Huisgen zwitterion

This class of compound is represented by 2,3-disubstituted-l,2,3-benzoxadiazoles and new caged structures. 2,3-Disubstituted-l,2,3-benzoxadiazoles 128 were prepared in high yield when the Huisgen zwitterion, formed between dialkyl azodicarboxylates 127 and triphenylphosphine, was reacted with 3-methoxy 4,6-disubstituted-l,2-benzoqui-nones 126 (Equation 23 Table 6) <20050L5139>. 

Nair et al. have investigated the reaction of MBH acetates with the Huisgen zwitterion to alTord p-amino acid derivatives 307 and 308 in the presence of triphenylphosphine by invoking a S- 2 process (Scheme 3.132). ... 

Another approach toward the synthesis of aryliminophosphoranes (27) involved a Mitsunobu-type reaction between aromatic amines, diethyl azodicarboxylate (DEAD) and triphenylphosphine at ambient temperature. Pentacoordinated intermediate (28) was formed after nucleophilic addition of the conjugated base of the NH-acid on the Huisgen zwitterions (29). Thus fragmentation of the initial adduct (30) under the reaction conditions provided access to iminophosphoranes (27) after removal of the hydrazide (31) (Scheme 6). 

A unifying hypothesis for the observed organic chemistry was advanced by Huisgen [132], who suggested that all tetramethylenes lie on a continuous scale between zwitterionic and diradical structures and may be regarded as resonance hybrids of the two extreme forms. The predominant nature of the tetramethylene intermediate is determined by the terminal substituents, and the termini can interact with each other by through-bond interaction [132, 134]. 

According to Huisgen,84 the formation of the ozonide by addition of the peroxidic zwitterion to a carbonyl group is a 1,3-dipolar addition. This explains the fact that, in the ozonization of open-chain olefins, ozonides are obtained as the principal products only when the carbonyl fragment has a sufficiently high dipolarophilic activity. This is so in the case of aldehydes, particularly formaldehyde simple ketones, on the other hand, are less reactive. For this reason, aliphatic tetrasubstituted ethylenes do not normally form ozonides.86... 

Another nice example of SRR is depicted in Scheme 8. The original reaction was developed by Diels and Harms in 1936 [61]. Reaction of isoquinoline 71 with dimethyl acetylenedicarboxylate (DMAD, 72) initially forms zwitterionic intermediate 73, which is reacted with a second equivalent of DMAD to form benzoqui-nolizine 74. This is, however, not a true 3CR reaction, since two components are identical. In 1967, Huisgen reported three variations of this reaction in which... 

Oxazolones are simply cyclic anhydrides of A-acyl-a-amino acids, and are constructed in the way that this implies. If the nitrogen also carries an aUcyl group, cyclisation " can only lead to an overall neutral product by adopting a zwitterionic stracture, for which no neutral canonical form can be written - a mesoionic structure. Mesoionic oxazolones (named miinchnones by Huisgen after their discovery at the University of Munchen, Germany) undergo ready dipolar cycloadditions,with loss of carbon dioxide from the initial adduct the examples" show the conversion of a miinchnone into a mesoionic thiazolone and into an imidazole. 

Huisgen defined a 1,3-dipoleas a species that may be described (as in Equation 1) by zwitterionic octet structures 6a <- 6b, and which may undergo cycloaddition reactions of the type 3 + 2 -> 5 with suitable multiple bonds (dipolarophile d=e) to give a neutral five-membered ring 7. 

In the second review (1963 b) of Huisgen, the ambiguity concerted or zwitterionic intermediate remained an open question. Woodward and Hoffmann s selection rules define the conditions under which concerted processes are allowed, but they do not forbid a two-step pathway. ... 

Among the nucleophilic zwitterions, Huisgen s zwitterions (50) reacted with both 27-ketoesters and 27-aldehydes to provide chromone-substituted pyrrole ring-system 55 as the major product. Only in some cases of 27-aldehydes, 63 a novel ring system was obtained as minor products. Zwitterion 47, that is, methyl isocyanoacetate displayed unbiased reactivity toward 27-ketoesters/aldehydes and yielded benzopyrones supporting substituted finan ring in high yields (54, Schemes 27.3 and 27.4). 

The most familiar example of zwitterionic [t 2 -f r 2]-cycloaddition is that of tetracyanoethylene (TONE) to activated ethylenes, such as vinyl ethers. Huisgen [28] has carefully reviewed the experimental evidence, which is due in large measure to him and his collaborators. It can be summarized briefly as follows ... 

The case illustrated in Fig. 6.8 corresponds to Huisgen and Mayr s [42, 43] 1-alkenyl ethyl ethers (R = H OR = C2H5) and to Al-Husaini and Moore s [45] cz5-trimethylsiloxypropenes (R = H OR = OSi(CH3)3). The substituted C atom of the ketene moves towards R and repulsion with S (CN in TBCK) causes L ( er -butyl in TBCK) to fold under the bulkier OR. Then, if repulsion between the latter two bulky substituents is not so severe that internal rotation - presumably via a more extended conformation of the zwitterion - becomes competitive with ring closure kr 2) the contrathermodynamic product is obtained. 

Huisgen has also studied the effects of substitution in the keten in the reactions of a series of alkylphenyl ketens to ethyl cis- and trans-propenyl ethers. With the cis-enol ethers the thermodynamically less stable cyclobutanone is always produced. This is the same result as that found in the addition of ketens to cyclopentadiene and other cis-olefins, and the mechanistic implications are the same. With the trans-enol ether, the thermodynamically more stable product is formed, and this observation can be rationalized in terms of a [tc2 + k2 J cycloaddition if the preferred orientation complex has the substituent on the keten between the alkoxy-group and a hydrogen rather than between a methyl group and a hydrogen on the enol ether. In all the cases studied, the cis-enol ether reacted more rapidly than its trans-isomer. This cis trans reactivity ratio is not found in [2 + 2] additions proceeding via zwitterionic intermediates. For example, the rate ratio for the reaction of TCNE with cis- and trans-1-alkenyl ethers is very close to unity. 

Mesomeric zwitterions like Munchnones, which are known as mesoionic compounds, also occur in other heterocyclic systems [276], Munchnones show the reactivity of 1,3-dipoles for instance, they react with acetylenes via the products 62 of a 1,3-dipolar cycloaddition to give pyrroles 63 after cycloreversion of 62 by loss of CO2 Huisgen pyrrole synthesis). 

Dipolar compounds (1,3-dipoles), first designated by Huisgen [1], are a class of 4tt-electron species that can be represented by zwitterionic (or ylide) forms with a separation of charge over three atoms. Basically, 1,3-dipoles are categorized into two subclasses, including the allyl type (carbonyl ylides, carbonyl imines, azomethine ylides, azomethine imines, and nitrones) and the propargyl/allenyl type (azides, diazoalkanes, nitrile ylides, nitrile imines, and nitrile oxides), as shown in Scheme 16.1. 

A large class of organic reactions that lead to the formation of five-membered heterocyclic molecules, have been designated as 1,3 dipolar cycloaddition reactions °. Huisgen has defined the 1,3 dipole to be a species which is represented by zwitterionic resonance structures (i.e. the standmd Lewis octet structures) and which undergoes 1,3 cycloadditions to a multiple bond system, the dipolarophile , as in structures (18) and (19). 

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