1.3- Dipolar species

Reaction of thiazoles with DMAD illustrates the overall reaction and the rearrangements which may be encountered. Thiazole or 2-methylthiazole (411 R=H and Me, respectively) in DMF reacted with DMAD to give an initial 1,4-dipolar species (412). Reaction with a second DMAD gave the 1 2 molar adduct, presumably (413). Ring opening to (414), followed by cyclization in the alternative mode, resulted in the formation of (415), the structure of which (R = Me) was established by X-ray analysis (78AHC(23)263) (see also Chapter 4.19). 

Photochemical elimination of carbon dioxide from suitable precursors has given a variety of reactive intermediates at low temperatures where they are often stable and can be studied further. This approach has been utilized in attempts to generate new 1,3-dipolar species, and photolysis of (515) gave an azomethine nitrene intermediate (516) (see Section 4.03.6)... 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

The azomethine imines exhibit the typical cycloaddition behavior expected of 1,3-dipolar species [fSJ] Numerous [3+2] cycloaddition reactions have been performed [201 204] Tetracyanoethylene adds to azomethine imines across the nitnle function instead of the C=C double bond This reaction is a rare example of this type of periselectivity [208] (equation 47)... 

The differenee in reaction rates of the amino alcohols to isobutyraldehyde and the secondary amine in strong acidic solutions is determined by the reactivity as well as the concentration of the intermediate zwitterions [Fig. 2, Eq. (10)]. Since several of the equilibrium constants of the foregoing reactions are unknown, an estimate of the relative concentrations of these dipolar species is difficult. As far as the reactivity is concerned, the rate of decomposition is expected to be higher, according as the basicity of the secondary amines is lower, since the necessary driving force to expel the amine will increase with increasing basicity of the secondary amine. The kinetics and mechanism of the hydrolysis of enamines demonstrate that not only resonance in the starting material is an important factor [e.g., if... 

The intermediacy of dipolar species such as 186 has been demonstrated by reaction of enamines with 2-hydroxy-1-aldehydes of the aromatic series (129). The enamine (113) reacts in benzene solution at room temperature with 2-hydroxy-1-naphthaldehyde to give the crystalline adduct (188) in 91 % yield. Oxidation with chromium trioxide-pyridine of 188 gave 189 with p elimination of the morpholine moiety. Palladium on charcoal dehydrogenation of 189 gave the known 1,2-benzoxanthone (129). 

Huisgen has reported in 1963 about a systematic treatment of the 1,3-dipolar cycloaddition reaction as a general principle for the construction of five-membered heterocycles. This reaction is the addition of a 1,3-dipolar species 1 to a multiple bond, e. g. a double bond 2 the resulting product is a heterocyclic compound 3. The 1,3-dipolar species can consist of carbon, nitrogen and oxygen atoms (seldom sulfur) in various combinations, and has four non-dienic r-electrons. The 1,3-dipolar cycloaddition is thus An +2n cycloaddition reaction, as is the Diels-Alder reaction. 

For a review on reactions of Group 6 metal carbenes with ylides and related dipolar species see Alcaide B, Cassarubios L, Dominguez G, Sierra MA (1998) Curr Org Chem 2 551... 

Although a free ionic end-group, —CH2CH(Ph), capable of propagating polymerization is formed on opening the ring, the resulting dipolar species does not contribute to electric conductance. 

Zimmerman(24,a6> has provided strong circumstantial evidence that zwitterionic intermediates can be involved in formation of cyclopropyl ketones from dienones. His approach was to generate the dipolar species via ground state chemistry and show that these rearrange to the photoproduct ... 

Zimmerman et al.(i2y pointed out that the bridged phenonium ion from (48) is more stable (lower energy route) than is the phenonium ion from (47), while the phenonium ions from (49) and (50) should be of about equal stability. An alternate explanation has been proposed by Kropp,a) who suggests that preferred migration to the position adjacent to the electron-rich oxygen in aprotic solvents arises from a preferred minimization of charge separation in in the dipolar species. 

Interaction of a carbonyl group with an electrophilic metal carbene would be expected to lead to a carbonyl ylide. In fact, such compounds have been isolated in recent years 14) the strategy comprises intramolecular generation of a carbonyl ylide whose substituent pattern guarantees efficient stabilization of the dipolar electronic structure. The highly reactive 1,3-dipolar species are usually characterized by [3 + 2] cycloaddition to alkynes and activated alkenes. Furthermore, cycloaddition to ketones and aldehydes has been reported for l-methoxy-2-benzopyrylium-4-olate 286, which was generated by Cu(acac)2-catalyzed decomposition of o-methoxycarbonyl-m-diazoacetophenone 285 2681... 

In addition to the specific adsorption of ions, it is also possible to adsorb neutral organic molecules at the interface and both Butler and Frumkin independently arrived at equivalent expressions for the free energy of adsorption of a neutral dipolar species, A, replacing the solvent, S. The free energy change takes the form ... 

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... 

Another example with porphyrinic dipolar species uses pyridinium salt derivatives as precursors of porphyrinic pyridinium ylides (Scheme 18) <05TL5487>. The procedure involves the reaction of porphyrin 58 with methyl bromoacetate, in refluxing chloroform, to give pyridinium salt 59. The latter, in the presence of K2CO3, reacts with 1,4-benzoquinone to yield only the mono-addition compound 60. Notably, when the reaction was performed in the presence of DBU, bis-addition occurred and the porphyrinic dimer 61 was the only isolated addition product. 

Porphyrins can also be used as precursors of 1,3-dipolar species, and this has been widely explored, mainly when targets are concerned with the synthesis of porphyrinic diads. 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

The germabenzene species 15 reacts in two different fashions with a variety of substrates to give cylcoaddition products (Scheme 7).30 With MesCNO and 2,3-dimethylbutadiene, 15 behaves similarly to a compound with a single Ge-C double bond, whereas in reactions with styrene and phenylacetylene, 15 behaves as a 1-germabuta-l,3-diene to give Diels-Alder-type adducts. The germanium-carbon doubly bonded species 23 reacts with nitriles in several different ways, including as a 1,2-dipolar species with Bu CN, as a 1,4-dipolar species with PhCN, and as a base with various /3-functionalized nitriles (Scheme 8). 

Dipolar species have been observed in the cycloaddition of polar intermediates. Thus cyclobutanes can be formed by non concerted processes involving zwitter ionic intermediates. The combination of an electron rich alkene (enamimes, enol ethers) and an alkene having electron withdrawing groups (nitro a cyano substituted alkenes) first gives a zwitter ion which can rotate about the newly formed bond before cyclization and gives both a cis and a trans adduct. 

Such 1, 3 dipolar additions show a striking similarity with diene additions. If the 1, 3 dipolar species is a stable compound, the reaction takes place just by mixing the components with or without heating. They take place in absence of any catalyst or light. 

Cyclopropanones are also reactive toward cycloadditions of various types. Probably a dipolar species is first formed from reversible cleavage of cyclopropanone ring. 

Cyclodditions to Carbonyl Derivatives. Electrophilic transient carbenes are known to react with carbonyl derivatives through the oxygen lone pair to give carbonyl ylides 26.43 These 1,3-dipolar species are usually characterized by [3 + 2]-cycloaddition reactions or can even be isolated44 a small amount of the corresponding oxiranes is sometimes obtained.433,45 To date, no reaction of transient nucleophilic carbenes with carbonyl derivatives has been reported. 

The term sonochemistry is used to describe a subject which uses sound energy to affect chemical processes and the terminology is in keeping with that of the longer established methods such as electrochemistry (the use of electricity to achieve chemical activation). These older technologies require some special attribute of the system being activated in order to produce an effect e. g. the use of microwaves (dipolar species), electrochemistry (conducting medium) and photochemistry (the presence of a chromophore) whereas sonochemistry requires only the presence of a liquid to produce its effects. 

Cyclopropanones are also reactive toward certain types of cycloadditions. Theoretical modeling indicates that a dipolar species resulting from reversible cleavage of the cyclopropanone ring is the reactive species.96 cis-Disubstitutcd cyclopropanes with bulky substituents exhibit NMR features that indicate a barrier of 10-13 kcal/mol for... 

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