Other 1,3-Dipolar Cycloadditions

3-dipolar cycloaddition of pyrazolidinone-based dipoles (azomethine imides) to terminal alkynes with electron-withdrawing groups, promoted by the dinuclear copper complex [Cu(p-OH)(tmen)]2Cl2 = 

Azomethine imines react with propiolates under copper catalysis to form N,N-bicyclic pyrazolidinone. Different catalysts have been used in this reaction Cul in the presence of A/ -methyldicyclohexylamine [103] copper(l)-exchanged zeolites [102,104] copper hydroxide catalyst, Cu(0H) /Al203 (Cu 1.5 mol%) [105] orthe efficient copper(I) acetate [106]. 

3-dipolar cycloadditions of diversely substituted nitrilimines with dipo-larophiles may form a variety of pyrazoles. In this way, the cycloadditions ofAf-[4-nitrophenyl]-C-[2-furyl] nitrilimine with styrene, 2-propyne-l-ol, or vinyl acetate in ethanol afforded the corresponding pyrazole products with complete regiose-lectivity and good yields [107]. 

The copper(I)-catalyzed 1,3-dipolar cycloaddition reaction between alkynes and nitrile oxides reported by Sharpless [108] and Hansen et al. [109] has made considerable progress in the synthesis of isoxazoles. This methodology enables the preparation of unsymmetrical 3,5-disubstituted isoxazoles with specific regioselectivity at satisfactory rates and yields. A large number of ort/zo-substituted arylboronic acids were evaluated for their ability to accelerate nitrile oxides [3-1-2] cycloaddition to alkynoic acids [110]. Copper-doped silica cuprous sulfate (CDSCS, 0.05 mol%) as a nanocatalyst and NaHCOj in a solution of z-PrOH/H20 (1 1, V/V) have been used in the reaction of diverse alkynes and in situ generated nitrile oxide [111]. 

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The first report on metal-catalyzed asymmetric azomethine ylide cycloaddition reactions appeared some years before this topic was described for other 1,3-dipolar cycloaddition reactions [86]. However, since then the activity in this area has been very limited in spite of the fact that azomethine ylides are often stabilized by metal salts as shown in Scheme 6.40. 

The ring-opening process leading to 164 (route a) is analogous to that which has been demonstrated to follow the cycloadditions of tosyl azide to certain enamines176. Similar results have been reported for the reaction of 2,3-diphenylcyclopropenone with 2-diazopropane177. Other 1,3-dipolar cycloadditions with thiirene dioxides could also be affected (see below). 

Other 1,3-dipolar cycloadditions of chiral azomethine ylides with Cgo (98) and reactions of chiral azomethine ylides derived from l-benzyl-4-phenyl-2-imidazoline with different electron-deficient alkenes have been performed (99). 

Many other 1,3-dipolar cycloadditions are known, amongst which is the addition of diazomethane (CH2N2). Expulsion of nitrogen from the adduct leads to the formation of a cyclopropane ring. Another way of achieving the same result involves the addition of a carbene such as the Simmons Smith reagent. This is generated from methylene iodide (CHjIj) and a zinc/copper couple. 

The experimentally observed regioselectivity of these and other 1,3-dipolar cycloadditions has, until recently, been a most difficult phenomenon to explain. 

As observed in other dipolar cycloadditions, there are three stereochemical issues that must be addressed (Scheme 2.3). These issues include the regioselec-tivity, the stereoselectivity, and the facial selectivity of the cycloaddition. The first two will be discussed in this section, while the latter will be discussed in Sections 2.3 and 2.4 as it relates to specihc examples. 

The reaction of the acid chloride phenylhydrazone (11) with base gives the nitrile-imine 1,3-dipolar compound (12) which reacts with potassium thiocyanate to give the A2-thiadiazo-line (13 Scheme 1). Thus the cycloaddition occurs at the C=S and not the C=N bond. This regioselectivity can be explained in terms of the frontier orbital treatment. Due to the electron rich nature of the thiocyanate anion, its reaction with (12) is expected to be controlled by the LUMO and HOMO of (12) and the thiocyanate respectively. As the HOMO of the thiocyanate anion has the larger orbital coefficient on the sulfur atom, it can be concluded that the larger orbital coefficient in the LUMO of (12) is on the carbon atom. This is also in agreement with other dipolar cycloadditions (82H( 19)57). 

Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

Cycloadditions. 1,3 Dipolar cycloadditions certainly have been the most important means of forming fluorinated five-membered rings Ruonnated substances, however, have also been used in other classic five-membered-nng-... 

In a more recent study on 1,3-dipolar cycloaddition reactions the use of succi-nimide instead of the oxazolidinone auxiliary was introduced (Scheme 6.19) [58]. The succinimide derivatives 24a,b are more reactive towards the 1,3-dipolar cycloaddition reaction with nitrone la and the reaction proceeds in the absence of a catalyst. In the presence of TiCl2-TADDOLate catalyst 23a (5 mol%) the reaction of la with 24a proceeds at -20 to -10 °C, and after conversion of the unstable succinimide adduct into the amide derivative, the corresponding product 25 was obtained in an endojexo ratio of <5 >95. Additionally, the enantioselectivity of the reaction of 72% ee is also an improvement compared to the analogous reaction of the oxazolidinone derivative 19. Similar improvements were obtained in reactions of other related nitrones with 24a and b. 

The above described approach was extended to include the 1,3-dipolar cycloaddition reaction of nitrones with allyl alcohol (Scheme 6.35) [78]. The zinc catalyst which is used in a stoichiometric amount is generated from allyl alcohol 45, Et2Zn, (R,J )-diisopropyltartrate (DIPT) and EtZnCl. Addition of the nitrone 52a leads to primarily tmns-53a which is obtained in a moderate yield, however, with high ee of up to 95%. Application of 52b as the nitrone in the reaction leads to higher yields of 53b (47-68%), high trans selectivities and up to 93% ee. Compared to other metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions of... 

In 1997 the application of two different chiral ytterbium catalysts, 55 and 56 for the 1,3-dipolar cycloaddition reaction was reported almost simultaneously by two independent research groups [82, 83], In both works it was observed that the achiral Yb(OTf)3 and Sc(OTf)3 salts catalyze the 1,3-dipolar cycloaddition between nitrones 1 and alkenoyloxazolidinones 19 with endo selectivity. In the first study 20 mol% of the Yb(OTf)2-pyridine-bisoxazoline complex 55 was applied as the catalyst for reactions of a number of derivatives of 1 and 19. The reactions led to endo-selective 1,3-dipolar cycloadditions giving products with enantioselectivities of up to 73% ee (Scheme 6.38) [82]. In the other report Kobayashi et al. described a... 

The development of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions is probably going to continue during the next decade. High level of control of the reactions of nitrones has been obtained, and for these reactions one of the next challenges is to explore new substrates that are designed for application in synthesis. The development of metal-catalyzed asymmetric reactions of the other... 

This chapter will try to cover some developments in the theoretical understanding of metal-catalyzed cycloaddition reactions. The reactions to be discussed below are related to the other chapters in this book in an attempt to obtain a coherent picture of the metal-catalyzed reactions discussed. The intention with this chapter is not to go into details of the theoretical methods used for the calculations - the reader must go to the original literature to obtain this information. The examples chosen are related to the different chapters, i.e. this chapter will cover carbo-Diels-Alder, hetero-Diels-Alder and 1,3-dipolar cycloaddition reactions. Each section will start with a description of the reactions considered, based on the frontier molecular orbital approach, in an attempt for the reader to understand the basis molecular orbital concepts for the reaction. 

The other catalytic approach to the 1,3-dipolar cycloaddition reaction is the inverse electron-demand (Fig. 8.17, right), in which the nitrone is coordinated to the Lewis acid, which for the reaction in Scheme 8.7 was found to be deactivated compared to the uncatalyzed reaction. In order for a 1,3-dipolar cycloaddition to proceed under these restrictions the alkene should be substituted with electron-donating substituents. 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

On the other hand, a very high asymmetric induction was observed in the 1,3-dipolar cycloaddition of (/ )-( + )-p-tolyI vinyl sulphoxide 578 with acyclic nitrones. The reaction... 

The cycloaddition of thiirene dioxide with phenyldiazomethane gave 3,4,5-triphenylpyrazole (165a) and the acyclic a-diazobenzyl 1,2-diphenylvinyl sulfone (164a), both suggested to originate in the common 1,3-dipolar cycloaddition intermediate 1626 (equation 66). Diphenylthiirene dioxide reacts similarly with other diazoalkanes (161b-e). 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

The above stereochemical results have been explained on the basis of the Criegee mechanism with the following refinements (1) The formation of 14 is stereospecific, as expected from a 1,3 dipolar cycloaddition. (2) Once they are formed, 16 and IS remain attracted to each other, much like an ion pair. (3) Compound 16 exists in syn and anti forms, which are produced in different amounts and can hold... 

This review covers primarily the results of intramolecular 1,3-dipolar cycloadditions reported by us in the past 15 years in perspective to closely related work by others. 

R = H, Scheme 27). On the other hand, reaction of 255a with N-methylhydrox-ylamine hydrochloride produces a mixture of two regioisomers 257 and 258 (R = Me). When the E-l(10)-unsaturated 5-oxo-5,10-secosteroid 255b was treated with hydroxylamine hydrochloride (R = H) or AT-methylhydroxylamine hydrochloride (R = Me), isoxazolidine 259 was formed regio- and stereoselec-tively in high yield via intramolecular 1,3-dipolar cycloaddition of the nitrone intermediate 256 (R = H or Me). 

The overall pathway for the conversion of the unsaturated azido ether 281 to 2,5-dihydrooxazoles 282 involves first formation of the dipolar cycloaddition product 287, which thermolyzes to oxazoline 282 or is converted by silica gel to oxazolinoaziridine 288. While thermolysis or acid-catalyzed decomposition of triazolines to a mixture of imine and aziridine is well-documented [71,73], this chemoselective decomposition, depending on whether thermolysis or exposure to silica gel is used, is unprecedented. It is postulated that acidic surface sites on silica catalyze the triazoline decomposition via an intermediate resembling 289, which prefers to close to an aziridine 288. On the other hand, thermolysis of 287 may proceed via 290 (or the corresponding diradical) in which hydrogen migration is favored over ring closure. 

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