Cycloaddition /reactions dipolarophiles

Cycloaddition reactions of aziridines with a wide assortment of dipolarophiles have been studied. The reaction of dialkyl azodicarboxylates with the cf5-aziridine (27) is stereospecific... 

There is a large elass of reactions known as 1,3-dipolar cycloaddition reactions that are analogous to the Diels-Alder reaction in that they are coneerted [4jc -I- 2jc] eyeloaddi-tions. ° These reactions can be represented as in the following diagram. The entity a—b—c is called the 1,3-dipolar molecule and d—e is the dipolarophile. 

Kobayashi and co-workers reported similar enantioselectivity switch in the bi-nol-yterrbium(III) triflate complex-catalyzed cycloaddition reactions [69] between N-benzylidenebenzylamine N-oxide and 3-crotonoyl-2-oxazolidinone [70]. The reaction in the presence of MS 4 A showed an exclusively high enantioselectivity of 96% ee, while that in the absence of MS 4 A (-50% ee) or in the presence of pyridine N-oxide (-83% ee) had the opposite enantioselectivity (Scheme 7.24). This chirality switch happens generally for the combination of a wide variety of nitrones and dipolarophiles. 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

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. 

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

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>. 

Dipolar cycloaddition reaction of suitable dipolarophiles to azomethine imines is a well-known method leading to the pyrazolo[l,2-tf]pyrazole ring system and the methodology was duly reviewed in CHEC-II(1996) <1996CHEC-II(8)747>. During the covered period, some new applications have appeared. 

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>. 

Padwa and co-workers employed a rhodium-catalyzed [3+2] cycloaddition reaction to generate a number of 3-hydroxy-2-pyridones, including the tricyclic 146, obtained using fV-phenylmaleimide 145 as the dipolarophile. The rhodium-catalyzed cyclization of 143 generates an isomiinchnone intermediate 144, which undergoes the cycloaddition (Scheme 11) <1997JOC438>. 

Pyranopyrroloimidazoles have been prepared stereospecifically by an intramolecular 1,3-dipolar cycloaddition reaction. Either enantiomer of the imidazoline derivative 176 (the -enantiomer is shown) may react with the bromoacetyl-containing acrylate dipolarophile 177, in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to give the diastereomerically pure tricyclic product 178 in moderate yield (Equation 15). This reaction involves quaternization of the imidazole N, reaction of the quaternary salt with base to give the 1,3-dipole, which can then react, intramolecularly and stereospecifically, with the tethered dipolarophile <1997TL1647>. 

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-... 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

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). 

It was found that 2-propenyloxymagnesium bromide reacts much more readily with nitrile oxides than other known dipolarophiles of electron-deficient, electron-rich, and strained types, including 3-buten-2-one, ethyl vinyl ether, and norbomene, respectively (147). Therefore, this BrMg-alkoxide is highly effective in various nitrile oxide cycloaddition reactions, including those of nitrile oxide/Lewis acid complexes. 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

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-... 

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