obc 1 , 3-Dipolar cycloadditions of azomethine imines

Azomethine imines are considered 1,3-dipoles of the aza-allyl type which are transient intermediates and should be generated in situ but can also be stable and isolable compounds. They react with electron-rich and electron-poor olefins as well as with acetylenic compounds and allenoates mainly by a [3 + 2] cycloaddition but they can also take part in [3 + 3], [4 + 3], [3 + 2 + 2] and [5 + 3] with different dipolarophiles. These 1,3-dipolar cycloadditions (1,3-DC) can be performed not only under thermal or microwave conditions but also using metalloand organocatalytic systems. In recent years enantiocatalyzed 1,3-dipolar cycloadditions have been extensively considered and applied to the synthesis of a great variety of dinitrogenated heterocycles with biological activity. Acyclic azomethine imines derived from mono and disubstituted hydrazones could be generated by prototropy under heating or by using Lewis or Brønsted acids to give, after [3 + 2] cycloadditions, pyrazolidines and pyrazolines. Cyclic azomethine imines, incorporating a C–N bond in a ring, such as isoquinolinium imides are the most widely used dipoles in normal and inverse-electron demand 1,3-DC allowing the synthesis of tetrahydro-, dihydroand unsaturated pyrazolo[1,5-a]isoquinolines in racemic and enantioenriched forms with interesting biological activity. Pyridinium and quinolinium imides give the corresponding pyrazolopyridines and indazolo[3,2-a]isoquinolines, respectively. In the case of cyclic azomethine imines with an N–N bond incorporated into a ring, N-alkylidene-3-oxo-pyrazolidinium ylides are the most popular stable and isolated dipoles able to form dinitrogen-fused saturated and unsaturated pyrazolopyrazolones as racemic or enantiomerically enriched compounds present in many pharmaceuticals, agrochemicals and other useful chemicals.


Acyclic azomethine imines
These types of dipoles have been postulated as intermediates in [3 + 2] cycloaddition reactions and are derived from hydrazones and carbazates (Scheme 1) leading to pyrazolines and pyrazolidines, and their derivatives.The corresponding precursors can be prepared from monosubstituted and 1,2-disubstituted hydrazines.

Monosubstituted hydrazines
7][18][19] Normally, electron-deficient dipolarophiles are used, but also simple alkenes in the case of intramolecular processes. 10A recent intramolecular process has been applied to the synthesis of androstenoarylpyrazolines 3 using BF 3 •OEt 2 as a Lewis acid, previously used for intermolecular cycloadditions (Scheme 2). 20The reaction takes place stereoselectively at 0 °C in high yields from the corresponding hydrazones 1 by a BF 3 -promoted formation of intermediate azomethine imines 2.
Three-component or consecutive intermolecular 1,3-DC of azomethine imines with α-oxoketenes 5 has been performed under thermal conditions.Both hydrazones and dipolarophiles are generated in situ, affording the corresponding pyrazolidinones 6 in a stereoselective manner (Scheme 3).21a Intermediate dipolarophiles 5 are generated from 2-diazo-1,3-diones 4 under microwave heating.When isatins are used as a carbonyl precursor the corresponding spirooxindoles 7 are obtained in a stereoselective manner (Scheme 3).Recently, a microwave-assisted intramolecular 1,3-DC of azomethine imines, in situ generated from indole-2-carboxaldehydes 8 and phenylhydrazine, has been described.This process takes place in the presence of HCl as an additive in ethanol, providing [a]-annelated pyrazolopyrroloindoles 9 in a regio-and stereoselective manner (Scheme 4).21b The reaction in the presence of other additives such as AcOH, BF 3 •OEt 2 or iodine gave either lower yields or no reaction.
The stereocontrolled synthesis of cis-cyclopentanopyrazolidines has been carried out from the α-methoxy-α,β-unsaturated ester 10 bearing an α-keto ester at the end of the chain (Scheme 5). 22In the case when thiosemicarbazide is used, the intermediate azomethine imine is generated under heating, giving the tricyclic thiohydantoin 11.N-Acyl or N-alkoxycarbonyl hydrazines gave, under thermal conditions, the corresponding cycloadducts 12 in good yields (Scheme 5).This approach was previously described by the same group to prepare potential precursors of palau'amine (Scheme 6). 23he high stereoselectivity observed in these cycloadditions can be explained by the formation of a chair-like transition state 15, which favors the overlap between the π-orbitals of the dipole and dipolarophile (Scheme 7).
Alternatively, it was possible to prepare the corresponding hydrazones 16 from 10 using a catalytic amount of HCl in  ethanol at room temperature, and then the 1,3-DC takes place at ambient temperature in the presence of one equivalent of FeCl 3 in dichloromethane, giving products 12 in good yields (Scheme 8). 22e first example of a catalytic asymmetric intramolecular [3 + 2] cycloaddition of hydrazones with olefins was performed in the presence of a chiral zirconium catalyst. 24Different 4-nitrobenzoylhydrazones 17 gave trans-pyrazolidines 18 with high diastereo-and enantioselectivity in the presence of Zr(Oi-Pr) 4 (10 mol%) and the Binol derivative 19 at room temperature in dichloromethane (Scheme 9).
A chiral silicon Lewis acid has been used in the intermolecular 1,3-DC of benzoylhydrazones 20 with vinyl ethers 23 (Scheme 11). 26The process needs 1.5 equivalents of compound 25, derived from pseudoephedrine, to take place, giving the corresponding pyrazolidines 24 at room temperature in high trans-diastereoselectivity and excellent ee.The intermediacy of complex 26, isolated and characterized by X-ray crystallography, 27 explains the approach of the ether by the Si face of the hydrazone (27).Samarium diiodide reduction of pyrazolidines 22 gave the corresponding anti-1,3-diamines.
Hydrazones derived from ethyl glyoxylate and aliphatic or aromatic aldehydes react with cyclopentadiene (28) at room temperature in the presence of TMSOTf (10 mol%) as a catalyst.The enantiocatalytic process was next assayed with an in situ generated Binol-phosphate derived silicon Lewis acid from 30 and Ph 2 SiCl 2 (Scheme 12). 28Cycloadduct 29 was obtained in a high syn/anti diastereomeric ratio (95 : 5) and up to 89% ee, but in a low yield (13%).
The mechanism of N-triflylphosphoramide-catalyzed asymmetric [3 + 2] cycloadditions was explored using DFT (MO6-2X) calculations. 31Protonation of hydrazones 20 by these Brønsted acids produces ion-pair complexes, which are more reactive than those formed from azomethine imines by 1,2-prototropy of the hydrazone through the transition state I (Scheme 15).These ion-pair hydrazonium-phosphoramide anions are reactive in [3 + + 2] cycloadditions and only small distortions 32 of them are required in the transition state II giving in this case the cis-pyrazolidines 24.The origin of enantioselectivities was also explained.

1,2-Disubstituted hydrazines
The condensation of 1,2-disubstituted hydrazines and N-substituted carbazates or hydrazides with carbonyl compounds generates in situ directly the corresponding acyclic azomethine imines, 33 which can be trapped in situ by dipolarophiles through an inter-or intramolecular [3 + 2] cycloaddition. 10In this case, they react preferentially with electron-deficient dipolarophiles under thermal conditions.
Intermolecular 1,3-DC of azomethine imines 37, generated in situ from aldehydes and N 1 -alkyl-N 2 -acyl hydrazines 36, takes place with electron-deficient dipolarophiles under refluxing toluene using a Dean-Stark trap (Scheme 16). 34The corresponding 3,4-disubstituted pyrazolidines 38-40, derived from benzaldehyde, were obtained as a mixture of cis/trans diastereomers in low yields.The first and only example of an enantiocatalytic threecomponent 1,3-DC of aldehydes, hydrazides and alkynes was performed using a PyBox 45/Cu(I) complex as a catalyst and a chiral binaphthyl dicarboxylic acid 46 as a cocatalyst (Scheme 17). 35N 1 -Benzylbenzoylhydrazide 41 was used for the generation of the corresponding azomethine imine intermediates 42, which react with terminal alkynes affording pyrazolines 43 in a chemoselective manner (>95 : 5); only small amounts of compounds 44 resulting from the nucleophilic addition of copper acetylide to 42 were also obtained.Aromatic and aliphatic aldehydes can be used in the presence of 4 Å MS to eliminate the water formed during the condensation step.Moreover, aromatic and aliphatic alkynes can be used as well, affording the corresponding pyrazolines 43 in high enantioselectivities (Scheme 17).
A representative 3,4-disubstituted pyrazoline 43a (with R 1 = R 2 = Ph) was further transformed into different heterocyclic compounds 47 and 48, as well as the diamine 49 by reduction of the last one with samarium diiodide (Scheme 18).cyclic azomethine imines of the type 51 can be prepared from the corresponding aldehydes 50 bearing a halogen atom at the γor δ-position.A cascade of cyclization and 1,3-DC gave all-cis tricyclic compounds 52 in high yields (Scheme 19). 36zomethine imines 54 can be prepared by MW heating of benzoylhydrazides 53 bearing an alkyne in the chain through an intramolecular hydroamination reaction (Scheme 20). 37The reactivity of one example 54a with methyl acetylenedicarboxylate gave the fused pyrazoline 55 in a moderate yield.

Isoquinolinium-N-aryl imides
N-Iminoisoquinolin-2-ium ylides 57 are the most recently used cyclic azomethine imines bearing a C-N bond in the ring. 10hey have been mainly used in metal-catalyzed [3 + 2] cycloadditions not only with electron-deficient dipolarophiles but also with electron-rich alkenes.In addition, organocatalyzed processes, including asymmetric ones, have also been studied.A direct method to access this type of intermediate is the cascade cyclization reaction of the aldehyde 56 with hydrazines to afford azomethine imines 57, 38 which can be trapped in situ with N-phenylmaleimide (NPM) (Scheme 21). 36Cycloadducts 58 were obtained as mixtures of endo : exo diastereomers (2 : 1-3 : 1).The reaction of the aldehyde 56 with benzylhydrazine in the presence of dimethyl maleate gave the cycloadduct 59 with all-cis relative configuration.The same 3 : 1 mixture of cycloadducts 60 was obtained by a reaction of the aldehyde 56 with hydrazine hydrate in the presence of dimethyl maleate or fumarate.In the case of dimethyl acetylenedicarboxylate a 5 : 1 mixture of diastereomeric fused pyrazolines 61 was isolated under toluene reflux (Scheme 21).
Asymmetric inverse-electron-demand 1,3-DC of C,N-cyclic azomethine imines 57 with tert-butyl vinyl ether could be performed firstly with the chiral dicarboxylic acid 74 as a Brønsted acid (Scheme 25). 40The corresponding adducts 72 were obtained with different regioselectivities by interaction of the LUMO of the dipole with the HOMO of the alkene.Moreover, exo-cycloadducts 72 were obtained in high yields and enantioselectivities. Vinylogous aza-enamines gave mainly exo-cycloadducts 73 in high yields and good enantioselectivities.The hydrazone unit of compound 73 (with R 1 = Br, R 2 = H) was transformed into the corresponding cyano group by magnesium monoperoxyphthalate in 80% yield.
The thermal [3 + 2] cycloaddition reaction of azomethine imines 57 with α-substituted allenoates 75 occurs under mild reaction conditions to provide adducts 76 as a mixture of diastereomers in a highly regioselective manner (Scheme 26). 41he major endo-diastereomer could be separated and isolated by flash chromatography or recrystallization.In the case of γ-substituted allenoates 77 the 1,3-DC takes place in lower yields giving mainly exo-cycloadducts 78.
The same group performed an enantioselective 1,3-DC using an intermediate dienamine 57 and enals (R 2 = aryl), and a silylated prolinol 102 as an organocatalyst.By the subsequent reduction of the aldehyde functionality the corresponding alcohols 100 were isolated in good yields, diastereo-and enantioselectivities (Scheme 34). 51However, when aliphatic enals (R 2 = alkyl) were used, regioisomeric derivatives 101 were obtained according to the formation of α,β-unsaturated iminium ions as intermediates.Similar iminium-dienamine reactivity has been reported independently with prolinols 99 and 102 by Alemán and Fraile. 52 new type of 1,3-DC has been recently performed with azomethine imines 57 and N-acyliminium ions 105 affording cycloadducts 103 (Scheme 35). 53The chiral Lewis base 104 acted as an organocatalyst forming the corresponding activated intermediates 105 by reaction with mixed anhydrides.
Another family of isoquinolinium ylides are the corresponding unsaturated systems which should be prepared in situ When the former process was carried out with 2-alkynyl benzaldehydes 110, p-toluenesulfonyl hydrazide and unsaturated carbonyl compounds in the presence of bromine or iodine, the multicomponent reaction afforded isoquinolines 108 with alkyl groups at the 1 and 5 positions. 55A similar process has been performed using AgOTf as a catalyst, which after a 6-endo-dig cyclization produced the isoquinolinium-2-yl imide 111.The three-component reaction between 2-alkynyl benzaldehydes 110, tosyl hydrazide and α,β-unsaturated carbonyl compounds gave functionalized H-pyrazolo[5,1-a]isoquinoline-1-carboxylates 112 (Scheme 37). 56hen an acetylenic dipolarophile is used, only a halogen or silver triflate promotes the [3 + 2] cycloaddition.Thus, N′-(2alkynylbenzylidene)hydrazides 106 react with acetylenes either catalyzed by silver triflate or promoted by bromine or iodine in the presence of NaOAc.In the case of dimethyl acetylenedicarboxylate (DMAD) in the presence of either AgOTf or bromine the fused dihydroisoquinolines undergo a rearrangement involving an N-N homolysis to give compounds 113 or 114, respectively (Scheme 38). 57However, in the presence of iodine the fused 1,2-dihydroisoquinolines 115 are obtained.
An alternative route to pyrazoloisoquinolines 116 (X = H) used bromoalkynes as dipolarophiles.In this case, the alkynylation of 111, formed by the silver-catalyzed cyclization of 106, takes place by a C-H activation.The bromoalkyne is activated via oxidative addition to CuI, which through a concerted metallation-deprotonation process would give intermediates 122.After reductive elimination, intermediates 123 undergo a 5-endo-dig-cyclization to give 124, followed by subsequent aromatization to form the final H-pyrazolo[5,1-a]isoquinolines 116 (Scheme 41). 61-Trifluoromethylpyrazolo   62 In the case of the silver triflate-catalyzed cyclization of compounds 106 in the presence of the in situ generated pyridyne 127 from 126, the corresponding regioisomeric H-pyrazolo[5,1-a]isoquinolines 128 and 129 were prepared in modest yields (Scheme 43).Recently, the threecomponent reaction of aldehydes 110, sulfonyl hydrazide and benzyne, affording the corresponding H-pyrazolo[5,1-a]isoquinolines in very good yields (83-98%), has been described.63c Propargyl amines afford [3 + 2] cycloadditions with N-iminoisoquinolinium ylides 111 generated in situ from hydrazides 106, to give the corresponding H-pyrazolo[5,1-a]isoquinolines 130 bearing an aminomethyl substituent at the 5-position (Scheme 44).64 Silyl enol ethers have been used as dipolarophiles with N-iminoisoquinolinium ylides 111, generated in situ from hydrazides 106.Thus, the tandem process affords the 5,6-disubstituted H-pyrazolo[5,1-a]isoquinolines 131 in good yields (Scheme 45).65 The multicomponent reaction of 2-alkynyl benzaldehydes 110, tosyl hydrazide, methanol and α,β-unsaturated aldehydes catalyzed by silver triflate gave H-pyrazolo[5,1-a]isoquinolines 132 with excellent regioselectivity (Scheme 46).66 Preliminary biological assays of these compounds show their promising activity as CDC25B, TC-PTP, and PTP1B Similarly, the bromine-promoted cyclization of hydrazides 106 afforded the brominated N-iminoisoquinolinium ylides 107, which also react with α,β-unsaturated aldehydes in the presence of methanol to give the fused brominated isoquinolines 133 (Scheme 47).67 Based on the former methods for the in situ generation of isoquinolinium-2-yl imides 134, these azomethine imines have been recently prepared and isolated by the one-pot reaction of 2-alkynyl benzaldehydes 110, hydrazides and final silver triflate catalyzed cyclization (Scheme 48).68 A silver-catalyzed process involving 2-alkynyl benzaldehydes 110, tosyl hydrazide and carbonyl compounds is a simple and direct strategy for the synthesis of H-pyrazolo[5,1-a]isoquinolines 131 (Scheme 49).69 Alternatively, by using primary alcohols and hydrazides 106 instead of aldehydes 110, the presence of the Dess-Martin reagent (DMP) as an oxidant is compulsory to afford 6-monosubstituted H-pyrazolo[5,1-a]isoquinolines 135 (Scheme 50).70a,b The same transformation can be performed by a silver triflate-palladium chloride cooperative catalysis.The presence of oxygen promotes the palladium-catalyzed oxidation of the alcohol to the corresponding aldehyde or ketone.The in situ generated enolate attacks the isoquinolinium-2-yl imide, followed by condensation and aromatization to afford products 135 in 47-90% yield.70c Silver triflate-copper(II) acetate cooperative catalysis has been used for the cyclization/[3 + 2] cycloaddition of N′-(2-alkynylbenzylidene) hydrazides 106 with allenoates 77 in the presence of dioxygen to afford H-pyrazolo[5,1-a]isoquinolines 136 (Scheme 51).71a The proposed mechanism involves a peroxycopper(III) intermediate 138, which evolves to 139 and, after elimination of Cu(II)-OH, generates a carbonyl compound 140.Final aromatization yielded products 136 in moderate to good yields.When this reaction was performed with Ph 3 P as a catalyst the corresponding isoquinolines 136 were obtained with an R 3 CH 2 group instead of the ketone functionality.71b Silver-rhodium(I) cooperative catalysis has been used for the reaction of hydrazides 106 with cycloprop-2-ene-1,1-dicarboxylate 72 or with 2-vinyloxirane 73  copper(II)-catalyzed oxidation of an aliphatic C-H bond of the tertiary amine in air (Scheme 53).74 A related process using palladium dibromide as a cocatalyst gave isoquinolines 131, which has been performed starting from the hydrazides 106 instead of aldehydes 110 (Scheme 53).75a The same transformation has been previously performed using Fe 2 (CO) 9 as a cocatalyst (5 mol%) and tert-butyl hydroperoxide (3 equiv.)affording products 135 in 46-83% yields.75b Methylene indolinones have been used as dipolarophiles for the diastereoselective construction of fused H-pyrazolo-[3,2-a]isoquinolines 143 as a mixture of diastereomers (Scheme 54).76 In this case, the Wu et al. 56 methodology was applied to a process starting from N′-(alkynylbenzylidene) hydrazides 106 under silver-catalyzed 6-endo cyclization to generate the N-iminoisoquinolinium ylide 111.

Pyridinium and quinolinium imides
Pyridinium imides 147, also called N-iminopyridinium ylides or pyridin-N-imines, are masked cyclic azomethine imines incorporating C-N into the ring, which react mainly with acetylenic dipolarophiles. 10They are unstable and have to be generated in situ from N-aminopyridinium halides and since the several types of substituted pyridines, quinolines and isoquinolines. 82y using alkynes as dipolarophiles pyrazolopyridines can be prepared 83 which exhibit a wide range of biological activities including dopamine D3 receptor antagonist and partial agonist, 84 dopamine D4 antagonist, 85 as well as adenosine A1 receptor antagonist, 86 and antiherpetic 87 and antiallergenic 88 properties.Consequently, they are applicable in the treatment of neurological disorders such as schizophrenia, attentiondeficit disorder, and Parkinson's disease.
Polystyrene-bound alkenes 152 have been used for the solid-phase synthesis of pyrazolopyridines 153 by in situ generation of pyridinium imides 147 from N-aminopyridinium salts 151 followed by TFA cleavage (Scheme 57).Alternatively, by using NaOMe in THF/MeOH the corresponding methyl esters can be isolated. 89n the case when arynes are used as dipolarophiles and pyridinium imides 148 with different electron-withdrawing groups on the imide nitrogen, it was found that the pyrido[1,2-b]indazoles 155 are obtained in high yields (Scheme 58) using the tosyl derivatives 154, whereas the benzoyl, pivaloyl, benzyloxycarbonyl, and tert-butyloxycarbonyl ones gave lower results. 90This methodology has been also used with N-tosylisoquinolinium imides to afford indazolo [3,2-a]isoquinolines.

N-Alkylidene-3-oxopyrazolidin-1-ium-2-ides
Azomethine imines 166, derived from pyrazolidin-3-ones 165, are usually prepared by condensation with carbonyl compounds. 10They can be isolated, especially in the case of aro-matic aldehydes, by heating in anhydrous methanol catalyzed by means of trifluoroacetic acid (Scheme 63). 10,94 new route to azomethine imines has recently been described using hydrazones derived from ketones and N-alkoxycarbonylhydrazines 167 and alkenes (Scheme 64). 95nder microwave assisted heating at 150 °C the intermediate isocyanate is formed and through a concerted alkene aminocarbonylation pathway the corresponding azomethine imines 168 are produced in good yields.Several types of acyclic and cyclic alkenes can be used, including vinyl ethers and enamides.With terminal alkenes (R 4 = H) a total regioselectivity was observed.
4.1.2Copper-catalyzed cycloadditions.In 2003 Fu et al. described for the first time that CuI (5 mol%) catalyzed the cycloaddition of the azomethine imine 166 (R 1 = Ph) with ethyl acrylate at room temperature in the presence of 0.5 equivalent of Cy 2 NMe in dichloromethane, giving regioselectively the corresponding cycloadduct in 88% yield.After establishing these reaction conditions, different chiral ligands were assayed, the phosphaferrocene oxazoline 193 giving the highest enantioselectivity for cycloadducts 192 in the reaction with terminal alkynes (Scheme 72). 112The same reaction conditions have been applied to the kinetic resolution of racemic substituted azomethine imines 166 (Scheme 73). 113he [3 + 2] cycloaddition of azomethine imines 169 with the N-acryloylpyrazolidinone 194 catalyzed by the chiral complex Cu(OTf ) 2 •bisoxazoline 196 gave regio-and diastereoselectively exo-cycloadducts 195 in good yields (Scheme 74). 114hese processes have been performed only with pyrazolidinone 194, which is able to be chelated by the copper complex and different C5-substituted azomethine imines.
By using propiolylpyrazoles 202 as acetylenic dipolarophiles, terminal and internal alkynes gave very good enantio- selection in the [3 + 2] cycloaddition of azomethine imines 166 catalyzed by a chiral π-cation catalyst 204 (Scheme 78). 119The main difference of this type of copper catalyst compared to the previous ones is that the copper(I) acetylide-mediated cycloaddition of azomethine imines with terminal alkynes is not operating (Method A).Instead, a Lewis acid-catalyzed cyclo-addition by coordination with the carbonyl group (Method B) takes place (Scheme 79).
The racemic copper-catalyzed [3 + 2] cycloaddition has been performed not only with CuI but also with Cu(I) zeolites as the heterogeneous ligand-free catalysts. 120,121They are easy to be removed by simple filtration and can be recycled up to six times without decreasing the efficiency.Heterogeneous supported copper hydroxide Cu(OH) x /Al 2 O 3 has also been used as an efficient reusable catalyst. 122he catalytic asymmetric cross-1,3-DC of two different dipoles, azomethine ylides generated from iminoesters 205 and imines 166, gave highly substituted 1,2,4-triazinanes with total diastereo-and enantioselectivity.(S, S P )-t-Bu-Phosferrox 207 as a ligand and AgOAc or Cu(MeCN)BF 4 salts have been assayed as chiral catalysts for this [3 + 3] cycloaddition.The best results were obtained with the Cu complex giving the cycloadducts 206 in high yields, diastereo-(>20 : 1) and enantioselectivities (Scheme 80). 123ndependently, a similar [3 + 3] cycloaddition has been performed using the ferrocenyl P,N-chiral ligand 208 and the Cu(MeCN) 4 ClO 4 salt as a catalyst.This process takes place giving products 206 with good yields (71-89%), diastereo-(>20 : 1) and enantioselectivities (50-96%). 124Isocyanides 209 and azomethine imines 169 gave a [3 + 3]  cycloaddition to give pyrazole[1,2-a]triazin-8(4H)-ones 210 (Scheme 81). 125The process takes place with high stereocontrol using CuI as a catalyst and DBU as a base at room temperature.Silver salts and other copper salts provided lower yield than CuI.The proposed mechanism involves the formation of the α-cuprioisocyanide followed by nucleophilic addition to the imine and final insertion of the isonitrile 211 into the N-Cu bond to give the imidoyl-copper intermediate 212 and final protonation.
Recently, a Ni(II)-catalyzed enantioselective [3 + 2] cycloaddition of azomethine imine 166 and alkylidene malonates as dipolarophiles has been described.In this case trans-pyrazolone derivatives 216 have been obtained with total diastereoselectivity and good enantioselectivities by using a chiral N,N′dioxide 217 as the chiral ligand (Scheme 83). 127The reaction also proceeds by a dipole-HOMO/dipolarophiles-LUMO inter- action, the Ni-complex acting as a chiral Lewis acid coordinating the two carbonyl groups of the alkylidene malonate.
The reaction proceeds at 80 °C in acetonitrile affording only the corresponding trans-pyrazolinonepyrazolidines 227 (Scheme 87). 132,133nder similar reaction conditions homoallylic alcohols have been used for this type of [3 + 2] cycloaddition.In this case only 20 mol% of DIPT, one equivalent of MgBr 2 and 1.5 equivalents of n-BuMgCl were used providing also the transcycloadducts 230 in 23-93% yield and 63-93% ee. 133,134In the proposed transition state 229, the azomethine imine is coordinated to magnesium by the nitrogen and the carbonyl group to afford pyrazolidinones 230 (Scheme 88).The same group has developed a desymmetrization of 1,4-pentadien-3-ol by the asymmetric 1,3-DC of azomethine imines using magnesium diisopropyl tartrate as a chiral Lewis acid in up to 98% ee. 135oyle et al. have studied enol diazoacetate 162 as a dipolarophile for the [3 + 2] cycloaddition with azomethine imines 166 catalyzed by Sc(OTf ) 3 or In(OTf ) 3 as Lewis acids. 136The corresponding cycloadducts 232 are obtained diastereoselectively in good yields.Selective 1,2-C→C and N→C migrations catalyzed by rhodium(II) salts or CuPF 6 were observed to give six membered rings.However, using rhodium(II) acetate the corresponding [3 + 3] annulation products cis-231 were regioand diastereoselectively obtained (Scheme 89). 137The azomethine imine attacks the vinylogous position of the Rh(II)vinyl carbine 232 to give the intermediate 233, which after subsequent ring formation followed by extrusion of the catalyst gives the fused bicyclic pyrazolidinones 231.
When this reaction is catalyzed by N-heterocyclic carbenes, a highly stereoselective formal [3 + 3] cycloaddition takes place to provide pyridazinones 240 (Scheme 93). 141The addition of the N-mesitylbenzimidazolyl carbene, generated from the benzimidazolium iodide 242, by an addition/acylation sequence with 166 affords the final bicyclic heterocycles 240.
The enantioselective [3 + 2] cycloaddition of cyclic enones and azomethine imines 166 has been performed in the presence of the chiral primary amine 9-amino-9-deoxyepiquinine 244 and 2,4,6-triisopropylbenzenesulfonic acid (TIPBA) as a catalyst (Scheme 94). 142The corresponding tricyclic pyrazolidinones 243 were obtained in good yields, diastereo-and enantioselectivities.The Cinchona derived catalyst activates the enone forming a ketiminium cation and an additional hydrogen bonding between the OH and the CvO groups to produce the endo and Re-face selectivities in the final cycloadducts.
Another example of a base-catalyzed [3 + 3] cycloaddition of azomethine imines 166 takes place with 1,4-dithiane-2,5-diol 247.DABCO catalyzes this process (Scheme 96) in methanol giving products 248 resulting from the attack of the base to mercaptoacetaldehyde followed by addition to the azomethine imine and subsequent intramolecular cyclization, the diastereoselectivity being controlled by the anomeric effect. 144-Methyl and 5-phenyl substituted azomethines 166 gave the all cis-cycloadducts 248.
The reaction involving diethyl 2-vinylidene succinate 255 was more complicated giving mixtures of five-, six-, and sevenmembered rings either with tri-n-butyl-or trimethylphosphine (Scheme 100). 146It has been proposed that zwitterionic intermediates A and B gave the five-and the six-or seven-membered ring, respectively.
Chiral bis-phosphoric acid 272 has been used as the Brønsted acid catalyst for the 1,3-DC of alkylideindolinones 271 with azomethine imines 166 to afford spiro pyrazolidin-3,3′-oxindoles 273 (Scheme 106). 150By MS and DFT calculation experiments the best transition state has been established in which both the alkylideneindolines and the azomethine imines are hydrogen bound with the OH group of both phosphoric acid moieties.
The phosphoric acid 30 (Ar = 9-anthracenyl) has shown good diastereo-and moderate enantioselectivities in the organocatalyzed enantioselective inverse-electron-demanding 1,3-DC of azomethine imines 166 with o-hydroxy-α-methylstyrene 274.Thus, [3 + 2] cycloaddition takes place in 1,3difluorobenzene giving mainly cycloadducts 275 through a two-step mechanism.The presence of the hydroxy group at the ortho position is crucial for the reaction to occur.A dual activation mode by hydrogen bonding interaction between the two substrates and the catalyst together with the conjugative effect initiated by the o-hydroxy group played an essential role in the proposed transition state A (Scheme 107). 151

Conclusions
In the last 10 years, the chemistry of acyclic and especially cyclic azomethine imines has experienced a renaissance in synthesis of heterocycles of wide structural diversity, such as pyrazolidines, pyrazoloisoquinolines and pyrazolopyrazolones, among others.Their reactivity in 1,3-dipolar cycloadditions (1,3-DC) with a great variety of dipolarophiles in a highly regioand diastereoselective manner has found many applications in the synthesis of dinitrogen heterocycles.Depending on the dipolarophile partially or totally saturated heterocycles can be prepared generally by a [3 + 2] cycloaddition but also by higher order cycloadditions.Most of the methodologies recently studied are in the field of asymmetric synthesis using chiral Lewis bases and Brønsted acids as organocatalysts depending on the dipolarophile and metal complexes bearing chiral ligands.The study of asymmetric catalytic methods has just started and further synthetic applications to be developed in this field would be important in the near future.

Scheme 7 Scheme 6
Scheme 7 Proposed mechanism for the formation of cycloadducts 12.
Gold-catalyzed[3 + 3] cycloadditions of azomethine imines 166 and propargyl esters have been observed to proceed by a stepwise mechanism with a gold(III) carbenoid 221 as an intermediate.The reaction takes place in the presence of 5 mol% of picolinate-gold dichloride (159) as a catalyst affording adducts 220 with moderate to high diastereoselectivity (Scheme 85). 130N-Allenyl amides 222 underwent 1,3-DC of azomethine imines 166 under gold(I) catalysis to provide [3 + 2] cycloadducts 223 (Scheme 86). 131This process can occur through a gold allene intermediate, which can give another intermediate 224 by an outer-sphere nucleophilic addition.Subsequent intramolecular cycloaddition of 224 yielded the iminium intermediate 225, which after deauration gave the final cycloadduct 226.
In this case, a similar intermediate metal carbine 232 (Scheme 89) is trapped by another molecule of the diazoketone 234 to give diastereoselectively products 235 by means of the chiral dirhodium(II) carboxamidate 236.4.1.4Metal-free-catalyzed cycloadditions.Different types of Lewis bases such as amines, phosphines and Lewis and Brønsted acids have been used for the racemic and enantioselective 1,3-DC of azomethine imines with dipolarophiles.