Dipole with dipolarophiles

In principle, cycloadditions of 1,3-dipoles with dipolarophiles may occur in a concerted or stepwise manner (108). On the basis of intensive, meticulous experimental work, Huisgen and his group unequivocally established the concerted course for this reaction (15,109,110). A model was proposed for the transition state, whereby the 47i-electron system present in 1,3-dipoles interacts with the 71-bond of the dipolarophile (Scheme 6.12). 

The cycloaddition reaction of dipoles has been known since the 18th century, later, Huisgen introduced the concept of a 1,3-dipole [30]. One of the earhest examples of copper(II) acetylacetonate [Cu(acac)2] catalyzed 1,3-dipole formation involved the controlled decomposition of an a-diazo ketone [31]. Some cases utilized copper as the metal species and demonstrated the feasibility of cycloaddition reactions and these 1,3-dipoles with dipolarophiles. These reactions set the stage for the evaluation of additional transition metals capable of catalyzing this transformation. The earliest example of rhodium(II)-catalyzed a-diazo ketone decomposition to form a 1,3-dipole was described by Teyssie and co-workers [32]. Despite this promising beginning, it was not until many years later that rhodium(II) was used generally for the formation of such 1,3-dipoles [6-12,21,29,30] (Fig. 1). 

The transition state of the concerted 1,3-dipolar cycloaddition reaction is controlled by the frontier molecular orbitals of the substrates. Hence, the reaction of dipoles with dipolarophiles involves either a LUMO-dipole/ HOMO-dipolarophile reaction or a HOMO-dipole/LUMO-dipolarophile interaction, depending on the nature of the dipole and the dipolarophile. 

Table 2 illustrates 1,3-dipoles with a double bond and with internal octet stabilization, commonly referred to as the propargyl-allenyl anion type. These are all reactive dipoles and a large number of five-membered heterocycles can be constructed from these readily available dipoles, especially when the dipolarophile is varied to include heterocumulenes, etc. 

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. 

Formation of trans isomers in overwhelming predominance in the ISOC reaction leading to five-membered rings (Entries a-d) has been ascribed to the orientation in which H% H , and R are on the exo face of TS 182b (this avoids a possible strain between R and NO or between H and [48b] that is presumably present in TS 182 a). Since elimination of silanol involving H in no way interferes with the orientation of H and R, a trans relationship between H and is abundantly clear. This fully accords with the widely accepted view that approach of the dipole and dipolarophile takes place in two parallel planes [49] and that the endo TS is preferred in the absence of obvious steric effects [50]. Formation of approximately 5% cis isomer when the dipolarophile terminus is disubstituted is accountable in terms of the cycloaddition taking place via TS 182a. 

Aldimines, Ketimines, and Related Compounds as Dipolarophiles Reactions of aldimines with nitrile oxides proceed readily to give 1,2,4-oxadiazolines independently of the nature of substituents both in dipole and dipolarophile molecules. 1,2,4-Oxadiazolines were prepared by the regiospe-cihc 1,3-dipolar cycloaddition of nitrile oxides with fluoro-substituted aldimines (295). Phosphorylnitrile oxides gave with azomethines, PhCH NR, phosphory-lated 1,2,4-oxadiazolines 129 (296). Expected 1,2,4-oxadiazolines were also obtained from azomethines, derived from 4-formylcoumarine (179) and 1,3-diphenylpyrazole-4-carbaldehyde (297). 

The [3+2] cycloaddition of terminal alkynes has been investigated with several dipoles. These dipolarophiles are competent in the cycloaddition, however, the corresponding isoxazolines cannot be isolated. Instead, the cycloadduct undergoes spontaneous rearrangement to provide acylaziridine products (Table 2.52) (229). Disubstituted alkynes also undergo this process, however, in lower yield. This rearrangement occurs with all nitronates studied (Chart 2.3) (66,230,231). 

Due to the increased reactivity of the reaction in the presence of a Lewis acid, the reaction scope was extended to singly activated alkenes. Previous results had shown either no reaction or extremely poor yields. However, under the Lewis acid catalyzed conditions, acrylonitrile furnished a 1 1, endo/exo mixture of products. The addition of the catalyst gave unexpected regiochemistry in the reaction, which is analogous with results described in Grigg s metal catalyzed reactions. These observations in the reversal of regio- and stereocontrol of the reactions were rationalized by a reversal of the dominant, interacting frontier orbitals to a LUMO dipole-HOMO dipolarophile combination due to the ylide-catalyst complex. This complex resulted in a further withdrawal of electrons from the azomethine ylide. 

A number of intramolecular cycloadditions of alkene-tethered nitrile oxides, where the double bond forms part of a ring, have been used for the synthesis of fused carbocyclic structures (18,74,266-271). The cycloadditions afford the cis-fused bicyclic products, and this stereochemical outcome does not depend on the substituents on the alkene or on the carbon chain. When cyclic olefins were used, the configuration of the products found could be rationalized in terms of the transition states described in Scheme 6.49 (18,74,266-271). In the transition state leading to the cis-fused heterocycle, the dipole is more easily aligned with the dipolarophile if the nitrile oxide adds to the face of the cycloolefin in which the tethering chain resides. In the trans transition state, considerable nonbonded interactions and strain would have to be overcome in order to achieve good parallel alignment of the dipole and dipolarophile (74,266). 

The intramolecular cycloaddition of nitrile oxides to substituted furans was reported to occur with low stereoselectivity (274). Inserting a stereogenic unit within the chain connecting the dipole and dipolarophile did not increase the stereoselectivity (274). 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

Whereas 260 does not react with electron-rich dipolarophiles, the more delocalized isomiinchnone 261 does react with both electron-rich and -deficient dipolarophiles (154). A detailed FMO analysis is consistent with these observations and with the regiochemistry exhibited by diethyl ketene acetal and methyl vinyl ketone as shown in Scheme 10.36. The reaction of 261 with the ketene acetal to give 262 is LUMO-dipole HOMO-dipolarophile controlled (so-called lype III process). In contrast, the reaction of 261 with methyl vinyl ketone to give 263 is HOMO-dipole LUMO-dipolarophile controlled (so-called lype I process). In competition experiments using a mixture of A-phenylmaleimide and ketene acetal only a cycloadduct from the former was isolated. This result is consistent with a smaller energy gap for... 

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. 

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