Reactions with Dipolarophiles Cycloadditions

Pyrylium-3-olates, formally 3-hydroxy-pyryliums rendered overall neutral by loss of the phenolic proton, though this is not usually the method for their formation, undergo cycloadditions across the 2,6-positions and in so doing parallel the reactivity of pyridinium-3-olates (8.7). Even unactivated alkenes will cycloadd when tethered and thus the process is intramolecular. Usually, the pyrylium-3-olate is generated by elimination of acetic acid from a 6-acetoxy-2//-pyran-3(67/)-one (a pyranulose acetate ) (see 18.2). 

Borohydride reduction of the ketone carbonyl in such adducts, then ozonolysis, generates 2,5-cis dis-ubstituted tetrahydrofurans.  

Another ingenious route for the generation of the dipolar species involves the carbonyl-0-alkylation or 0-silylation of 3-oxygenated 4-pyrones. The example below shows 0-methylation of a kojic acid derivative, then deprotonation of the 3-hydroxyl using a hindered base to trigger the dipolar cycloaddition. 

---

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

Cycloadditions. Desilylation of 1 in CH,CN with LiF results in an azomethine ylide (a), which undergoes cycloaddition reactions with dipolarophiles and activated alkenes to give pyrrolidines. 

Mesoionic oxazolones (munchnones) 297 can be generated by cyclodehydration of N-substituted a-amino acids 295 or by alkylation of oxazolones 296 (Scheme 7.98). These compounds are reactive and versatile 1,3-dipoles that undergo cycloaddition reactions with dipolarophiles to generate a variety of heterocyclic systems. In particular, this is an extremely versatile methodology to prepare pyrroles that result from elimination of carbon dioxide from the initial cycloadduct. Numerous examples have appeared in the literature in recent years and several have been selected for discussion. The reader should consult Part A, Chapter 4 for an extensive discussion and additional examples. 

Some 1,3-dipoles possess HOMO and LUMO energies that allow for fast Sustmann type I additions with electron-poor dipolarophiles and for fast Sustmann type III additions with electron-rich dipolarophiles. In reactions with dipolarophiles with intermediate electron density, such dipoles merely are substrates of the much slower Sustmann type II additions. A plot of the rate constants of the 1,3-dipolar cycloadditions of such dipoles as a function of the HOMO energy of the dipolarophiles—or as a function of their LUMO energy that varies with the same trend—then has a U-shape. One such plot is shown in Figure 15.39 for 1,3-dipolar cycloadditions of diazomalonates. 

The cyclodehydration of 2-substituted-A/-acylthiazolidine-4-carboxylic acids yields bicyclic munchnones. This mesoionic ring system acts as a cyclic azomethine ylid and can undergo 1,3-dipolar cycloaddition reactions with dipolarophiles. A range of chiral pyrrolo[l,2-c]thiazoles have been prepared by this method both intermolecularly and intramolecularly. 

The products are azomethine ylids, and can be trapped by [3+21 cycloaddition reactions with dipolarophiles (look back at Chapter 35). 

Several 3-hydroxy-2//-pyrazolo[4,3-c]isoquinolinium inner salts undergo reaction with dipolarophiles in 1,3-cycloaddition reactions <03JOC8700>. The best yields with the cleanest mixture of compounds is when R = PMB and dimethyl acetylenedicarboxylate (DMAD) is the dipolarophile. 

In the thermolysis of phenylvinyloxiranes stabilized with a cyano group, the ylides have been confirmed in the cycloaddition reaction with dipolarophiles. " ... 

The second method was based on a cycloaddition reaction of olefinic and acetylenic dipolarophiles to xanthinium-(N7) ylides. Xanthinium-(N7) ylides 22 were generated from 7-substituted 1,3,9-trimethylxanthinium tosylates 21 by deprotonation with triethylamine in dry acetonitrile followed by reaction with dipolarophiles 23 and 25 (dimethyl fumarate, fumaronitrile, methyl acrylate, acrylonitrile and the like). Reaction with dimethyl fumarate afforded the endo-(24a) and exo-(24b) adducts in a 3 2 ratio. The stereochemistry of these compounds was established by H-NMR and X-ray analysis (84H2199). With derivatives of acrylic acid 25, only endo adducts (26)... 

Saturated azlactones, such as the isomeric 21 and 22, possess mesoionic character and behave as dipolar species in 1,3-dipolar cycloaddition reactions with dipolarophiles,49- 1 e.g., acetylene -dicarboxy-lates lEq. (12). Decarboxylation of the adduct from either 21 or 22 gives the same pyrrole derivative (23). 

Rhodium(II)-catalyzed reactions between diazosulfones and aldehydes yielded an entry to carbonyl ylides, which underwent inter- and intra-molecular cyclization reactions with dipolarophiles, such as alkynes and alkenes, to afford tetrasubstituted furans in modest to good yields <01SL646>. The rhodium(ll) acetate catalyzed reaction of 3-diazobenzopyran-2,4(3 -dione with terminal alkynes provided a mixture of 2-substituted furo[3,2-c]coumarin and furo[2,3-f ]coumarin, presumably through a formal [3+2] cycloaddition reaction <01S735>. Furo[3,2-c]coumarins were also produced from 4-hydroxycoumarins and a-haloketones via a tandem 0-alkylation-cyclization procedure <01TL3503>... 

Nitrile oxides as starting materials or intermediates in cycloaddition reactions with dipolarophiles produce variable amounts of furoxans 3 (Scheme 8.1) as side products, as recalled before. In order to reduce the amount of furoxan, such reactions are usually carried out with an excess of dipolarophUe or under gradual reagent supply. 

As formal a, /i-unsaturated sulfones and sulfoxides, respectively, both thiirene dioxides (19) and thiirene oxides (18) should be capable, in principle, of undergoing cycloaddition reactions with either electron-rich olefins or serving as electrophilic dipolarophiles in 2 + 3 cycloadditions. The ultimate products in such cycloadditions are expected to be a consequence of rearrangements of the initially formed cycloadducts, and/or loss of sulfur dioxide (or sulfur monoxide) following the cycloaddition step, depending on the particular reaction conditions. The relative ease of the cycloaddition should provide some indication concerning the extent of the aromaticity in these systems2. 

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

Conjugated heteropentalene mesomeric betaines are electron rich with high-energy HOMO and can be regarded as masked 1,3-dipolarophiles. Their main reactions are electrophilic substitution and cycloaddition reactions with electron-deficient 1,3-dipolarophiles, both were duly discussed in CHEC-II(1996) <1996CHEC-II(8)747>. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

Benzocyclobutene, when generated by oxidation of its iron tricarbonyl complex, can function as the dipolarophile in 1,3-dipolar cycloaddition reactions with arylnitrile oxides (Scheme 113).177 Unfortunately the synthetic versatility of this type of process is limited because of the unreactivity of other 1,3-dipolar species such as phenyl azide, benzonitrile N-phenylimide, and a-(p-tolyl)benzylidenamine N-oxide.177... 

Aroylnitrile oxides can also be generated from diaroyl furoxans 183 under micro-wave irradiation [33]. Formation of the nitrile oxide intermediate 184 and its cycloaddition with dipolarophiles proceeds at atmospheric pressure within minutes in the absence of solvent and in good yields (Scheme 9.56). The reaction occurs by the rear-... 

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

Heterocycles Both non-aromatic unsaturated heterocycles and heteroaromatic compounds are able to play the role of ethene dipolarophiles in reactions with nitrile oxides. 1,3-Dipolar cycloadditions of various unsaturated oxygen heterocycles are well documented. Thus, 2-furonitrile oxide and its 5-substituted derivatives give isoxazoline adducts, for example, 90, with 2,3- and 2,5-dihydro-furan, 2,3-dihydropyran, l,3-dioxep-5-ene, its 2-methyl- and 2-phenyl-substituted derivatives, 5,6-bis(methoxycarbonyl)-7-oxabicyclo[2.2.1]hept-2-ene, and 1,4-epoxy-l,4-dihydronaphthalene. Regio- and endo-exo stereoselectivities have also been determined (259). 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

Iodoacetylene (prepared in situ from ethynylmagnesium bromide or tributyl (ethynyl)tin with iodine) was used as a dipolarophile in the 1,3-dipolar cycloaddition reactions with nitrile oxides to produce 2-(5-iodoisoxazol-3-yl)pyridine and 3-(4-fluorophenyl)-5-iodoisoxazole in good yield (70%-90%). Subsequently,... 

The carbon-nitrogen triple bond of aryl thiocyanates acts as a dipolarophile in 1,3-dipolar cycloadditions. Reactions with nitrile oxides yield 5-arylthio-1,2,4-oxadiazoles 227 (X = O Y = S). Aryl selenocyanates behave similarly forming 5-arylseleno-l,2,4-oxadiazoles 227 (X = 0 Y = Se). Reactions of 5-aryl-... 

Other Types of Nitronates in [3 + 2]-Cycloaddition Reactions with Olefins As mentioned above, of all known types of nitronates, only alkyl and silyl nitronates can be involved in [3 + 2]-cycloaddition reactions with olefins. However, furoxans (161), which can also be considered as cyclic nitronates, can react with active dipolarophiles under extreme conditions to give nitrosoacetals (162) (Scheme 3.131, Eq. 1). 

---