1.3- Dipoles azomethine imines

As the sp nitrogen atom in many heterocycles can be alkylated and aminated, the construction of an azomethine ylide or azomethine imine dipole is readily attainable as shown in Scheme 13. These ylides are very reactive and undergo cycloaddition with a... 

Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

Trifluoromethyl-substituted 1,3-dipoles of the allyl type. Trifluoromethyl-substituted azomethine imines ate readily available on reaction of hexafluo-... 

Trifluoromethyl-substitutedazimines are surprisingly stable compounds. They are accessible by 1,3-dipole metathesis from tnfluoromethyl-substituted azomethine imines and certain nitroso compounds [187, 188] On photolysis, an electrocyclic ring closure first gives the triaziridines, which are stable at room temperature. On heating above 80-100 C, a valence tautomenzation takes place and azimines are formed [189] (equation 43). 

The benzocinnolinium azomethine imines 76 (R = Ph, OEt) react readily with DEAZD by 1,3-dipolar cycloaddition to give the corresponding tetra-zolidine derivatives (Eq. 10).124 The masked azomethine imine 77 is particularly unreactive as a 1,3-dipole, although PTAD reacts cleanly where other dipolarophiles either failed to react or gave complex mixtures (Eq. 11).125... 

Other 1,3-dipoles, such are azides and azomethine imines, have also been employed in microwave-induced cycloadditions. The main results reported are reviewed in this section. 

This list shows that the five-membered meso-ionic heterocycles related to the azomethine imine 1,3-dipole (43) comprise the largest group and that meso-ionic compounds related to the nitrosoimines (39), thionitrosoimines (41), and carbonyl imines (42) are not yet known. Clearly synthetic challenges still exist in the field of meso-ionic compounds. 

Alkylidene-phosphapyrazolines 98-101 are much more thermally stable than their relatives 88, which do not possess the exo-methylene substitution. Dediazo-niation of 98 required heating in toluene at 110°C and gave one or more of the following products, probably via intermediate diphenylmethylene(vinylidene)phos-phoranes methylenephosphiranes, (2-siloxyvinyl)phosphanes, 2//-l,3-oxaphos-pholes, and l-alkylidene-2,3-dihydro-l//-benzo[c]phospholes (169). Thermolysis of 100 ( R = t-Bu, 1-adamantyl) afforded isolable 2-phosphabutadienes (169). The photochemical elimination of N2 from 98 generated cyclic azomethine imine dipoles 104 (Scheme 8.24), which rearrange to compounds 105 and 106 that could be further trapped with DMAD to form 107 (170). 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

Furans (133) are obtained from acyltriafulvenes [(acylmethylene)cyclopropenes] (131) and azomethine-imines, -ylides or oxides (132) (75TL3919). The reaction involves the transfer of the group X from the azomethine dipole to the triafulvene and may proceed as shown in Scheme 28. I... 

Hydrazones have also been used as azomethine imine precursors to achieve cycloadditions.157 Proto-nated hydrazones act under suitable conditions as quasi-azomethine imines in polar [3+ + 2] cycloadditions. Thus, r.cetaldehyde phenylhydrazone (201) was found to react with styrene in the presence of sulfuric acid in a regiospecific manner to give pyrazolidine (203 Scheme 47) as a diastereomeric mixture.157 The most commonly used azomethine imine has a phenyl group attached to one end of the dipole and hence has a raised HOMO relative to the unsubstituted system. Because the coefficients at the terminal atoms of the dipole are smaller in the LUMO than they are in the HOMO, the phenyl group does not lower the energy of the LUMO as much as it raises the energy of the HOMO. With electron-deficient di-polarophiles like methyl acrylate, the reaction is dipole HOMO-controlled, and mixtures can be expected. In fact, a 1 1 mixture of regioisomers was obtained in the reaction of (201) with acrylonitrile (equation 9).157... 

Mesoionic compounds have been known for many years and have been extensively utilized as substrates in 1,3-dipolar cycloadditions.158-160 Of the known mesoionic heterocycles, munchnones and sydnones have generated the most interest in recent years. These heterocyclic dipoles contain a mesoionic aromatic system i.e. 206) which can only be depicted with polar resonance structures.158 Although sydnones were extensively investigated after their initial discoveiy in 1935,160 their 1,3-dipolar character was not recognized until the azomethine imine system was spotted in the middle structure of (206). C-Methyl-N-phenylsydnone (206) combines with ethyl phenylpropiolate to give the tetrasub-... 

The azomethine imine (151), having the alkene attached to the terminal dipole nitrogen, was generated in situ from the corresponding hydrazine by reaction with benzaldehyde (Scheme 47).79 As is typical in these reactions, condensation at the more basic benzyl-substituted nitrogen occurred, rather than at the acyl-substituted nitrogen. Cyclization of (151) afforded the 5,5-fused pyrazolidine and no bridged product. 

Azomethine imines which contain an intervening aromatic ring between the dipole and dipolarophile are accessible from aryl aldehydes and readily undergo cyclization. Thus, imine (154), where the dipolarophile is attached at the carbon of the dipole, afforded cis- and rrans-fused tricyclic pyrazolidines in which the alkene stereochemistry was retained (Scheme 48).78 ... 

In theory, a pyrazole could react towards dienophiles or dipolarophiles as an azadiene (A) or as a 1,3-dipole of the azomethine imine category (B), both situations being identical with regard to the number of 7r-electrons involved (Figure 25) (see also Section 4.02.1.9.1). There is also the possibility that it may react as an alkene (C) or as an imine (D) towards dienes or 1,3-dipoles. In the case of ethenylpyrazoles a final possibility of a Diels-Alder reaction involving an exo- and endo-cyclic double bond must be considered. 

Highly reactive dipoles like azomethine imines (135) form [3 + 2] cycloadducts (136) with sulfenes (Scheme 81). 

Azomethine Imines. The commonly used azomethine imine (270) has phenyl groups at both ends and hence has a raised HOMO relative to the unsubstituted system. Because the coefficients at the terminal atoms of the dipole are smaller in the LUMO than they are in the HOMO, the phenyl groups do not lower the energy of the LUMO as much as they raise the energy of the HOMO. These effects on the energy are recorded in Table 4-3 and reproduced in Fig. 4-66. 

Komatsu et al. have developed unique methods for the generation of 1,3-dipoles from organosilanes (Scheme 10.222). Linder thermal conditions, N-(a-silylbenzyl) imines and -amides are converted, via 1,2- or 1,4-silatropic shift of the silyl group, into azomefhine ylides (153 from the amide) which react with dipolarophiles [578]. Similar thermal 1,4-silyl migrations of a-silylnitrosamines and S-a-silylben-zyl thioesters provide convenient routes to azomethine imines 154 [579] and fhio-carbonyl ylides 155 [580], respectively. 

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