 87–95%. With regard to the terminal alkyne, the reactions proceeded cleanly with groups on the azomethine imine 24 furnishing the products 25 in high yields and ee values in the range of electron-deficient and electron-rich aromatic, alkyl, silyl and protected alcohol R2 groups, again 87–95%. With regard to the terminal alkyne, the reactions proceeded cleanly with electron-deficient and 2 with high enantioselectivities (ee’s up to 93%). Mechanistic studied revealed that, in contrast to the electron-rich aromatic, alkyl, silyl and protected alcohol R groups, again with high enantioselectivities previously proposed concerted cyclization pathway [27], the cycloadduct products 25 are formed via (ee’s up to 93%). Mechanistic studied revealed that, in contrast to the previously proposed concerted a step-wise reaction mechanism. It involves a 1,2-addition of the metal acetylide 30 to the azomethine cyclization pathway [27], the cycloadduct products 25 are formed via a step-wise reaction mechanism. imine 24 followed by intramolecular cyclization Lewis acid-activated alkyne 31. The latter It involves a 1,2-addition of the metal acetylide 30 to of thethe azomethine imine 24 followed by intramolecular assumptionofwas by successful cyclization alkyne 28 to bicyclic 29 by with retained cyclization theconfirmed Lewis acid-activated alkyne 31. Theoflatter assumption was product confirmed successful ee value. While CuHMDS combined with BINAP-type ligand enabled exclusive formation of products cyclization of alkyne 28 to bicyclic product 29 with retained ee value. While CuHMDS combined with 25, a complete reversal of regioselectivity (formation of 26) 25, wasa observed bisoxazoline L11 or BINAP-type ligand enabled exclusive formation of products complete when reversal of regioselectivity 2,20 -bipyridyl ligand was used.when bisoxazoline L11 or 2,2′-bipyridyl ligand was used. (formation of 26) was observed O O N 24

R2

N

+

AgHMDS or CuHMDS (10 mol%) (S)-DIP-BINAP (11 mol%)

N N

THF or CPME, 40 oC, MS 5Å

R1

Me PPh2 PPh2

Me O

O N Ph

N L11

Ph

O R2

O

N

NH

N

*

R1 25: 17 examples 83-98% yield 82-93% ee

R1

N R2

R1

26

27

R2

R1 = Ph, 4-MeC6H4,4-ClC6H4, 4-CNC6H4, 4-MeOC6H4,PhCH=CMe,1-Nap, Pr, Hex R2 = Ph, 4-MeC6H4,4-MeOC6H4,4-ClC6H4 4-F-C6H4, Bu, Hex, TES, CH2OBn

L10: (S)-DIP-BINAP O NH Ph

Ph 28 (24 ee) CuHMDS (10 mol%) (S)-DIP-BINAP (11 mol%)

N

Ph

*

Ph 29 (24 ee)

25

O N N

*

R1

O

N

CuHMDS

H-HMDS

N

Cu

R2 R2 Cu

intramolecular cyclization

30

O

O N N N [Cu] N 1,2-addition R1 * 24 R1 31 R2

Scheme Scheme 10. 10. Regioselective Regioselectiveformation formationof of 5,7-disubstituted 5,7-disubstituted bicyclic bicyclic pyrazoline pyrazoline derivatives. derivatives. Tetrahydrofuran Tetrahydrofuran == THF, CPME = = cyclopentyl ether, MS MS == molecular molecular sieves, sieves, TES TES == triethylsilyl, triethylsilyl, DIP-BINAP DIP-BINAP == THF, CPME cyclopentyl methyl methyl ether, 2,2′-bis(3,5-diisopropylphenylphosphino)-1,1′-binaphthalene.3. Synthesis of pyrazolidines 2,20 -bis(3,5-diisopropylphenylphosphino)-1,10 -binaphthalene.

3. Synthesis of Pyrazolidines 3.1. By Metal-Catalyzed Cycloadditions Acylhydrazones can be visualized as imine equivalents, and their benzoyl derivatives have been shown to react with several nucleophiles under Lewis acid catalytic conditions or in the presence of

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3. Synthesis of Pyrazolidines 3.1. By Metal-Catalyzed Cycloadditions Acylhydrazones can be visualized as imine equivalents, and their benzoyl derivatives have been shown to react with several nucleophiles under Lewis acid catalytic conditions or in the presence Molecules 2018, 23, 3 10 of 30 of Lewis base promoter. Acylhydrazones have also been explored as general 1,3-dipoles, and it has beenLewis found that the [3+2] cycloadditionhave reaction of acylhydrazones with olefins and is possible under base promoter. Acylhydrazones also been explored as general 1,3-dipoles, it has been Lewis acid catalytic conditions [28]. Additionally, asymmetric intramolecular [3+2] cycloadditions found that the [3+2] cycloaddition reaction of acylhydrazones with olefins is possible under Lewis of acylhydrazones have been described by Kobayashi using chiral zirconium catalyst leading acid catalytic conditions [28]. Additionally, asymmetric intramolecular [3+2] cycloadditions of to condensed pyrazolidine [29].byThe chiral zirconium catalyst was catalyst prepared in situtofrom acylhydrazones have derivatives been described Kobayashi using chiral zirconium leading condensed pyrazolidine derivatives [29]. Theligand chiral (12 zirconium was prepared in in situ from or Zr(OPr) %) and selected (R)-BINOL mol %).catalyst The reaction was run benzene 4 (10 mol Zr(OPr) 4 (10 mol %) and selected (R)-BINOL ligand (12 mol %). The reaction was run in benzene or dichloromethane in the presence of 50 mol % of PrOH as an additive at room temperature yielding dichloromethane in the presence of 50 mol % of PrOH as an additive at room temperature yielding the corresponding fused pyrazolidine derivatives as major trans isomers (cis/trans ratio > 1/99) and corresponding fused pyrazolidine derivatives as major trans isomers (cis/trans ratio > 1/99) and withthe ee from 72 up to 97% (Scheme 11). Although that precise reaction pathway in these reactions with ee from 72 up to 97% (Scheme 11). Although that precise reaction pathway in these reactions is is not clarified, it was clearly shown that cis/trans selectivity was controlled by the chirality of not clarified, it was clearly shown that cis/trans selectivity was controlled by the chirality of the chiral the chiral catalyst. For example, when (S)-L12 was used as a catalyst instead of (R)-L12 under catalyst. For example, when (S)-L12 was used as a catalyst instead of (R)-L12 under the same reaction the same reactionthe conditions, the corresponding of cycloadduct of (S)-citronellal-derived conditions, corresponding cis isomer cis of isomer cycloadduct of (S)-citronellal-derived 44-nitrobenzoylhydrazone was obtained with good selectivity. nitrobenzoylhydrazone was obtained with good selectivity.

Scheme 11. Asymmetric intramolecular [3+2] cycloaddition of hydrazones using a chiral zirconium

Scheme 11. Asymmetric intramolecular [3+2] cycloaddition of hydrazones using a chiral catalyst. zirconium catalyst.

However, in this methodology, the substrate scope was restricted, and the reactions were limited to only an intramolecular type of [3+2] cyclisation. on, was the same group developed efficientwere However, in this methodology, the substrateLater scope restricted, and the the reactions zirconium-catalyzed enantioselective [3+2] intermolecular cycloaddition of hydrazones to olefins limited to only an intramolecular type of [3+2] cyclisation. Later on, the same group developed leading to optically-active pyrazolidine, pyrazoline and 1,3-diamine derivatives [30]. In this case, to the efficient zirconium-catalyzed enantioselective [3+2] intermolecular cycloaddition of hydrazones benzoylhydrazones were found to be superior substrates over the 4-nitrobenzoyl analogues. olefins leading to optically-active pyrazolidine, pyrazoline and 1,3-diamine derivatives [30].The In this amount of olefin used also effected the reactivity, and the yields were significantly improved by using case, benzoylhydrazones were found to be superior substrates over the 4-nitrobenzoyl analogues. two equiv. of substituted olefins. Hydrazones derived from a β-branched aldehyde, a sterically-hindered The amount of olefin used also effected the reactivity, and the yields were significantly improved aldehyde, enolizable aldehydes and functionalized aldehydes all readily reacted with ethene-1,1by using two equiv. of without substituted olefins. Hydrazones derived from a β-branched aldehyde, diylbis(methylsulfane) any side reactions, and the corresponding substituted pyrazolidines a sterically-hindered aldehyde, aldehydes and functionalized aldehydes all readily reacted 35 were obtained in high yieldenolizable and high levels of enantioselectivity (Scheme 12). with ethene-1,1-diylbis(methylsulfane) without any side reactions, and the corresponding substituted Furthermore, the variety of hydrazones derived from α-branched and β-branched aliphatic pyrazolidines 35 were obtained in high yield and high levels of enantioselectivity (Scheme 12). aldehydes reacted readily with different vinyl ethers as olefins furnishing the pyrazolidines 37 containing aFurthermore, N,O-acetal functionality in high yields and enantioselectivities (Scheme 13).and In this particular case, the variety of hydrazones derived from α-branched β-branched aliphatic p-nitrobenzoyl weredifferent found to be moreethers suitable than their benzoyl analogues 37 aldehydes reactedhydrazones readily with vinyl asderivatives olefins furnishing the pyrazolidines due to their higher reactivity under thein catalytic conditions. moderate diastereoselectivities containing a N,O-acetal functionality high yields and However, enantioselectivities (Scheme 13). In this were obtained in the majority of the cases (diastereomer ratio (dr) > 1/1), whereas derivatives both diastereomers particular case, p-nitrobenzoyl hydrazones were found to be more suitable than their showed excellent enantioselectivity in most instances (ee > 81%). Concerning the mechanistic aspect benzoyl analogues due to their higher reactivity under the catalytic conditions. However, moderate of the transformations, the authors suggested a concerted reaction pathway over the alternative diastereoselectivities were obtained in the majority of the cases (diastereomer ratio (dr) > 1/1), whereas stepwise pathway. The mechanism of the transformation was among the other facts elucidated on boththe diastereomers showed excellent enantioselectivity in most instances (eeconfiguration > 81%). Concerning observation that both diastereomers of the products have the same absolute at the the mechanistic aspect of transformations, carbon atom bearing thethe R1 substituent (Schemethe 13).authors suggested a concerted reaction pathway

over the alternative stepwise pathway. The mechanism of the transformation was among the other

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facts elucidated on the observation that both diastereomers of the products have the same absolute 1 configuration the Molecules 2018,at23, 3 carbon atom bearing the R substituent (Scheme 13). 11 of 30 Molecules 2018, 23, 3

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Scheme 12. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1-diylbis

Scheme 12. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1Scheme 12. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1-diylbis (methylsulfane) using a chiral zirconium catalyst. diylbis(methylsulfane) using a chiral zirconium catalyst. (methylsulfane) using a chiral zirconium catalyst. Scheme 12. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1-diylbis (methylsulfane) using a chiral zirconium catalyst.

Scheme 13. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1-diylbis Scheme 13. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1-diylbis (methylsulfane) using a chiral zirconium catalyst. Scheme 13. Asymmetric intermolecular [3+2] cycloaddition of hydrazones with ethene-1,1(methylsulfane) using a chiral zirconium catalyst. diylbis(methylsulfane) usingintermolecular a chiral zirconium catalyst. Scheme 13. Asymmetric [3+2] cycloaddition with ethene-1,1-diylbis The developed methodology was elegantly applied offorhydrazones the synthesis of enantioenriched (methylsulfane) using a chiral zirconium catalyst. The developed methodology was elegantly applied for the synthesis compound MS-153 of biological importance. The [3+2] cycloaddition of hydrazoneof38enantioenriched to propyl vinyl

compound MS-153 of biological cycloaddition ofeehydrazone 38 propyl The proceeded developed methodology was elegantly for97% the synthesis of toenantioenriched ether with 76% yieldimportance. and 84% eeThe for [3+2] theapplied major and for the minor isomer.vinyl The developed methodology was elegantly for the synthesis of enantioenriched etherThe proceeded with 76% yield and 84% ee treatment for theapplied major and 97% ee−78 for the minor isomer. compound MS-153 of biological The [3+2] cycloaddition of°C hydrazone 38 to The propyl p-nitrobenzoyl functionality wasimportance. removed by with LiAlH 4 at in THF followed by compound MS-153 biological importance. The [3+2] of hydrazone 38 to propyl vinyl p-nitrobenzoyl functionality was removed treatment with LiAlH 4 at −78 °C in THF followed by nicotinoylation. Theofwith obtained intermediate 40 was a cycloaddition useful starting material the of vinyl ether proceeded 76% yield and by 84% ee for the major and 97% eefor for thesynthesis minor isomer. ether proceeded withobtained 76% yield and the 84%removal ee40forwas theofamajor and 97% ee for theusing minor isomer. The ◦ nicotinoylation. The intermediate useful starting material for the synthesis of MS-153 derivatives. However, after the phenylthio group Raney-Ni, ent The p-nitrobenzoyl functionality was removed by treatment with LiAlH4 at −78 C in THF followed p-nitrobenzoyl functionality wasenantioselectivity removed by treatment with LiAlH14). 4 at −78 °C in THF followed by MS-153 derivatives. However, after the removal of the phenylthio group using Raney-Ni, ent MS-153 was obtained with high (88% ee) (Scheme by nicotinoylation. The obtainedintermediate intermediate 40 was a useful starting material for the synthesis of nicotinoylation. The obtained 40 was(88% a useful starting material for the synthesis of MS-153 was obtained with high enantioselectivity ee) (Scheme 14). MS-153 derivatives. However, after the removal of the phenylthio group usingusing Raney-Ni, ent MS-153 MS-153 derivatives. However, after the removal of the phenylthio group Raney-Ni, ent was MS-153 obtained with high enantioselectivity (88% ee) (88% (Scheme 14). was obtained with high enantioselectivity ee) (Scheme 14).

Scheme 14. Synthesis of ent MS-153 pyrazoline derivative. (a) Zr(OPr)4 (20 mol %), (R)-3,3’-I2BINOL Scheme 14. ent MS-153 Zr(OPr) (R)-3,3’-Ichloride 2BINOL −784 (20 °C; mol (c) %), nicotinoyl ((R)-L13) (24Synthesis mol %),oftoluene, 10 pyrazoline °C, 24 h; derivative. (b) LiAlH4,(a)THF, 4, THF, −78buffer, °C; (c) ((R)-L13) (24 mol %), toluene, 10 (d) °C,Raney-Ni 24 h; (b)(W-2), LiAlH DMAP, r.t.; EtOH-acetate r.t.nicotinoyl chloride hydrochloride, i-Pr2EtN, Scheme 14. Synthesis of ent MS-153 pyrazoline derivative. (a) Zr(OPr)4 buffer, (20 molr.t. %), (R)-3,3’-I2BINOL hydrochloride, i-Pr2of EtN, r.t.; (d) Raney-Ni (W-2), EtOH-acetate Scheme 14. Synthesis entDMAP, MS-153 pyrazoline derivative. (a) Zr(OPr)4 (20 mol %), (R)-3,3’-I2 BINOL 4 , THF, −78 °C; (c) nicotinoyl ((R)-L13) (24 mol %), toluene, 10 °C, 24 h; (b) LiAlH ◦ C, 24(easily Phenyl(24and tert-butylsilane reagents andchloride phenyl or ((R)-L13) mol %), toluene, 10 h; (b)prepared LiAlH4 , from THF, pseudoephedrine −78 ◦ C; (c) nicotinoyl chloride 2EtN, DMAP,reagents r.t.; (d) Raney-Ni (W-2), EtOH-acetate buffer, r.t. hydrochloride, i-Pr Phenyl and tert-butylsilane (easily prepared from pseudoephedrine and et phenyl or tert-butyltrichlorosilane as a mixture of diastereomers at silicon) introduced by Leigghton al. were

hydrochloride, i-Pr2 EtN, DMAP, r.t.; (d) Raney-Ni (W-2), EtOH-acetate buffer, r.t. tert-butyltrichlorosilane as a mixture diastereomers [31]. at silicon) introduced Leigghton et al. were applied for acylhydrazone-enol etherofcycloadditions Phenylsilane wasbyfound to facilitate the Phenyl and tert-butylsilane reagents (easily prepared from pseudoephedrine and phenyl or applied for acylhydrazone-enol ether cycloadditions [31]. Phenylsilane found facilitate the cycloaddition of N′-(3-phenylpropylidene)benzohydrazide with ethoxyethenewas to yield thetocorresponding Phenyl and tert-butylsilane reagents (easily prepared from pseudoephedrine and phenyl tert-butyltrichlorosilane as a mixture of diastereomers at silicon) introduced by Leigghton et al. were cycloadditionin of61% N′-(3-phenylpropylidene)benzohydrazide ethoxyethene to yield the ether corresponding pyrazolidine with 6:1 diastereoselectivity and 77%with ee. The use of tert-butyl vinyl resulted or applied for acylhydrazone-enol ether cycloadditions [31]. Phenylsilane was found to facilitate theet al. tert-butyltrichlorosilane as a mixture of diastereomers at silicon) introduced by Leigghton pyrazolidine 61% with 6:1indiastereoselectivity and 77% Theand use of tert-butyl vinyl ether in significant in improvement both diastereoselectivity (dree.24:1) enantioselectivity (90% resulted ee), and cycloaddition of N′-(3-phenylpropylidene)benzohydrazide with ethoxyethene to yield the corresponding in significant improvement in both diastereoselectivity (dr 24:1) and enantioselectivity (90% ee), and pyrazolidine in 61% with 6:1 diastereoselectivity and 77% ee. The use of tert-butyl vinyl ether resulted in significant improvement in both diastereoselectivity (dr 24:1) and enantioselectivity (90% ee), and

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were applied for acylhydrazone-enol ether cycloadditions [31]. Phenylsilane was found to facilitate the cycloaddition of N 0 -(3-phenylpropylidene)benzohydrazide with ethoxyethene to yield the corresponding pyrazolidine in 61% with 6:1 diastereoselectivity and 77% ee. The use of tert-butyl vinyl ether resulted in significant improvement in both diastereoselectivity (dr 24:1) and enantioselectivity at Molecules 2018, 23, 3(90% ee), and the transformation was found to perform the best in toluene 12 of 30 room temperature (Scheme 15). Variety of benzoylhydrazones derived from aliphatic (Ph(CH2 )2 CHO, the 2transformation was found to and perform the best in toluene at room temperature (Scheme 15). and BnOCH CHO, CyCHO, t-BuCHO) (hetero)aromatic (benzaldehyde, 4-fluorobenzaldehide Variety of benzoylhydrazones derived from aliphatic (Ph(CH 2 ) 2 CHO, BnOCH 2 CHO, furan-2-carbaldehyde) aldehydes reacted readily with tert-butyl vinyl ether (three equiv.) inCyCHO, the presence t-BuCHO) and (benzaldehyde, 4-fluorobenzaldehide furan-2-carbaldehyde) of phenylsilane (1.5(hetero)aromatic equiv.), yielding 3,5-disubstituted pyrazolidines and 43 up to 85% yield, >19:1 dr readily 15). with Unlike tert-butyl ether (three equiv.) in the presence of phenylsilane 36 and aldehydes ee’s abovereacted 90% (Scheme thevinyl Zr(II)-catalyzed cycloaddition of benzoylhydrazones (1.5 equiv.), yielding 3,5-disubstituted pyrazolidines 43 up to 85% yield, >19:1 dr and ee’s above 90% (Scheme 13), in this case, the β-substituted enol ethers reacted highly stereoselectively (>10:1 dr, 97% ee) (Scheme 15). Unlike the Zr(II)-catalyzed cycloaddition of benzoylhydrazones 36 (Scheme 13), in this with N 0 -(3-phenylpropylidene)benzohydrazides 42 providing enantio-enriched 3,4,5-trisubstituted case, the β-substituted enol ethers reacted highly stereoselectively (>10:1 dr, 97% ee) with N′-(32 = Me, pyrazolidine 43 (Scheme 15, Example A). with the acetaldehyde-derived (R43 phenylpropylidene)benzohydrazides 42 Selectivity providing enantio-enriched 3,4,5-trisubstitutedhydrazone pyrazolidine 2 Scheme 15) is15, significantly relative to that observed with larger R groups when phenylsilane (Scheme Example A).reduced Selectivity with the acetaldehyde-derived hydrazone (R2 = Me, Scheme 15) 2 41a is applied. Replacing the phenyl moiety in chiral silicon Lewis acid 41a with sterically is significantly reduced relative to that observed with larger R groups when phenylsilane 41a ismore demanding group 41bmoiety resulted in significant improvement insterically stereoselectivity when more applied. tert-butyl Replacing the phenyl in chiral silicon Lewis acid 41a with more demanding 0 -ethylidene-4-nitrobenzohydrazide tert-butylNgroup 41b resulted in significant improvement stereoselectivity when vinyl more electrophilic electrophilic 44 wasin reacted with tert-butyl ether to provide N′-ethylidene-4-nitrobenzohydrazide 44 45 was(Scheme reacted 15, with tert-butyl ether to of provide (5R)-3-(tert-butoxy)-5-methylpyrazolidine Example B) vinyl in good yield 85% and (5R)-3-(tert-butoxy)-5-methylpyrazolidine 45 (Scheme 15, Example B) in good yield of 85% stereoselectivity (>15:1 dr, 98% ee). Two additional synthetic steps furnished the targeted and MS-153 stereoselectivity (>15:1 yield dr, 98% ee).>Two synthetic steps furnished targeted MS-153 substrate in 70% overall and 99%additional ee (Scheme 15, Example B) [32]. the Furthermore, a concise substrate in 70% overall yield and > 99% ee (Scheme 15, Example B) [32]. Furthermore, a concise synthesis of manzacidin C based on the second generation [33] chiral silicon Lewis acid, which promoted synthesis of manzacidin C based on the second generation [33] chiral silicon Lewis acid, which diastereo- and enantioselective acylhydrazone-alkene [3+2] cycloaddition, has also been reported by promoted diastereo- and enantioselective acylhydrazone-alkene [3+2] cycloaddition, has also been the same group [34]. The corresponding enantioenriched 3,5,5-trisubstituded pyrazolidine precursor reported by the same group [34]. The corresponding enantioenriched 3,5,5-trisubstituded pyrazolidine was precursor subsequently used for the synthesis ofsynthesis crucial 1,3-bisamide intermediate, which was obtained was subsequently used for the of crucial 1,3-bisamide intermediate, which was in 73% obtained yield andinhigh stereoselectivity (>20:1 dr and(>20:1 94% ee). 73% yield and high stereoselectivity dr and 94% ee).

Scheme 15. (A) Chiral silicon Lewis acid mediated asymmetric synthesis of 3,4,5-substituted pyrazolidines;

Scheme 15. (A) Chiral silicon Lewis acid mediated asymmetric synthesis of 3,4,5-substituted (B) application of the methodology for the enantioselective synthesis of (R)-MS-153. pyrazolidines; (B) application of the methodology for the enantioselective synthesis of (R)-MS-153.

In addition to the above-described silicon Lewis acid-promoted [3+2] cycloadditions of acylhydrazones, Tsogoeva et al. [35] developed a catalytic system comprised of chiral Brønsted acid (chiral BINOL phosphates) and silicon Lewis acid (R2SiX2). The combination of both acids acted cooperatively in the stereoselective intermolecular cycloaddition of acylhydrazones with cyclopentadiene

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In addition to the above-described silicon Lewis acid-promoted [3+2] cycloadditions of acylhydrazones, Tsogoeva et al. [35] developed a catalytic system comprised of chiral Brønsted acid (chiral phosphates) and silicon Lewis acid (R2 SiX2 ). The combination of both13acids Molecules 2018, BINOL 23, 3 of 30 acted cooperatively in the stereoselective intermolecular cycloaddition of acylhydrazones with cyclopentadiene providing a convenient and for facile for the of pyrazolidines. Assumed providing a convenient and facile process theprocess synthesis of synthesis pyrazolidines. Assumed synergism synergism the BINOL phosphate (R)-L14 Ph2 SiCl also tested. Lewis acid between thebetween BINOL phosphate (R)-L14 and Ph2SiCl 2 was and also tested. Lewis acid (dichlorodiphenylsilane) 2 was (dichlorodiphenylsilane) alonewhereas was inactive inphosphate catalysis, whereas BINOL itselfmoderate showed alone was inactive in catalysis, BINOL itself showed lowphosphate reactivity and 1 2 1 2 low reactivity and (99:1 moderate enantioselectivity dr,=47% ee, 2example: R = Et,16). R The = 4-(NO enantioselectivity dr, 47% ee, example: R (99:1 = Et, R 4-(NO )-C6H4, Scheme combination 2 )-C6 H4 , Scheme 16). The combination of bothPh components ratio (R)-L14/ to Phbe in 2/1active, was established of both components in ratio (R)-L14/ 2SiCl2 in 2/1in was established the2 most producing 2 SiCl to the most active, producing the pyrazolidines asexcellent major cis enantioselectivities isomers in good to thebecorresponding pyrazolidines 48 corresponding as major cis isomers in good48to excellent enantioselectivities (Scheme 16). (Scheme 16).

Scheme 16. cycloaddition of acylhydrazones with cyclopentadiene catalyzed by cooperative Scheme 16.1,3-Dipolar 1,3-Dipolar cycloaddition of acylhydrazones with cyclopentadiene catalyzed by action of chiral Lewis and Brønsted acids. cooperative action of chiral Lewis and Brønsted acids.

Copper(II)-catalyzed diastereo- and enantioselective cycloadditions of azomethine imines to Copper(II)-catalyzed diastereo- and enantioselective cycloadditions of azomethine imines 2-acryloyl-3-pyrazolidinones were developed by Sibi et al. deriving the corresponding exo to 2-acryloyl-3-pyrazolidinones were developed by Sibi et al. deriving the corresponding exo cycloadducts with high diastereoselectivities (up to > 96:4 cis/trans) and enantioselectivities for cis cycloadducts with high diastereoselectivities (up to > 96:4 cis/trans) and enantioselectivities for isomer up to 98% ee [36]. The Cu(OTf)2/L15-catalytic system was found to be the most efficient in cis isomer up to 98% ee [36]. The Cu(OTf)2 /L15-catalytic system was found to be the most producing the corresponding cycloadducts 51 as a major syn diastereomers and with excellent efficient in producing the corresponding cycloadducts 51 as a major syn diastereomers and with enantioselectivities (Scheme 17). Chiral Lewis acid prepared from Cu(OTf)2 and additional excellent enantioselectivities (Scheme 17). Chiral Lewis acid prepared from Cu(OTf)2 and additional bis(oxazoline) ligands such as t-Bu-BOX, Ph-BOX and Bn-BOX were also studied as catalysts; bis(oxazoline) ligands such as t-Bu-BOX, Ph-BOX and Bn-BOX were also studied as catalysts; however, when the Cu(OTF)2/t-Bu-BOX system was used as a catalyst, syn products were formed in however, when the Cu(OTF)2 /t-Bu-BOX system was used as a catalyst, syn products were formed good yields and with lower diastereoselectivity. On the other hand, Cu(OTF)2/Ph-BOX and in good yields and with lower diastereoselectivity. On the other hand, Cu(OTF)2 /Ph-BOX and Cu(OTF)2/Bn-BOX catalytic systems behaved similarly yielding exo/endo product in ~5/1 and 82% ee Cu(OTF)2 /Bn-BOX catalytic systems behaved similarly yielding exo/endo product in ~5/1 and 82% of the major isomer. When applying the Cu(OTf)2/L15-catalytic system, generally excellent yields and ee of the major isomer. When applying the Cu(OTf)2 /L15-catalytic system, generally excellent yields good diastereo- and high enantioselectivities were possible from cycloadditions of a variety of C5 and good diastereo- and high enantioselectivities were possible from cycloadditions of a variety and N′-arylmethylidene-substituted azomethine imines 50 and different α,β-unsaturated pyrazolidinone of C5 and N 0 -arylmethylidene-substituted azomethine imines 50 and different α,β-unsaturated imides 49 (Scheme 17). However, when the methodology was extended to β-substituted pyrazolidinone imides 49 (Scheme 17). However, when the methodology was extended to β-substituted α,β-unsaturated pyrazolidinone imides such as pyrazolidinone chrotonate, no reaction was observed α,β-unsaturated pyrazolidinone imides such as pyrazolidinone chrotonate, no reaction was observed or the cycloadducts were formed in moderate yields and in low enantioselectivities. or the cycloadducts were formed in moderate yields and in low enantioselectivities. An additional example of copper(II)-catalyzed [3+2] cycloadditions of N,N′-cyclic azomethine An additional example of copper(II)-catalyzed [3+2] cycloadditions of N,N 0 -cyclic azomethine imines is Cu(OAc)2-catalyzed cycloaddition of azomethine imines to methyleneindolinones described imines is Cu(OAc)2 -catalyzed cycloaddition of azomethine imines to methyleneindolinones described by Sun and coworkers [37]. Among tested Lewis acids (Cu(OAc)2, AgOTf, Sc(OTf)3, Zn(OTf)2, CuI, by Sun and coworkers [37]. Among tested Lewis acids (Cu(OAc)2 , AgOTf, Sc(OTf)3 , Zn(OTf)2 , CuI, Cu(acac)2 and Cu[MeCN]4PF6), Cu(OAc)2 was found to be the most efficient in acetonitrile as a solvent Cu(acac)2 and Cu[MeCN]4 PF6 ), Cu(OAc)2 was found to be the most efficient in acetonitrile as a solvent of choice. Generally, when Cu(OAc)2 was used as a Lewis acid catalyst, the reactions proceeded of choice. Generally, when Cu(OAc)2 was used as a Lewis acid catalyst, the reactions proceeded smoothly to afford the desired spiro adducts 55 in moderate to high yields (70–82%) and good smoothly to afford the desired spiro adducts 55 in moderate to high yields (70–82%) and good stereoselectivities (9:1 up to 15:1) forming trans diastereomer as the major isomer (Scheme 18). stereoselectivities (9:1 up to 15:1) forming trans diastereomer as the major isomer (Scheme 18). Notably, Notably, the heteroaryl (2-thienyl) and alkyl substituted azomethine imines were tolerated in the the heteroaryl (2-thienyl) and alkyl substituted azomethine imines were tolerated in the reaction reaction and derived the corresponding products 55p and 55q in 77%, 14:1 dr and 81%, 8:1 dr, and derived the corresponding products 55p and 55q in 77%, 14:1 dr and 81%, 8:1 dr, respectively respectively (Scheme 18). An enantioselective variant of this reactions was also carried out screening (Scheme 18). An enantioselective variant of this reactions was also carried out screening a series of a series of chiral ligands (i-Pr- and t-Bu-substituted oxazoline ligands and i-Pr-Phosferrox ligand), affording the corresponding product 55a in moderate yield and low enantioselectivity (up to 48% ee).

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chiral ligands (i-Pr- and t-Bu-substituted oxazoline ligands and i-Pr-Phosferrox ligand), affording the corresponding 55a in moderate yield and low enantioselectivity (up to 48% ee). Molecules 2018, product 23, 3 14 of 30 Molecules 2018, 23, 3

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Scheme 17. Copper(II)-catalyzed enantioselective [3+2] cycloadditions of N,N′-cyclic azomethine

Scheme 17. Copper(II)-catalyzed enantioselective [3+2] cycloadditions of N,N 0 -cyclic azomethine Scheme 17.2-acryloyl-3-pyrazolidinones. Copper(II)-catalyzed enantioselective [3+2] cycloadditions of N,N′-cyclic azomethine imines with imines withwith 2-acryloyl-3-pyrazolidinones. imines 2-acryloyl-3-pyrazolidinones.

Scheme 18. Cu(AcO)2-catalyzed diastereoselective [3+2] cycloadditions of N,N′-cyclic azomethine

Scheme 18. Cu(AcO)2-catalyzed diastereoselective [3+2] cycloadditions of N,N′-cyclic azomethine 0 Scheme 18. Cu(AcO) 2 -catalyzed diastereoselective [3+2] cycloadditions of N,N -cyclic azomethine imines imineswith withmethyleneindolinones. methyleneindolinones. imines with methyleneindolinones.

Recently, and enantioselective enantioselective [3+2] [3+2] cycloaddition cycloadditionofof Recently, Feng Feng et et al. al. developed developed highly highly diastereodiastereo- and methyleneindolinones with N,N′-cyclic azomethine imines, which was successfully catalyzed byaa of Recently, Feng et al. developed highly diastereoand enantioselective [3+2] cycloaddition methyleneindolinones with N,N′-cyclic azomethine imines, which was successfully catalyzed by 0 N,N′-dioxide-ligated-Mg(OTf) 2 complex [38]. It should be stressed that unlike in the above-described N,N′-dioxide-ligated-Mg(OTf) [38]. It shouldimines, be stressed that unlike in the above-described methyleneindolinones with N,N2 complex -cyclic azomethine which was successfully catalyzed by Cu(OAc) 2-catalyzed in case, the major cis diastereomer prevailed. Three different 0 -dioxide-ligated-Mg(OTf) Cu(OAc) 2-catalyzedexamples examples2[37], [37], in this this case,Itthe major diastereomer prevailed. Three different a N,N complex [38]. should becis stressed that unlike in the above-described alkaline metal salts (Ca(OTf) 2 , Ba(ClO 4 ) 2 , and Mg(OTf) 2 were tested in combination with several chiral alkaline metal salts (Ca(OTf)2, Ba(ClO4 2 2 were tested in combination with several chiral Cu(OAc) 2 -catalyzed examples [37], in this case, the major cis diastereomer prevailed. Three different N,N′-dioxide ligands derived from (S)-proline, (S)-Ramipril and (S)-pipecolic acid. However, the N,N′-dioxide ligands derived from (S)-proline, (S)-Ramipril and (S)-pipecolic acid. However, the alkaline metal salts (Ca(OTf) 2 , Ba(ClO4 )2 , and Mg(OTf)2 were tested in combination with several complex nearly quantitative quantitative yield yieldin inthe thetest testreaction. reaction.The The complexofofMg(OTf) Mg(OTf)22 could could offer offer only only one isomer in nearly chiral N,N 0 -dioxide ligands derived from (S)-proline, (S)-Ramipril and (S)-pipecolic acid. However, optimized catalyst (L16-Mg(OTf) (L16-Mg(OTf)2,2,1:1) 1:1)in indichloromethane dichloromethane optimizedreaction reactionconditions conditions constituting constituting of 5 mol % of catalyst the complex of Mg(OTf)2 could offer only one isomer in nearly quantitative yield in the test atat30 in excellent excellent yields yieldsand andenantioselectivities enantioselectivities 30°C °Cinin48 48hhyielded yielded the the corresponding corresponding spiro adducts in reaction. The optimized reaction conditions constitutingat 5 mol % of catalyst (L16-Mg(OTf) 2 , 1:1) (Scheme 19). Methyleneindolinones bearing atof different positions ofthe the phenylring ringhad had (Scheme 19). Methyleneindolinones bearing substituents different positions of phenyl ◦ C in 48 h yielded the corresponding spiro adducts in excellent yields and in dichloromethane at 30 littleinfluence influenceon onthe theselectivity selectivity (dr (dr 19:1 19:1 in most cases with little with ee’s ee’s 90–99%). 90–99%).Furthermore, Furthermore,good goodresults results enantioselectivities (Scheme 19). Methyleneindolinones bearing at differenton positions werealso alsoobtained obtained when changing changing the electronic and steric nature at were when the steric naturesubstituents at metameta- or orpara-position para-position onthe the arylmoiety moietyof ofthe theN,N′-cyclic N,N′-cyclicazomethine azomethine imines. However, aryl However, the the azomethine azomethineimines imineswith withaasubstituent substituent

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of the phenyl ring had little influence on the selectivity (dr 19:1 in most cases with ee’s 90–99%). Furthermore, good results were also obtained when changing the electronic and steric nature at metaMolecules 2018, 23, 15 of 30 or para-position on3 the aryl moiety of the N,N 0 -cyclic azomethine imines. However, the azomethine imines with a substituent at the ortho position in the phenyl ring in general gave lower yields of at the orthowith position in the phenyl ring in general gaveR2lower yields of cycloadducts with decreased cycloadducts decreased enantioselectivity (e.g., = 2-F-C 6 H4 , 64% yield, 50% ee, Scheme 19). enantioselectivity (e.g., R2 = 2-F-C6H4, 64% yield, 50% ee, Scheme 19). The relationship between the The relationship between the enantiomeric excess of the cycloadduct and L16 showed a weak negative enantiomeric excess of the cycloadduct and L16 showed a weak negative nonlinear effect, suggesting nonlinear effect, suggesting that both monomeric and oligomeric catalytic species exist in the solution, that both monomeric and oligomeric catalytic species exist in the solution, but the monomeric but the monomeric complex might act as the more active one since its existence was clearly confirmed complex might act as the more active one since its existence was clearly confirmed by observing the by observing molecular [L16 Mg2+ +spectra. OTf− ] in ESI-MS spectra. −] in+ESI-MS molecularthe mass of [L16 + mass Mg2+ +of OTf

0 -dioxide-Mg(OTf) Scheme Stereoselective N,N N,N′-dioxide-Mg(OTf) 2-catalyzed 1,3-dipolar cycloaddition of Scheme 19. 19. Stereoselective 2 -catalyzed 1,3-dipolar cycloaddition of methyleneindolinones with N,N′-cyclic azomethine imines. 0 methyleneindolinones with N,N -cyclic azomethine imines.

An attractive and unique 1,3-dipolar cycloaddition reaction of azomethine imines 60 to

An attractive 1,3-dipolar cycloaddition reaction of azomethine iminesmultinucleating 60 to allylic [39,40] allylic [39,40] and and unique homoallylic [41] alcohols 59, based on a magnesium-mediated and chiral homoallylic [41] alcohols 59, based on a magnesium-mediated multinucleating chiral reaction reaction system utilizing diisopropyl (R,R)-tartrate [(R,R)-DIPT] as a chiral reagent was system utilizing (R,R)-tartrate as was a chiral reagent was developed Ukaji developed bydiisopropyl Ukaji and Inomata et al. The[(R,R)-DIPT] transformation shown to be applicable to bothby aryland alkyl-substituted azomethine imines. The corresponding optically-enriched and Inomata et al. The transformation was shown to be applicable to both aryl- trans-pyrazolidines and alkyl-substituted 61 were imines. obtainedThe with excellent regio-, diastereo- and enantioselectivity, with 61 results to 98% ee azomethine corresponding optically-enriched trans-pyrazolidines wereup obtained with (Scheme 20). As an example, a mixture of allyl alcohol and (R,R)-DIPT was reacted with alkylmagnesium excellent regio-, diastereo- and enantioselectivity, with results up to 98% ee (Scheme 20). As an example, halideof asallyl a magnesium source followedwas by the addition azomethine imine. The reactions were a mixture alcohol and (R,R)-DIPT reacted withofalkylmagnesium halide as a magnesium performed at 80 °C and alkanonitriles (MeCN or EtCN) were found to be the most suitable solvents. source followed by the addition of azomethine imine. The reactions were performed at 80 ◦ C and The use of a catalytic amount of (R,R)-DIPT was also effective when accompanied by the addition of alkanonitriles (MeCN or EtCN) were found to be the most suitable solvents. The use of a catalytic one equiv. of MgBr2. The proposed transition state model consists of a carbonyl oxygen of azomethine amount of (R,R)-DIPT was also effective when accompanied by the addition of one equiv. of MgBr2 . imine, rather than imine nitrogen, coordinated to the magnesium salt of (R,R)-DIPT. In this model, The proposed transition stateapproaches model consists of a carbonyl oxygen azomethine imine, rather than the pro-R allyloxy moiety the azomethine imine group,ofgiving the R,R,R-configuration imine nitrogen, coordinated to the magnesium salt of (R,R)-DIPT. In this model, the pro-R allyloxy (confirmed by the X-ray analysis of cycloadduct derivatives) of the cycloadducts. moiety approaches the azomethine imine group,togiving the R,R,R-configuration (confirmed X-ray The diastereodivergent process leading enantiopure pyrazolidine derivatives 64 andby 65the from analysis of cycloadduct derivatives) of N,N′-cyclic the cycloadducts. 3-acryloyl-2-oxazolidinone 62 and azomethine imines 63 employing Ni(II)-catalyzed asymmetric [3+2] cycloadditions was developed [42]. Amongpyrazolidine the tested catalytic systems, situ The diastereodivergent process leading to enantiopure derivatives 64the andin65 from 0 formed binaphthyl-quinolinediimine-based Ni(II) complex, (R)-L17–Ni(II), exhibited favorable 3-acryloyl-2-oxazolidinone 62 and N,N -cyclic azomethine imines 63 employing Ni(II)-catalyzed activity yielding the corresponding derivatives 64 as major trans diastereomer asymmetric [3+2] cycloadditions waspyrazolidine developed [42]. Among thea tested catalytic systems,and the in with high enantioselectivity. Under the catalysis of (R)-L17–Ni(ClO4)2·6H2O in chloroform at 40–50 °C and in the presence of molecular sieves (MS) 4 Å, the reaction proceeded well and was independent

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of the electronic character of the benzene ring substituents (Scheme 21). It is of note here that the enantio- and diastereoselectivity improved in some cases upon increasing the reaction temperature Molecules 23,temperature 3 from2018, room up to 50 °C, which could be attributed to enhanced ligand exchange rate16ofof 31 the transition state Ni(II)-complex. Although the reaction of C-cyclohexyl substituted azomethine imine resulted in moderate yield and 74% ee, the cycloaddition of naphthyl and heteroaryl analogues situafforded formed excellent binaphthyl-quinolinediimine-based Ni(II) complex, (R)-L17–Ni(II), exhibited favorable enantioselectivities (Scheme 21).

activity yielding the corresponding pyrazolidine derivatives 64 as a major trans diastereomer and with high enantioselectivity. Under the catalysis of (R)-L17–Ni(ClO4 )2 ·6H2 O in chloroform at 40–50 ◦ C and Molecules 2018, 23, 3 16 of 30 in the presence of molecular sieves (MS) 4 Å, the reaction proceeded well and was independent of the electronic character of the benzene ring substituents (Scheme 21). It is of note here that the enantioof the electronic character of the benzene ring substituents (Scheme 21). It is of note here that the andenantiodiastereoselectivity improved in some cases upon increasing the reaction from room and diastereoselectivity improved in some cases upon increasing the temperature reaction temperature ◦ C, which could be attributed to enhanced ligand exchange rate of the transition temperature up to 50 from room temperature up to 50 °C, which could be attributed to enhanced ligand exchange rate of state the reaction of C-cyclohexyl substituted azomethine imine resulted in theNi(II)-complex. transition stateAlthough Ni(II)-complex. Although the reaction of C-cyclohexyl substituted azomethine moderate yield and 74% ee, the cycloaddition and heteroaryl afforded excellent imine resulted in moderate yield and 74% ee, of thenaphthyl cycloaddition of naphthylanalogues and heteroaryl analogues enantioselectivities 21). afforded excellent(Scheme enantioselectivities (Scheme 21). Scheme 20. The stereoselective 1,3-dipolar cycloaddition of N,N′-cyclic azomethine imines with allylic alcohols by the use of Grignard reagents and diisopropyl (R,R)-tartrate.

The results of the Ni(II)-catalyzed reaction are comparable to those of analogous Cu(II)-catalyzed reaction [36], where exo-cycloadduct (yielding the cis-diastereomer) was the major product, complementarily since in these cases, the endo-cycloaddition occurred. The difference in diastereoselectivity between the Cu(II)- and the Ni(II)-catalyzed cycloaddition of structurally-similar substrates can be explained by the alternative approach of the azomethine imine dipole depending on the metal geometry of catalytic chiral Lewis acid complex. The Cu(II)-catalyzed cycloaddition most probably proceeds via a distorted square-planar complex, which favors the exo-approach of a Scheme 20. The stereoselective 1,3-dipolar cycloaddition of N,N′-cyclic azomethine imines with allylic 0 -cyclic Scheme 20. The stereoselective 1,3-dipolar cycloaddition of N,N azomethine imines allylic dipole. However, the Ni(II)-catalyzed [3+2] cycloaddition likely proceeds through anwith octahedral alcohols by the use of Grignard reagents and diisopropyl (R,R)-tartrate. alcohols by the use of Grignard reagents and diisopropyl (R,R)-tartrate. complex forcing the endo-approach of a dipole. The results of the Ni(II)-catalyzed reaction are comparable to those of analogous Cu(II)-catalyzed reaction [36], where exo-cycloadduct (yielding the cis-diastereomer) was the major product, complementarily since in these cases, the endo-cycloaddition occurred. The difference in diastereoselectivity between the Cu(II)- and the Ni(II)-catalyzed cycloaddition of structurally-similar substrates can be explained by the alternative approach of the azomethine imine dipole depending on the metal geometry of catalytic chiral Lewis acid complex. The Cu(II)-catalyzed cycloaddition most probably proceeds via a distorted square-planar complex, which favors the exo-approach of a dipole. However, the Ni(II)-catalyzed [3+2] cycloaddition likely proceeds through an octahedral complex forcing the endo-approach of a dipole.

Scheme 21. (R)-BINIM-4Me-2QN–Ni(II)-catalyzed asymmetric [3+2] cycloadditions of N,N′-cyclic Scheme 21. (R)-BINIM-4Me-2QN–Ni(II)-catalyzed asymmetric [3+2] cycloadditions of N,N 0 -cyclic azomethine imines with 3-acryloyl-2-oxazolidinone. azomethine imines with 3-acryloyl-2-oxazolidinone.

Togni et al. developed Ni(II)-Pigiphos enantioselective 1,3-dipolar cycloaddition of various The results of the Ni(II)-catalyzed are comparable thoseWhen of analogous Cu(II)-catalyzed C,N-cyclic azomethine imines 66 toreaction α,β-unsaturated nitrilesto [43]. N-benzoylamino-3,4reaction [36], where exo-cycloadduct (yielding the cis-diastereomer) was the dihydroisoquinolinium betaine was reacted with acrylonitrile in the presence of major 5 mol product, % of complementarily since4)2 in these cases, thetheendo-cycloaddition occurred. The difference [Ni(PPP)(MeCN)](BF in dichloromethane, completion of the reaction was observed after 0.5 h in

diastereoselectivity between the Cu(II)- and the Ni(II)-catalyzed cycloaddition of structurally-similar substrates can be explained by the alternative approach of the azomethine imine dipole depending on the metal geometry of catalytic chiral Lewis acid complex. The Cu(II)-catalyzed cycloaddition most Scheme 21. (R)-BINIM-4Me-2QN–Ni(II)-catalyzed asymmetric [3+2] cycloadditions of N,N′-cyclic probably proceeds via a distorted square-planar complex, which favors the exo-approach of a dipole. azomethine imines with 3-acryloyl-2-oxazolidinone. However, the Ni(II)-catalyzed [3+2] cycloaddition likely proceeds through an octahedral complex forcing the endo-approach of a dipole. Togni et al. developed Ni(II)-Pigiphos enantioselective 1,3-dipolar cycloaddition of various C,N-cyclic azomethine imines 66 to α,β-unsaturated nitriles [43]. When N-benzoylamino-3,4dihydroisoquinolinium betaine was reacted with acrylonitrile in the presence of 5 mol % of [Ni(PPP)(MeCN)](BF4)2 in dichloromethane, the completion of the reaction was observed after 0.5 h

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Togni et al. developed Ni(II)-Pigiphos enantioselective 1,3-dipolar cycloaddition of various C,N-cyclic azomethine imines 66 to α,β-unsaturated nitriles [43]. When N-benzoylamino-3,4dihydroisoquinolinium betaine was reacted with acrylonitrile in the presence of 5 mol 17%of of Molecules 2018, 23, 3 30 [Ni(PPP)(MeCN)](BF4 )2 in dichloromethane, the completion of the reaction was observed after 0.5 h yielding notnot onlyonly goodgood diastereomeric accessaccess of the trans-isomer, but also excellent yielding 3,4-regioisomer, 3,4-regioisomer,with with diastereomeric of the trans-isomer, but also enantioselectivity (96% ee). Under the optimized reaction conditions, the substrates functionalized excellent enantioselectivity (96% ee). Under the optimized reaction conditions, the substrates with different electron-donating or electron-withdrawing groups yieldedgroups moderate enantiomeric functionalized with different electron-donating or electron-withdrawing yielded moderate excesses, form excesses, 60% up toform 88% ee (Scheme The wereexo-selectivities good to moderate, decreasing enantiomeric 60% up to22). 88% ee exo-selectivities (Scheme 22). The were good to from 13.3:1 to 5.6:1 in decreasing the electron-donating ability of the substituent (Me, H, Br, F) on moderate, decreasing from 13.3:1 to 5.6:1 in decreasing the electron-donating ability of the substituent the position para to the 1,3-dipole. The relative trans-stereoselectivity of the major cycloadduct (Me, H, Br, F) on the position para to the 1,3-dipole. The relative trans-stereoselectivity of the major 1 H and 2D 1NMR spectroscopy. Furthermore, the absolute 67 was established each caseinbyeach cycloadduct 67 was in established case by H and 2D NMR spectroscopy. Furthermore, the configurations (3R,4R) could be established by X-rayby crystallography of enantiopure single crystals absolute configurations (3R,4R) could be established X-ray crystallography of enantiopure single of the major diastereomer. The potential influence of a more functionalized cyanoolefins on the crystals of the major diastereomer. The potential influence of a more functionalized cyanoolefins on exo-selectivity of the transformation was also investigated using crotononitrile, methacrylonitrile, the exo-selectivity of the transformation was also investigated using crotononitrile, methacrylonitrile, trans-cinnamonitrile The reactivity reactivity of of this this substituted substituted acrylonitriles acrylonitriles was was much trans-cinnamonitrile and and cis-2-pentenonitrile. cis-2-pentenonitrile. The much more inferiorcompared comparedtotothe theacrylonitrile, acrylonitrile, cycloaddition occurred with trans-cinnamonitrile more inferior asas nono cycloaddition occurred with trans-cinnamonitrile and and cis-2-pentenenitrile under the same reaction conditions. Furthermore, methacrylonitrile yielded cis-2-pentenenitrile under the same reaction conditions. Furthermore, methacrylonitrile yielded 52% 52% the corresponding regioisomeric mixture of cycloadducts (3,4-cycloadduct/3,5-cycloadduct, of theofcorresponding regioisomeric mixture of cycloadducts (3,4-cycloadduct/3,5-cycloadduct, 3.7/1) ◦ 3.7/1) after 40 However, C. However, addition crotononitrile(four (fourequiv., equiv., cis/trans cis/trans mixture) mixture) to after 48 h 48 at h40at°C. addition of ofcrotononitrile to N-benzoylamino-3,4-dihydroisoquinolinium betaine at r.t. over two days resulted largely in the N-benzoylamino-3,4-dihydroisoquinolinium betaine at r.t. over two days resulted largely in the formation ofthe thetrans-3,4-cycloadduct trans-3,4-cycloadduct = 7.3/1) in yield 66% and yield62% and of the trans-isomer formation of (dr(dr = 7.3/1) in 66% ee 62% of theeetrans-isomer (Scheme (Scheme 22, e.g., 67g). On the basis of the above-mentioned results, it can be concluded 22, e.g., 67g). On the basis of the above-mentioned results, it can be concluded that the stericthat sizethe of steric size of the dipolarophile is a crucial factor in these 1,3-dipolar cycloadditions. the dipolarophile is a crucial factor in these 1,3-dipolar cycloadditions.

Scheme 22. 22. Ni(II)-Pigiphos-catalyzed functionalized C,N-cyclic C,N-cyclic Scheme Ni(II)-Pigiphos-catalyzed 1,3-dipolar 1,3-dipolar cycloaddition cycloaddition of of functionalized azomethine imines to cyanoolefins. azomethine imines to cyanoolefins.

Feng et al. represented the first example of asymmetric reaction of azomethine imines 70 with Feng et al. represented the first example of asymmetric reaction of azomethine imines 70 with alkylidene malonates 69 using N,N′-dioxide-Ni(II) complexes [44]. Different metal sources such as alkylidene malonates 69 using N,N 0 -dioxide-Ni(II) complexes [44]. Different metal sources such as Sc(OTf)3, Mg(ClO4)2 and Co(ClO4)2·6H2O were evaluated; however, the N,N′-dioxide-Ni(ClO4)2·6H2O Sc(OTf)3 , Mg(ClO4 )2 and Co(ClO4 )2 ·6H2 O were evaluated; however, the N,N 0 -dioxide- Ni(ClO4 )2 ·6H2 O promoted the reaction giving rise to the corresponding endo-cycloadduct 71 as a single isomer promoted the reaction giving rise to the corresponding endo-cycloadduct 71 as a single isomer (dr > 99:1). (dr > 99:1). Different nickel sources were also examined (Ni(BF4)2·6H2O and NiBr2), but no improvement in the cycloaddition was observed. The counter anion has a crucial effect on both the yield and the selectivity in the azomethine imine-alkylidene malonate cycloaddition. Upon the optimization of the reaction conditions, the ratio of 1:1.2 between Ni(ClO4)2·6H2O and N,N′-dioxide ligand L18 was chosen as optimal, and the reaction performed the best in dichloromethane. It is important to note that the solvent effects the reaction greatly since very low conversions were obtained in solvents such

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Different nickel sources were also examined (Ni(BF4 )2 ·6H2 O and NiBr2 ), but no improvement in the cycloaddition was observed. The counter anion has a crucial effect on both the yield and the selectivity in the azomethine imine-alkylidene malonate cycloaddition. Upon the optimization of the reaction conditions, the ratio of 1:1.2 between Ni(ClO4 )2 ·6H2 O and N,N 0 -dioxide ligand L18 was chosen as optimal, and the reaction performed the best in dichloromethane. It is important to note that the solvent effects Molecules 2018, 23, 3the reaction greatly since very low conversions were obtained in solvents such 18 of as 30 toluene, THF, MeCN and EtOAc. The catalytic composition was also investigated, and a slightly positive nonlinear effect was obtained between the enantiomeric excess of the ligand ligand and and the the product, product, suggesting that the the minor minor oligomeric oligomericaggregation aggregationof ofthe theN,N′-dioxide-Ni(ClO N,N 0 -dioxide-Ni(ClO )2 ·6H might exist 4)4 2·6H 2O2 O might exist in · in the catalytic system. However, the ESI-MS studies of Ni(ClO ) 6H O and chiral ligand in a ratio the catalytic system. However, the ESI-MS studies of Ni(ClO4)24·6H 2 2O 2and chiral ligand in a ratio of (2+) −+ of 1:1.2 in dichloromethane confirmed existence of monomeric the monomeric nickel species + +Ni 1:1.2 in dichloromethane confirmed the the existence of the nickel species [L18 +[L18 Ni(2+) ClO 4 ] − ClO ] in solution. Using the optimized catalytic system, a variety of dipolarophiles, (cyclo)alkylin solution. Using the optimized catalytic system, a variety of dipolarophiles, (cyclo)alkyland 4 0 -cyclic azomethine imines, deriving (hetero)aryl-substituted alkylidene malonates, reacted with N,N N,N′-cyclic the corresponding trans-diastereomers with excellent enantioselectivities (from(from 83% up correspondingproducts productsasassole sole trans-diastereomers with excellent enantioselectivities 83 to up97% to 97ee) ee)(Scheme (Scheme23). 23).To Todemonstrate demonstratethe thescalability, scalability,aagram-scale gram-scale reaction reaction was was performed between diethyl 2-benzylidenemalonate and (Z)-1-benzylidene-1λ44-pyrazolidin-3-one under the optimized catalytic system system to to give give the the corresponding correspondingcycloadduct cycloadductin in85% 85%yield yieldand and92% 92%ee. ee.

0 -dioxide-Ni(ClO 4))2·6H Scheme 23. 23. Enantioselective Enantioselective N,N N,N′-dioxide-Ni(ClO 2O-catalyzed 1,3-dipolar cycloaddition of Scheme 4 2 ·6H2 O-catalyzed 1,3-dipolar cycloaddition of 0 alkylidene malonates with N,N′-cyclic azomethine imines. alkylidene malonates with N,N -cyclic azomethine imines.

3.2. By Cycloadditions 3.2. By Organocatalyzed Organocatalyzed Cycloadditions Rueping et N-triflylphosphoramide Brønsted acidacid C1 C1 as an Rueping et al. al. efficiently efficientlyemployed employedacidic acidic N-triflylphosphoramide Brønsted as organocatalyst in highly enantioselective cycloadditions between various alkenes and azomethine an organocatalyst in highly enantioselective cycloadditions between various alkenes and azomethine imines derived derived from from N-benzoylhydrazone N-benzoylhydrazone precursors. imines precursors. Thus, Thus, under under optimized optimized reaction reaction conditions, conditions, [3+2] cycloaddition of N-benzoyl protected hydrazones 72 (derived from aliphatic, aromatic and [3+2] cycloaddition of N-benzoyl protected hydrazones 72 (derived from aliphatic, aromatic heteroaromatic aldehydes or ethylorglyoxylate) to cyclopentadiene (73) afforded derivatives and heteroaromatic aldehydes ethyl glyoxylate) to cyclopentadiene (73)pyrazolidine afforded pyrazolidine 74 in 51–99% yields with excellent stereoselectivity (dr ≥ 96:4, 87–98% ee). Next, α-methylstyrene and derivatives 74 in 51–99% yields with excellent stereoselectivity (dr ≥ 96:4, 87–98% ee). 75Next, its (hetero)aryl analogues were used as dipolarophiles in [3+2] cycloaddition with N-benzoylα-methylstyrene 75 and its (hetero)aryl analogues were used as dipolarophiles in [3+2] cycloaddition protected hydrazones 72, hydrazones as azomethine imine precursors, valuable pyrazolidine with N-benzoyl-protected 72, as azomethine iminefurnishing precursors, furnishing valuable derivatives 76, bearing a quaternary and a trisubstituted stereocenter at the 3and 5-positions, in 52–95% pyrazolidine derivatives 76, bearing a quaternary and a trisubstituted stereocenter at the 3- and yields and 80–96% ee as single diastereomers (Scheme 24) [45]. 5-positions, in 52–95% yields and 80–96% ee as single diastereomers (Scheme 24) [45]. Suga and co-workers reported cycloadditions of N,N-cyclic azomethine imines 77 to acrolein (78) catalyzed by L-proline C2 and (S)-indoline-2-carboxylic acid C3. The initial cycloadducts 8 were, after reduction with NaBH4, isolated as the corresponding alcohols. Under the optimized reaction conditions, the L-proline C2-catalyzed reactions gave the cycloadducts 79 in 54–89% yields as the major endo-diastereomers (endo/exo = 83:27 to 99:1) with modest to good enantioselectivity

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(75–98% ee), in 29–95% yields. Different substituents on the azomethine imines were well tolerated. The authors have shown that exo-cycloadduct can be isomerized into endo-cycloadduct in19 the Molecules 2018, 23, 3 of 31 presence of L-proline C2 (Scheme 25) [46]. (2 equiv.) 73 N R

H N H

cat. C1 (2.5 mol%) DCE, 0 °C or r.t.

Ar O

R1 (3 equiv.)

H

16 examples 51-99% yield 87-98% ee dr > 96:4

H

R = (hetero)aryl alkyl, CO2Et

N HN

Arl = Ph

R

72 75

O

Ph

74 cat. C1 (5-10 mol%) DCE or CHCl3, r.t.

i-Pr i-Pr

N i-Pr

18 examples 52-95% yield 80-96% ee

Ar

HN N

R1

O P

76

O NHTf

O

i-Pr

R = alkyl R1 = (hetero)aryl

R

C1

i-Pr

O Ar

HN N BnO 63%; 95% ee

Ph

HN N

O

Ar S

HN N

Ar Ph

H

HN H

EtO2C

87%; 92% ee dr > 98:2 Ph

i-Pr

examples O

O

Ph

Ar = 4-O2N-C6H4

O

examples

O N

H

HN Ph H 69%; 90% ee dr > 98:2

i-Bu 92%; 92% ee

52%; 92% ee

Scheme Scheme 24. 24. [3+2] [3+2]Cycloaddition CycloadditionofofN-benzoyl N-benzoylprotected protectedhydrazones hydrazones toto cyclopentadiene cyclopentadiene and and α-methylstyrene derivatives. DCE = 1,2-dichloroethane. α-methylstyrene derivatives. DCE = 1,2-dichloroethane. CHO (2 equiv.) 9 examples imines 77 to acrolein Suga and co-workers reported cycloadditions of N,N-cyclic azomethine 78 O 54-89% yield O 1 C2 (30 mol%) (78) catalyzed by L-proline C2cat.and (S)-indoline-2-carboxylic acid C3. The initial cycloadducts 8 were, R endo/exo = 83:27 to 99:1 R1 CHCl3-MeOH (97 : 3 v/v), 25 °C eethe optimized reaction N alcohols. 31-83% after reduction with NaBH , isolated as the corresponding Under N 4 N R R, R179 = Me, conditions,RtheNL-proline C2-catalyzed reactions gave the cycloadducts in H54–89% yields as the CHO 2 R1 = alkyl, aryl R CO2H 2 R major endo-diastereomers (endo/exo = 83:27 to 99:1) with modest to good enantioselectivity (31–83% ee). N H C2 77 endo-79 Azomethine imines bearing o-chlorophenyland alkyl-substituents gave the corresponding products 79 in merely low to modest enantioselectivity (31–50% ee). exo to Interestingly, endo-isomerisation reactions catalyzed by 2 = Ph using C3; R, R1 = H, R79 (S)-indoline-2-carboxylic acid C3 furnished the corresponding cycloadducts with high exo-selectivity CHO (2 equiv.) (exo/endo = 91:9 to 99:1)78and good to excellent enantioselectivity (75–98% ee), in 29–95% yields. O R1 Different substituents oncat.the azomethine imines were well tolerated. The authors have shown C3 (30 mol%) N 11 examples 3-MeOH (97 : 3 v/v), 0 °C N that exo-cycloadductCHCl can be isomerized into endo-cycloadduct in the presence of L-proline C2 29-95% yield R exo/endo = 91:9 to 99:1 CHO (Scheme 25) [46]. 75-98% ee R2 CO2H α,α-Bis[3,5-di(trifluoromethyl)phenyl]prolinol C4 was applied as the organocatalyst of choice for R, R1 = Me, H exo-79 N 1 = cyclohexyl, aryl H of N,N-cyclic C3 the stereoselective cycloaddition azomethine imines 80 toRα,β-unsaturated aldehydes 81, furnishing the expected cycloadducts 82 in 50–95% yields with excellent stereoselectivities (exo/endo Scheme 25. L-proline C2- and (S)-indoline-2-carboxylic acid C3-catalyzed cycloadditions of = 81:19 to 98:2; 82–97% ee). Both electron-withdrawing and electron-donating substituents in the N,N-cyclic azomethine imines to acrolein. para-position of benzene ring of azomethine imines gave the corresponding products with excellent stereoselectivities. Regarding the applied enals 81,C4 thewas onesapplied with anasalkyl group worked of very well, α,α-Bis[3,5-di(trifluoromethyl)phenyl]prolinol the organocatalyst choice whereas reactions with cinnamaldehyde failed to give the expected products. Azomethine imine, for the stereoselective cycloaddition of N,N-cyclic azomethine imines 80 to α,β-unsaturated aldehydes 81, derived from isobutyraldehyde, was reacted with crotonaldehyde in the presence furnishing the expected cycloadducts 82successfully in 50–95% yields with excellent stereoselectivities (exo/endo of = MacMillan’s first generation organocatalyst C5 [47], giving the corresponding cycloadduct in 40% 81:19 to 98:2; 82–97% ee). Both electron-withdrawing and electron-donating substituents in the yield, 77% ee of and exo/endo = 95:5 (Scheme 26)imines [48]. gave the corresponding products with excellent para-position benzene ring of azomethine

stereoselectivities. Regarding the applied enals 81, the ones with an alkyl group worked very well,

HN N

HN N

Ph

BnO

HN N

S

dr > 98:2

Ph

i-Bu

63%; 95% ee

92%; 92% ee

52%; 92% ee

Scheme 24. Molecules 2018, 23, 3 [3+2] Cycloaddition of N-benzoyl protected hydrazones to cyclopentadiene and 20 of 31 α-methylstyrene derivatives. DCE = 1,2-dichloroethane. CHO (2 equiv.) 78 O

R1

cat. C2 (30 mol%) CHCl3-MeOH (97 : 3 v/v), 25 °C

N

R1

N R

N

R

R2 N H

77

9 examples 54-89% yield endo/exo = 83:27 to 99:1 31-83% ee

O

N

R, R1 = Me, H R1 = alkyl, aryl

CHO

CO2H

R2

C2

endo-79 exo to endo-isomerisation using C3; R, R1 = H, R2 = Ph

CHO (2 equiv.) 78 cat. C3 (30 mol%) CHCl3-MeOH (97 : 3 v/v), 0 °C

R1

O N

R

11 examples 29-95% yield exo/endo = 91:9 to 99:1 75-98% ee

N CHO

Molecules 2018, 23, 3

R2

CO2H

20 of 30

R, R1 = Me, H

exo-79 N whereas reactions with cinnamaldehyde failed to give the expected products. Azomethine imine, H C3 aryl R1 = cyclohexyl, derived from isobutyraldehyde, was successfully reacted with crotonaldehyde in the presence of Scheme 25. 25.L-proline L -proline and (S)-indoline-2-carboxylic acid C3-catalyzed cycloadditions of 40% Scheme C2-C2and (S)-indoline-2-carboxylic acid C3-catalyzed cycloadditions of N,N-cyclic MacMillan’s first generation organocatalyst C5 [47], giving the corresponding cycloadduct in N,N-cyclic azomethine imines to acrolein. imines to acrolein. yield,azomethine 77% ee and exo/endo = 95:5 (Scheme 26) [48].

α,α-Bis[3,5-di(trifluoromethyl)phenyl]prolinol C4 was applied as the organocatalyst of choice R1 CHO (2 equiv.) for the stereoselective cycloaddition81of N,N-cyclic azomethine imines 80 to α,β-unsaturated aldehydes 81, O O cat. C4 (10 mol%) furnishing the expected O cycloadducts 82 in 50–95% yields with excellent stereoselectivities (exo/endo = CF3CO2H (10 mol%) 1 R1 R electron-donating 81:19 to 98:2; 82–97% ee). BothTHF/H electron-withdrawing substituents in the N and N 2O, 20 °C N + N N para-position of benzene ring of azomethine imines gave the corresponding products with excellent N CHO CHO R stereoselectivities. Regarding the applied enals 81, theRones with an alkyl group worked very well, R F3C

80

exo-82 CF3

10 examples 50-95% yield endo/exo = 81:19 to 98:2 82-97% ee

CF3

R = aryl R1 = alkyl

OH N H

C4

F3C

O Bn

endo-82

O

Me N

for the preparation of

N

Me

N

N H2

CHO

Cl

nPr

C5

40%, endo/exo = 95:5; 77% ee

Scheme α,β-unsaturated aldehydes. Scheme 26. 26. Cycloaddition Cycloaddition of of N,N-cyclic N,N-cyclic azomethine azomethine imines imines to to α,β-unsaturated aldehydes.

Chen et al. applied 9-amino-9-deoxyepiquinine C6 in the presence of Chen et al. applied 9-amino-9-deoxyepiquinine C6 in the presence of 2,4,62,4,6-triisopropylbenzenesulfonic acid (TIPBA) for an efficient cycloaddition of various alkyl and triisopropylbenzenesulfonic acid (TIPBA) for an efficient cycloaddition of various alkyl and (hetero)aryl substituted N,N-cyclic azomethine imines 84 to 2-cyclopenten-, 2-cyclohexen- and (hetero)aryl substituted N,N-cyclic azomethine imines 84 to 2-cyclopenten-, 2-cyclohexen- and 2-cyclohepten-1-ones 83, giving the desired products 85 in excellent diastereoselectivity (dr > 99:1), 2-cyclohepten-1-ones 83, giving the desired products 85 in excellent diastereoselectivity (dr > 99:1), excellent enantioselectivity (85–95% ee) and in 67–99% yields. When 9-amino-9-deoxyepiquinidine C7 excellent enantioselectivity (85–95% ee) and in 67–99% yields. When 9-amino-9-deoxyepiquinidine C7 was applied, enantiomeric cycloadducts were obtained, retaining the same level of stereoselectivity was applied, enantiomeric cycloadducts were obtained, retaining the same level of stereoselectivity (Scheme 27). The 6-hydroxy group on the quinolone part of the organocatalysts C6 and C7, as well (Scheme 27). The 6-hydroxy group on the quinolone part of the organocatalysts C6 and C7, as well as as the presence of the sterically bulky TIPBA additive were essential for the high stereoselectivity of the presence of the sterically bulky TIPBA additive were essential for the high stereoselectivity of these these transformations [49]. transformations [49].

+

N N

n

83 (2 equiv.) n = 0, 1, 2

O

cat. C6 (10 mol%) TIPBA (20 mol%) THF, 4 Å MS, 40 °C

O

O

N n

R 84

H R

H

N

85 N

H

22 examples 67-99% yield dr >99:1 85-95% ee R = (hetero)aryl alkyl

O

N

NH2 C6

N N

H

2-cyclohepten-1-ones 83, giving the desired products 85 in excellent diastereoselectivity (dr > 99:1), excellent enantioselectivity (85–95% ee) and in 67–99% yields. When 9-amino-9-deoxyepiquinidine C7 was applied, enantiomeric cycloadducts were obtained, retaining the same level of stereoselectivity (Scheme 27). The 6-hydroxy group on the quinolone part of the organocatalysts C6 and C7, as well as the presence Molecules 2018, 23, 3of the sterically bulky TIPBA additive were essential for the high stereoselectivity 21 of of 31 these transformations [49].

N

+

O

cat. C6 (10 mol%) TIPBA (20 mol%) THF, 4 Å MS, 40 °C

O

O

N

N

n

n

H

R 84

83 (2 equiv.) n = 0, 1, 2

N

85 H

N

N N

O

O

H Ph

H

O

H

O

N

N

H

O

78%, 90% ee

C7 OH for the preparation of enantiomeric products

H

N

N

H NH2

OMe

iPr

N H

N

C6

OH

R = (hetero)aryl alkyl

O

NH2 examples

22 examples 67-99% yield dr >99:1 85-95% ee

H R

N O

76%, 91% ee

76%, 93% ee

Scheme 2-cyclohexen-, and 2Scheme 27. 27. Cycloaddition CycloadditionofofN,N-cyclic N,N-cyclicazomethine azomethineimines iminestoto2-cyclopenten-, 2-cyclopenten-, 2-cyclohexen-, and cyclohepten-1-ones. TIPBA, 2,4,6-triisopropylbenzenesulfonic acid. 2-cyclohepten-1-ones. TIPBA, 2,4,6-triisopropylbenzenesulfonic acid.

Molecules 2018, 23, 3

21 of 30

A chiral bis-phosphoric acid C8, bearing triple axial chirality, was developed by Wang and and co-workers and andsuccessfully successfullyutilized utilized in the 1,3-dipolar cycloaddition of N,N-cyclic azomethine in the 1,3-dipolar cycloaddition of N,N-cyclic azomethine imines imines 86 to methyleneindolinones 87. The chiral spiro[pyrazolidin-3,3’-oxindole] products 88 86 to methyleneindolinones 87. The chiral spiro[pyrazolidin-3,3’-oxindole] products 88 have been have been 68–94% yields, good to diastereoselectivity excellent diastereoselectivity (dr from and 6:1–20:1) and formed in formed 68–94% in yields, good to excellent (dr from 6:1–20:1) excellent excellent enantioselectivity (91–99% ee). Azomethine imines bearing(hetero)aryl different (hetero)aryl substituents, enantioselectivity (91–99% ee). Azomethine imines bearing different substituents, as well as as well as different electronic nature, bulkiness position of the substitution patterns on the different electronic nature, bulkiness or position of theor substitution patterns on the methyleneindolinones methyleneindolinones on the efficiency of and stereoselectivity of transformations had negligible effect onhad thenegligible efficiencyeffect and stereoselectivity transformations under the optimized under the optimized reaction conditions. DFT calculations have been performed to shed the light on reaction conditions. DFT calculations have been performed to shed the light on the mechanism of the the mechanism of the 1,3-dipolar (Scheme 28) [50]. 1,3-dipolar cycloaddition (Schemecycloaddition 28) [50]. O R2O2C

O N

+

N

R1

cat. C8 (10 mol%) CH2Cl2, 15 °C O

87

86

R2O2C

R O

R1

N Boc

R

N N

88

N Boc

18 examples 68-94% yield 91-99% ee dr from 6:1 to 20:1 R = (hetero)aryl R1 = H, Me, OMe, Cl, Br R2 = Me, Et, tBu

examples O EtO2C

O N N

O

tBuO2C

Ph O

O N Boc 68%; dr = 14:1, 91% ee

O O O P O OH O P OH O

N N

N Boc 92%; dr = 14:1, 98% ee

C8

Scheme 28. 28. 1,3-dipolar 1,3-dipolar cycloaddition cycloaddition of of N,N-cyclic N,N-cyclic azomethine azomethine imines imines to to methyleneindolinones. methyleneindolinones. Scheme

Kerrigan and co-workers reported 1,3-dipolar cycloadditions of the in situ-generated ketenes Kerrigan and co-workers reported 1,3-dipolar cycloadditions of the in situ-generated ketenes (formed from the corresponding acyl chlorides 90 and DIPEA) to azomethine imines 89 in the (formed from the corresponding acyl chlorides and DIPEA) azomethine imines 89 in the presence of quinuclidine organocatalyst C9 as the 90 catalyst of choice,tothus furnishing (2R,3S)-bicyclic presence of quinuclidine organocatalyst C9 as theenantioselectivity catalyst of choice,(≥96% thus furnishing (2R,3S)-bicyclic pyrazolidinones 91 in 52–99% yields, excellent ee) and moderate to high pyrazolidinones 91 in 52–99% yields, excellent enantioselectivity (≥96% ee) and moderate to high diastereoselectivity (dr 3:1–27:1). The method displays tolerance to aryl groups of azomethine imine diastereoselectivity (dr 3:1–27:1). Theand method displays tolerancesubstituents, to aryl groupswhile of azomethine imine containing both electron-donating electron-withdrawing with respect to containing both electron-donating anddifferent electron-withdrawing substituents, while withWith respect ketene ketene substituents, an acetoxy and alkyl substituents were employed. thetoacetoxy group, a markedly improved trans-diastereoselectivity was observed (dr 12:1 to 27:1). If pseudo enantiomeric catalyst C10 was applied, enantiomeric (2S,3R)-bicyclic cycloadducts 91 were obtained, retaining the same level of stereoselectivity (Scheme 29) [51].

Kerrigan and co-workers reported 1,3-dipolar cycloadditions of the in situ-generated ketenes (formed from the corresponding acyl chlorides 90 and DIPEA) to azomethine imines 89 in the presence of quinuclidine organocatalyst C9 as the catalyst of choice, thus furnishing (2R,3S)-bicyclic pyrazolidinones 91 in 52–99% yields, excellent enantioselectivity (≥96% ee) and moderate to22high Molecules 2018, 23, 3 of 31 diastereoselectivity (dr 3:1–27:1). The method displays tolerance to aryl groups of azomethine imine containing both electron-donating and electron-withdrawing substituents, while with respect to substituents, an acetoxy and different alkyl substituents were employed. With the acetoxy group, ketene substituents, an acetoxy and different alkyl substituents were employed. With the acetoxy agroup, markedly improved trans-diastereoselectivity was observed (dr 12:1 to 27:1). If pseudo enantiomeric a markedly improved trans-diastereoselectivity was observed (dr 12:1 to 27:1). If pseudo catalyst C10 was applied, (2S,3R)-bicyclic cycloadducts cycloadducts 91 were obtained, retaining the enantiomeric catalyst C10 enantiomeric was applied, enantiomeric (2S,3R)-bicyclic 91 were obtained, same levelthe of same stereoselectivity (Scheme 29) [51]. retaining level of stereoselectivity (Scheme 29) [51].

Scheme 29. 29. 1,3-dipolar of ketenes ketenes to to N,N-cyclic N,N-cyclic azomethine azomethine imines. imines. Scheme 1,3-dipolar cycloadditions cycloadditions of

Molecules 2018, 23, 3

22 of 30

Proline-derived thiourea organocatalyst byby Kesavan et al. [3+2] Proline-derived organocatalyst C11 C11was wasused used Kesavan et for al. the for formal the formal cycloaddition of azomethine imines 92 to malononitrile (93), yielding bicyclic pyrazolidinones 94 [3+2] cycloaddition of azomethine imines 92 to malononitrile (93), yielding bicyclic pyrazolidinones with embedded enaminonitrile functionality Azomethineimines imines 94 with embedded enaminonitrile functionalityinin68–92% 68–92%yield yieldand and41–98% 41–98% ee. ee. Azomethine containing cyclohexyl, cyclohexyl, heteroaromatic heteroaromatic and and diversely diverselysubstituted substitutedaromatic aromaticsubstituents substituentswere wereused. used. containing 2-methylmalononitrile also gave the the expected expected product product (78% (78%yield, yield,70% 70%ee), ee),while whileother otherdipolarophiles dipolarophiles benzoylacetonitrile and and (phenylsulfonyl)acetonitrile (phenylsulfonyl)acetonitrilefailed failedtotoreact. react. such as ethyl 2-cyanoacetate, 2-cyanoacetate, benzoylacetonitrile azomethine imine imine gets gets activated activatedvia viahydrogen hydrogenbonding bondingwith withthe thethiourea thioureamoiety, moiety, Presumably, the azomethine whereas the tertiary amine deprotonates/activates deprotonates/activatesthe themalononitrile malononitrile(Scheme (Scheme30) 30)[52]. [52]. NC

O

(1.2 equiv.)

CN 93

cat. C11 (10 mol%), toluene, r.t., 1 h

N

N

NH2

18 examples 68-92% yield 41-98% ee

CN

R = (hetero)aryl cyclohexyl

N

N R 92

O

Yield R 68 cyclohexyl 79 2-F-C6H4 3-F-C6H4 78 3-MeO-C6H4 92 4-F-C6H4 89 4-O2N-C6H4 80 4-MeO-C6H4 86 2-thiophenyl 81

ee 41 91 90 70 91 98 90 83

R 94

H Ph S N HN HN Me C11

CF3

CF3

Scheme Scheme 30. 30. [3+2] [3+2]cycloaddition cycloadditionof ofN,N-cyclic N,N-cyclicazomethine azomethineimines iminestotomalononitrile. malononitrile.

Chi and co-workers developed a new C–C bond activation of γ-mono-chlorine-substituted Chi and co-workers developed a new C–C bond activation of γ-mono-chlorine-substituted cyclobutenones 96 enabled by an isothiourea Lewis base organocatalyst C12. The 1,2-addition of cyclobutenones 96 enabled by an isothiourea Lewis base organocatalyst C12. The 1,2-addition of Lewis Lewis base C12 to 96 furnishes intermediate 97, which undergoes electrocyclic ring opening to base C12 to 96 furnishes intermediate 97, which undergoes electrocyclic ring opening to generate vinyl generate vinyl enolate intermediate 98. Selective α-addition of 98 to azomethine imine 95 followed enolate intermediate 98. Selective α-addition of 98 to azomethine imine 95 followed by cyclization by cyclization gives the final products 28 in excellent diastereo- and enantioselectivity (cis-selective, gives the final products 28 in excellent diastereo- and enantioselectivity (cis-selective, up to ≥ 98% up to ≥ 98% ee). The developed reaction tolerates different aromatic substituents at the β-carbon of ee). The developed reaction tolerates different aromatic substituents at the β-carbon of cyclobutenone cyclobutenone 96, while the mono-chlorine in the 3-position is essential for the positive outcome of 96, while the mono-chlorine in the 3-position is essential for the positive outcome of the reaction. the reaction. With regard to azomethine imine 95, substituents in position 8 other than hydrogen result in lower yields and enantiomeric excess, presumably due to steric hindrance (Scheme 31) [53]. O

Cl 96 (1.5 equiv.) R1

Cl

14 examples

Chi and co-workers developed a new C–C bond activation of γ-mono-chlorine-substituted cyclobutenones 96 enabled by an isothiourea Lewis base organocatalyst C12. The 1,2-addition of Lewis base C12 to 96 furnishes intermediate 97, which undergoes electrocyclic ring opening to generate vinyl enolate intermediate 98. Selective α-addition of 98 to azomethine imine 95 followed by cyclization the final products 28 in excellent diastereo- and enantioselectivity (cis-selective, Molecules 2018, 23, gives 3 23 of 31 up to ≥ 98% ee). The developed reaction tolerates different aromatic substituents at the β-carbon of cyclobutenone 96, while the mono-chlorine in the 3-position is essential for the positive outcome of With regard toWith azomethine 95, substituents position 8 other than hydrogen resulthydrogen in lower the reaction. regard toimine azomethine imine 95,insubstituents in position 8 other than yields and enantiomeric excess, presumably due to steric hindrance (Scheme 31) [53]. result in lower yields and enantiomeric excess, presumably due to steric hindrance (Scheme 31) [53]. O

Cl 96 (1.5 equiv.)

Bz

N

R1 cat. C12 (10 mol%), CHCl3 Et3N (10 equiv), r.t., 3 days

R N

Cl O H Bz N

cat. C12

95

14 examples 41-73% yield 16-98% ee

R1 H

N

R

R = aryl cyclohex-1-en-1-yl

99 Ph

Ph N

N

N

O Cl

S 97

N

Ph

95

cat. C12

O

N

S 98

R1

N

S Cl

C12

R1

selected products 11: Cl

Cl

O H Bz N

O H H

N

68%; 96% ee

Br

Bz N

O H H

N

63%; 92% ee

Cl

Cl

OMe

Bz N

O H H

N

43%; 98% ee

Bz N

H

Ph Me

N

41%; 16% ee

Scheme 31. Application of γ-mono-chloro substituted cyclobutenones in formal [3+2] cycloadditions Scheme 31. Application of γ-mono-chloro substituted cyclobutenones in formal [3+2] cycloadditions to C,N-cyclic azomethine imines. to C,N-cyclic azomethine imines.

Using chiral phosphine organocatalyst C13, Shi et al. managed to employ δ-substituted allenic esters 101 in an asymmetric [3+2] cycloaddition to C,N-cyclic azomethine imines 100, yielding tetrahydroquinoline derivatives 102 in 57–93% yields, with high diastereoselectivity (> 20:1 dr) and good enantioselectivity (68–93% ee). The employed allenoates 101 react as C2 -synthons via their δ- and γ-positions, for which the authors proposed a plausible reaction mechanism. Both simple and sterically-demanding alkyl allenoates 101 have been successfully employed, containing benzyl and various aryl substituents in the δ-position, while the reaction with allenoate containing δ-methyl-substituent failed. In the reaction of δ-Ph substituted allenoates 101 with various azomethine imines 100, the electron-rich alkyl-substituents on the azomethine imine seem to have a beneficial influence on the enantioselectivity of the reaction. N,N-cyclic azomethine imine does not react with δ-substituted allenic esters under the applied reaction conditions (Scheme 32) [54]. Ye and co-workers developed N-heterocyclic carbene-catalyzed [3+2] cycloaddition of α-chloroaldehydes 104 to C,N-cyclic azomethine imines 103. N-heterocyclic carbene was generated in situ from the corresponding triazolium salt C14 and DIPEA. The corresponding pyrazolidinone products 105 were obtained in good yields (65–93%), with moderate to good diastereoselectivity (3:1–8:1 dr) and excellent enantioselectivity (90–99% ee). It was found that both β-(hetero)aryl and alkyl α-chloroaldehydes 104, as well as azomethine imines 103 containing various N-arylcarbonyl groups worked well, affording the corresponding products 105 with high enantioselectivities. On the other hand, the reaction of α-chlorophenylacetaldehyde with azomethine imine, under optimized reaction conditions, furnished the desired product in decreased yield (30%) and enantioselectivity (55% ee), though significantly improved diastereoselectivity (dr > 20:1) (Scheme 33). A plausible catalytic cycle was postulated. It includes N-heterocyclic carbene addition to α-chloroacetaldehyde, thus generating Breslow intermediate [55], which decomposes to azolium enolate. Azolium enolate reacts with the azomethine imine in an addition-cyclization sequence, affording the final products 105 [56].

sterically-demanding alkyl allenoates 101 have been successfully employed, containing benzyl and various aryl substituents in the δ-position, while the reaction with allenoate containing δ-methyl-substituent failed. In the reaction of δ-Ph substituted allenoates 101 with various azomethine imines 100, the electron-rich alkyl-substituents on the azomethine imine seem to have a beneficial influence on the enantioselectivity of the reaction. N,N-cyclic azomethine imine does not Molecules 2018, 23, 3 24 of 31 react with δ-substituted allenic esters under the applied reaction conditions (Scheme 32) [54]. R1

R

N

N

CO2R2 R

cat. C13 (10 mol%) p-xylene, r.t., 24 h

Bz

20 examples 57-93% yield 68-93% ee dr >20:1

101 (1.5 equiv.) N

N Bz

R1 H

100

102

CO2R2

R = H, F, Cl, Br, Me, tBu R1 = aryl, Bn; R2 = alkyl

O

selected products:

O Me

N

N Bz

Br

Bn H

N

N Bz

Ph H CO2Bn

57%; 68% ee

Me

N

Fe

N Bz

Ph H CO2Bn

71%; 81% ee

P

P

O CO2Bn

O

C13

81%; 93% ee

Scheme 32.32. Chiral phosphine-catalyzed allenic esters esterstotoC,N-cyclic C,N-cyclic Scheme Chiral phosphine-catalyzedcycloaddition cycloaddition of of δ-substituted δ-substituted allenic azomethine azomethine imines. Molecules 2018, 23, 3imines. 24 of 30

Ye and co-workers developedO N-heterocyclic carbene-catalyzed [3+2] cycloaddition of α-chloroaldehydes 104 to C,N-cyclic azomethine H (2 equiv.) imines 103. N-heterocyclic carbene was generated R2 104 salt C14 and DIPEA. The corresponding pyrazolidinone Cl in situ from the corresponding triazolium 17 examples precat. C14 (20 mol%) products 105 were obtained in good yields (65–93%), with moderate to good 65-93%diastereoselectivity yield DIPEA (2 equiv.) O O 90-99% ee N (3:1–8:1 dr) and excellent enantioselectivity ee). that3:1 both β-(hetero)aryl and toluene, 4 Å MS,(90–99% 40 °C R It was found N N to 8:1 dr 1 R N R1 R alkyl α-chloroaldehydes 104, as well as azomethine imines 103 containing various 1N-arylcarbonyl R = H, Br; R = aryl 2 103 affording the corresponding products 105RwithOhigh enantioselectivities. groups worked well, R2 = (hetero)aryl, alkyl On the 105 other hand, selected the reaction of α-chlorophenylacetaldehyde with azomethine imine, under optimized products: reaction conditions, furnished the desired product in decreased yield (30%) and enantioselectivity N O (55% ee), though significantly improved diastereoselectivity (dr > 20:1) (Scheme 33). A plausible N Mes N N N N Bz Bz Bz N N catalytic cycle was postulated. It includes N-heterocyclic carbeneNaddition to α-chloroacetaldehyde, thus generating Breslow intermediate [55], which decomposes to Oazolium enolate. Azolium enolate BF4 Bn 8 O O O reacts with 82%; the drazomethine imine in an addition-cyclization sequence, affording the final = 8:1, 99% ee 84%; dr = 5:1, 98% ee 85%; dr = 4:1, >99% ee precat-C14 products 105 [56]. An organocatalyzed inverse electron demand 1,3-dipolar cycloaddition of C,N-cyclic azomethine Scheme 33.33. N-Heterocyclic ofα-chloroaldehydes α-chloroaldehydes C,N-cyclic Scheme N-Heterocycliccarbene-catalyzed carbene-catalyzed [3+2] [3+2] cycloaddition cycloaddition of toto C,N-cyclic imines 106 with imines. azlactones 107 has been established by Su and co-workers employing noncovalent azomethine azomethine imines. quinidine-derived bifunctional thiourea organocatalyst C15. The initial tetracyclic intermediates 108 are unstable and rearrange into the final products 109. Products 109 were obtained in high yields (85–99%) An organocatalyzed inverse electron demand 1,3-dipolar cycloaddition of C,N-cyclic azomethine with excellent stereoselectivity (88–98% ee,established dr ≥ 14:1). by In general, azlactonesemploying prepared from different imines 106 with azlactones 107 has been Su and co-workers noncovalent amino acids were very well tolerated, as well as azlactonesC15. containing diverse (hetero)aryl substituents quinidine-derived bifunctional thiourea organocatalyst The initial tetracyclic intermediates 108 in the C2-position. Azomethine imines with different substituents on the aromatic ring and various are unstable and rearrange into the final products 109. Products 109 were obtained in high yields substituents at the 4-position of the phenyl ring ofee, the protecting groupprepared were very well (85–99%) with excellent stereoselectivity (88–98% drarylsulfonyl ≥ 14:1). In general, azlactones from compatible the developed protocol (Schemeas34) [57]. different with amino acids were very well tolerated, well as azlactones containing diverse (hetero)aryl substituents in the C2-position. Azomethine imines with different substituents on the aromatic ring and various substituents at the 4-position of the phenyl ring of the arylsulfonyl protecting group were very well compatible with the developed protocol (Scheme 34) [57]. Zhu et al. developed an inverse electron demand cycloaddition between C,N-cyclic azomethine imines and electron-rich enecarbamates applying chiral phosphoric acids as organocatalysts. For the cycloaddition of benzyl N-vinyl carbamate (111) to azomethine imines 110 (containing both electron-donating and electron-withdrawing substituents, irrespective of their position on the aromatic ring), phosphoric acid C16 turned out to be the optimal catalyst, yielding the corresponding products

H (2 equiv.) 104 Cl precat. C14 (20 mol%) DIPEA (2 equiv.) toluene, 4 Å MS, 40 °C

R2

O N

R N Molecules 2018, 23, 3 103 selected products:

R1

N

R R2

105

O N O

R1

17 examples 65-93% yield 90-99% ee 3:1 to 8:1 dr 25 of 31 R = H, Br; R1 = aryl 2 R = (hetero)aryl, alkyl

112 in good to high yields (68–83%) with excellent regio- and stereo-selectivity (dr ≥ 19:1, 88–98% ee). N On the other hand, cycloadditions to dipolarophiles 113 possessing an electron-rich (Z)-internal bond O N Mes N N N needed re-optimization. Bz Thus, the binol-based phosphoric acid C17 was found to furnish the desired N N N Bz N Bz cycloadducts 114 in high yields (89–95%), excellent diastereoselectivity (dr ≥ 19:1) and good to excellent Bn (80–98% 4 aromatic 8 patterns O O substitution O (substituents) onBF enantioselectivity ee). Again, different the O ring of azomethine imines well tolerated, β-substituent 82%; dr = 8:1, 99% ee110 were 84%; dr = 5:1, 98% ee whereas 85%; dr =increasing 4:1, >99% eethe size of the precat-C14 of the (Z)-enecarbamate resulted in deceleration of the reaction, which at room temperature led to decreased enantioselectivity. Finally, reaction with [(E)-prop-1-en-1-yl]carbamate the Scheme 33. N-Heterocyclic carbene-catalyzed [3+2]benzyl cycloaddition of α-chloroaldehydes to afforded C,N-cyclic corresponding product with significantly reduced stereoselectivity (Scheme 35) [58]. azomethine imines.

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25 of 30

Scheme 34.34. Inverse electron demand cycloaddition C,N-cyclic azomethine imines Scheme Inverse electron demand 1,3-dipolar 1,3-dipolar ofofC,N-cyclic azomethine imines yl]carbamate afforded the corresponding productcycloaddition with significantly reduced stereoselectivity to azlactones. to azlactones. (Scheme 35) [58].

Zhu et al. developed an inverse electron demand cycloaddition between C,N-cyclic azomethine imines and electron-rich enecarbamates applying chiral phosphoric acids as organocatalysts. For the cycloaddition of benzyl N-vinyl carbamate (111) to azomethine imines 110 (containing both electron-donating and electron-withdrawing substituents, irrespective of their position on the aromatic ring), phosphoric acid C16 turned out to be the optimal catalyst, yielding the corresponding products 112 in good to high yields (68–83%) with excellent regio- and stereo-selectivity (dr ≥ 19:1, 88–98% ee). On the other hand, cycloadditions to dipolarophiles 113 possessing an electron-rich (Z)-internal bond needed re-optimization. Thus, the binol-based phosphoric acid C17 was found to furnish the desired cycloadducts 114 in high yields (89–95%), excellent diastereoselectivity (dr ≥ 19:1) and good to excellent enantioselectivity (80–98% ee). Again, different substitution patterns (substituents) on the aromatic ring of azomethine imines 110 were well tolerated, whereas increasing the size of the β-substituent of the (Z)-enecarbamate resulted in deceleration of the reaction, which at room temperature led to decreased enantioselectivity. Finally, reaction with benzyl [(E)-prop-1-en-1Scheme Scheme 35. 35. Inverse Inverseelectron electron demand demand cycloaddition cycloaddition between between C,N-cyclic C,N-cyclic azomethine azomethine imines imines and and electron-rich enecarbamates. electron-rich enecarbamates.

Wang and co-workers developed an asymmetric synthesis of tetrahydroquinoline derivatives via a [3+2] cycloaddition controlled by dienamine catalysis. Thus, the reaction of α,β-unsaturated aldehydes 116, containing (hetero)aromatic substituents in the γ-position, with C,N-cyclic azomethine imines 115 (either unsubstituted or containing 5-, 6- and 7-Me/MeO/Br substituents) catalyzed by chiral prolinol silyl ether C18 [59] furnished the desired tricyclic systems 117 in high

Scheme 35. Inverse electron demand cycloaddition between C,N-cyclic azomethine imines and 26 of 31 electron-rich enecarbamates.

Molecules 2018, 23, 3

Wang asymmetric synthesis synthesisof oftetrahydroquinoline tetrahydroquinolinederivatives derivatives Wangand andco-workers co-workers developed developed an an asymmetric via a [3+2] cycloaddition controlled by dienamine catalysis. Thus, the reaction of α,β-unsaturated via a [3+2] cycloaddition controlled by dienamine catalysis. Thus, the reaction of α,β-unsaturated aldehydes 116, containing containing (hetero)aromatic substituents in the γ-position, withazomethine C,N-cyclic aldehydes 116, (hetero)aromatic substituents in the γ-position, with C,N-cyclic azomethine imines 115 (either unsubstituted or containing 5-, 6and 7-Me/MeO/Br substituents) imines 115 (either unsubstituted or containing 5-, 6- and 7-Me/MeO/Br substituents) catalyzed by catalyzed by chiral silyl C18 [59] furnished the desired tricyclic systems in high chiral prolinol silylprolinol ether C18 [59]ether furnished the desired tricyclic systems 117 in high yield117 (82–92%) yield (82–92%) with excellent stereoselectivity (dr > 25:1, 90–99% ee). This reaction proceeds via with excellent stereoselectivity (dr > 25:1, 90–99% ee). This reaction proceeds via 4,5-reactivity of 4,5-reactivity of dienamine reactive intermediates. In stark contrast, performed with dienamine reactive intermediates. In stark contrast, reactions performed withreactions aliphatic α,β-unsaturated aliphatic α,β-unsaturated aldehydes 116 with azomethine imines 115, performed under yielded identical aldehydes 116 with azomethine imines 115, performed under identical reaction conditions, reaction conditions, yielded different [3+2]-cycloaddition products 119. Inproceeds the lattervia case, the reaction different [3+2]-cycloaddition products 119. In the latter case, the reaction 3,4-reactivity proceeds via 3,4-reactivity the iminium Products ion reactive 119 were of the iminium ion reactiveofintermediates. 119 intermediates. were formed inProducts 79–83% yields, dr > formed 25:1 andin 79–83% dr > 25:1 and 80–94% ee (Scheme 36) [60]. 80–94%yields, ee (Scheme 36) [60]. O

1) R1

(1.5 equiv.) 118

N N Arl

R1

4 examples 79-83% yield 80-94% ee dr >25:1

cat. C18 (20 mol%), CH2Cl2 2,4-DNBA (20 mol%) -20 °C, 12 h N

2) NaBH4, MeOH R=H

119

example

R

(1.5 equiv.) 116

cat. C18 (20 mol%), CH2Cl2 R 2,4-DNBA (20 mol%) -20 °C, 12 h

HO

O

1) R1

N

Arl

115

HO example

F3C CF3

HO

R = alkyl 5

N N Bz

81%; dr >25:1, 88% ee

N H

OSiMe3 S CF3

F3C

C18

R1

N N Arl

2) NaBH4, MeOH

N N Bz

HO 84%; dr >25:1, >99% ee

117

17 examples 82-92% yield 90-99% ee dr >25:1 R = H, Me, OMe, Br R1 = (hetero)aryl Arl = (substituted)benzoyl

Scheme to C,N-cyclic C,N-cyclic azomethine azomethineimines, imines, Scheme36. 36. [3+2] [3+2]Cycloaddition Cycloaddition of of α,β-unsaturated α,β-unsaturated aldehydes aldehydes to controlled controlledby byiminium iminiumcatalysis. catalysis.

Maruoka and co-workers developed an organocatalyzed inverse electron demand cycloaddition Maruoka and co-workers developed an organocatalyzed inverse electron demand cycloaddition of C,N-cyclic azomethine imines to electron-rich vinyl ether and vinylogous hydrazone catalyzed by of C,N-cyclic azomethine imines to electron-rich vinyl ether and vinylogous hydrazone catalyzed by axially chiral dicarboxylic acids. Thus, under optimized reaction conditions (organocatalyst C19), azomethine imines 120, bearing either electron-rich or electron-deficient substituents, reacted with tert-butyl vinyl ether (121) to furnish the expected cycloadducts 122 in excellent yields (90–99%) and stereoselectivities (92–97% ee, exo/endo > 95:5). Reactions of azomethine imines 120 with acrolein-derived vinylogous hydrazone 123 needed reoptimization of the reaction conditions (organocatalyst C20). The corresponding cycloadducts 124 were formed in excellent yields (94–99%) and high enantioselectivity (65–92% ee), albeit with modest diastereoselectivity (exo/endo = 2.8:1–6.7:1). The reaction with methacrolein-derived α-substituted vinylogous hydrazone generated preferentially the endo-diastereomer (exo/endo = 1.0:2.4) with moderate enantioselectivity (68% ee), while β-substituted hydrazone derived from crotonaldehyde failed to give the desired product (Scheme 37) [61].

acrolein-derived vinylogous hydrazone 123 needed reoptimization of the reaction conditions (organocatalyst C20). The corresponding cycloadducts 124 were formed in excellent yields (94–99%) and high enantioselectivity (65–92% ee), albeit with modest diastereoselectivity (exo/endo = 2.8:1–6.7:1). The reaction with methacrolein-derived α-substituted vinylogous hydrazone generated preferentially the endo-diastereomer (exo/endo = 1.0:2.4) with moderate enantioselectivity (68% ee), while β-substituted Molecules 2018, 23, 3 27 of 31 hydrazone derived from crotonaldehyde failed to give the desired product (Scheme 37) [61].

Scheme Scheme 37. 37. Organocatalyzed Organocatalyzed inverse inverse electron electron demand demand cycloaddition cycloaddition of of C,N-cyclic C,N-cyclic azomethine azomethine imines imines to vinyl ether ether and and vinylogous vinylogous hydrazone. hydrazone. to electron-rich electron-rich vinyl

4. 4. Conclusions Conclusions and and Outlook Outlook Since the seminal seminal papers papersof ofKobayashi Kobayashi[29] [29]and andFu Fu[13] [13]over over3030asymmetric asymmetric [3+2] cycloadditions Since the [3+2] cycloadditions of of azomethine imines have been reported. Asymmetric cycloadditions to alkynes are to limited to azomethine imines have been reported. Asymmetric cycloadditions to alkynes are limited terminal terminal and the use of chiralcatalysts Cu(I)-based catalysts [11]. The of regioselectivity acetylenesacetylenes and the use of chiral Cu(I)-based [11]. The regioselectivity cycloadditions of is cycloadditions is invertible by the use of Ag(I) catalysts. Although applicability of Cu(II)-based invertible by the use of Ag(I) catalysts. Although applicability of Cu(II)-based catalyst has been catalyst has been [24], asymmetric cycloadditions internal alkynes are Therefore, still very demonstrated [24],demonstrated asymmetric cycloadditions to internal alkynestoare still very scarce. scarce. Therefore, the development of asymmetric catalysts that would enable the enantioselective the development of asymmetric catalysts that would enable the enantioselective and regioselective and regioselective preparation of cycloadducts from non-symmetrical acetylenes represents a preparation of cycloadducts from non-symmetrical acetylenes represents a synthetic challenge to be met. synthetic challenge to be met. This is of particular importance, because such asymmetric reactions This is of particular importance, because such asymmetric reactions would allow for the preparation of would allow for the preparation of analogues of Eli-Lilly’s γ-lactam antibiotics. On the other hand, analogues of Eli-Lilly’s γ-lactam antibiotics. On the other hand, the majority of catalytic asymmetric [3+2] the majority of catalytic asymmetric [3+2] cycloadditions of azomethine imines to alkenes have been cycloadditions of azomethine imines to alkenes have been performed using various organocatalysts, performed using various organocatalysts, although examples of transition-metal-catalyzed reactions although examples of transition-metal-catalyzed reactions have also been reported [11,37,38,57]. The use have also been reported [11,37,38,57]. The use of other dipolarophiles, such as cumulenes, imines, of other dipolarophiles, such as cumulenes, imines, thiones, and nitriles, is another unexplored field of thiones, and nitriles, is another unexplored field of asymmetric cycloadditions of azomethine imines. asymmetric cycloadditions of azomethine imines. So far, only reactions with allenoates [62], ketenes [51] So far, only reactions with allenoates, [62] ketenes, [51] and nitriles [52] have been reported. and nitriles [52] have been reported. In conclusion, the number of representative examples of asymmetric [3+2] cycloadditions of azometnine imines to various types of dipolarophiles is currently sufficient to support viability and broad scope of these reactions. However, as this research topic is now at the end if its infancy period it offers interesting and attractive challenges to synthetic chemists. Acknowledgments: The authors acknowledge the financial support from the Slovenian Research Agency (research core funding No. P1-0179). B.S. acknowledges Sultan Qaboos University, Sultanate of Oman, for the generous position of visiting professorship. We thank Helena Brodnik Žugelj for technical support in preparation of the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

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