Munchnone imine

The cycloaddition reactions of isoquinolinium species produce fused isoquinoline products. The Af-ylide of 53, formed with base addition, couples with alkenes <99S51> or imines <99T7279> to afford tricyclic products, such as 54. Pyrrole-fused isoquinolines result from the reaction between mUnchnone imine intermediates and a,yff-ethylenic esters <99EJOC297>. N-Arylimides undergo 1,3-dipolar cycloaddition with strained frani-cyclooctenes, as opposed to common cycloalkenes, to tdford the pyrazolidine-fused ring system <99H(50)353>. 

Oxazolium 5-Imines (Munchnone Imines) 1,3 OxazoUum 4-Oxides (Isomunchnones)... 

Although several resonance structures can be imagined for munchnones (1,3-oxazolium 5-oxides or 1,3-oxazolium 5-olates) and isomunchnones (1,3-oxazolium 4-oxides or 1,3-oxazolium 4-olates), I will draw those forms depicted in 1 and 2, respectively, which capture the flavor of the 1,3-dipolar reactivity of these heterocycles. In addition, this chapter covers the relatively few new developments involving munchnone imines and isomunchnone rmines. The format follows that used by Gingrich and Baum. 

Because all of the work with munchnone imines that has been reported since the review by Gingrich and Baum was described by one research group and involves only cycloaddition chemistry, it is collected in this section. In a series of papers, Laude and co-workers " " examined 1,3-dipolar cycloaddition reactions of munchnone imines derived from Reissert compounds. For example, treatment of the readily assembled Reissert compounds 358 and 360 with HBF4 forms the munchnone imines 359 and 361, respectively (Fig. 4.119). " " Both 359 and 361 undergo smooth intramolecular 1,3-dipolar cycloaddition with the tethered alkyne unit to afford pyrroles 362 and 363, respectively, after extrusion of HNCO (Fig. 4.120). " " ... 

This group " also diverted the usual Diels-Alder cycloaddition pathway of Reissert salts with olefinic esters to a 1,3-dipolar cycloaddition pathway by the addition of triethylamine. Thus treatment of munchnone imine 364 with ethyl acrylate and triethylamine affords the 1,3-dipolar cycloaddition product 366 (30%) as the major product, formed by fragmentation of cycloadduct 365 (Fig. 4.121). The Diels-Alder product (not shown) is formed in 15% yield. Similar products to 366 are formed with dimethyl and diethyl maleate and fumarate. Laude and coworkers " also were able to trap munchnone imine 367 with dipolarophiles to furnish 368 (Fig. 4.122). No Diels-Alder cycloadducts derived from the oxazolium salt were detected. In contrast, fumarate and acrylate esters give only Diels-Alder cycloadducts from the tautomeric oxazolium salt (not shown). However, benzo-quinones and 1,4-naphthoquinone react in a 1,3-dipolar fashion with munchnone imine 372 derived from Reissert compound 369 to give 373 (Scheme 4.11). " Diels-Alder cycloadducts derived from oxazolium salt 371 were not observed. In a... 

TABLE 10.6. 1,3-DIPOLAR CYCLOADDITION REACTIONS OF IN SITU GENERATED MUNCHNONES AND N-(PHENYLSULEONYE)IMINES ... 

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-... 

Some reactions of munchnones occur via acylamino ketenes, the covalent valence tautomers of the betaines. The ketenes are intermediates in the thermolysis (see Scheme 22) and in the formation of azetidinones from imines (equation 69) they are thought to be involved in the aminolysis of the mesoionic compounds, which results in amides of a-acylamino acids, and in the formation of the benzodioxin (247) by the combined action of acetic anhydride and tetrachloro-o-benzoquinone on Af-benzoylalanine (equation 70). 

DC of imines and munchnones 145, in situ generated by treatment of 5(4//)-oxazolones with chlorotrimethylsilane, allowed a diastereoselective multicomponent synthesis of highly substituted imidazolines 146, containing a four-point diversity and two stereocenters. The process is applicable to aryl, alkyl, acyl, and heterocyclic substitutions and only the trans distereomers (with respect to and R ) of 146 were observed in almost all cases <03SI433>. 

In a similar fashion, the activation of azlactones with Lewis acids gives intermediate munchnones which can then be trapped with imines or alkenes to yield 2-imidazolines 92 or A -pyrrolines 93 respectively, with high diastereos-electivities (Scheme 20) <2002OL3533, 2004JA12776>. 

A three-component coupling of imines 278, alkynes 279, and acid chlorides 280 affords pyrroles 281 [178]. The active catalyst is proposed to be 282, which leads to the generation of mesoionic munchnones 283. An example is the synthesis of 284. 

The role of acid in influencing the cyclization of 14 with imines towards imidazolines products is at present unclear. One possibility is suggested by the work of Ferraccioli and Croce (16), who have shown that the electronic nature of the imine can have a significant influence upon its reactivity with Munchnone. In particular, while N-alkyl substituted imines react with Munchnones to form (3-lactams, more electron poor imines, such as the N-tosyl substituted substrates, have been found to undergo a 1,3-dipolar cyclization with 14 to form imidazoles. (16) In our case, the role of acid may be in protonation of the imine substrate, thereby creating a more electrophilic C=N which can undergo a dipolar cycloaddition with 14 (path A, Scheme 2). Subsequent heterolysis of the C-0 bond in 18, would yield the observed imidazoline-carboxylate 17. 

As presented in some detail by Gingrich and Baum (see their Table 4.31 and Scheme 4.51) azlactones react with ot,p-unsaturated imines to give ot-pyridones. Sandhu and co-workers continued the studies in this area, and they now view this reaction as involving initial electrophilic attack on the azlactone (munchnone) followed by cyclization to an ot-pyridone, rather than prior ring-opening to the corresponding ketene tautomer, as was originally proposed (Table 4.1). With azlactone 52 and A-aryl cinnamaldehyde anils 53, in the presence of acetic anhydride, the 4-substituted azlactones 54 are isolated (Fig. 4.15). Dalla Croce... 

Clerici and co-workers investigated the behavior of munchnones with isothiazole 1,1-dioxide 241. As shown in Table 4.17, the products 242 are formed in good yields, along with minor amounts of the tautomeric imine (not shown). The azalactones-munchnones were generated from the corresponding iV-acylamino acids and acetic anhydride. 

Ferraccioli and co-workers employed the reaction of munchnones with N-(phenylsulfonyl)imines as a general synthesis of imidazoles 319 (Table 4.20). Regioselectivity is very high and was determined using NOE measurements. The munchnones were prepared in situ using DCC in toluene (25°-60°C). 

A subsequent study by this group uncovered a small amount of the regio-isomer 323 in the reaction of munchnone 320 with imine 321 (Fig. 4.110). The... 

Dalla Croce and co-workerspursued the chemistry of unsaturated A-(phe-nylsulfonyl)imines 330 and munchnone 42 (Fig. 4.112). While the major products are the imidazoles 331, pyrroles 332 and amides 333 also are formed in this reaction. The structure of amide 333a was confirmed by X-ray crystallography. 

This same group generated bicychc munchnones (e.g., 334) and trapped them with imines to afford either imidazoles 335 or spirocyclic p-lactams 336, depending on conditions, although mixtures are produced and yields of the p-lactams are invariably low (Fig. 4.113). The latter can arise by nucleophilic attack on the munchnone itself or the ring-opened ketene tautomer (vide infra). 

The reaction of in situ generated munchnone 42 with unsaturated imine 354 gives p-lactam 355, in contrast to the results described earlier for other imines (e.g., 42 + 330 331,332, 333) (Fig. 4.117).Presumably, this reaction involves ring-opened ketene 42a. 

TABLE 4.20 1,3-DIPOLAR CYCLOADDITION REACTIONS OF IN-STTU-GENERATED MUNCHNONES AND A-(PHENYLSULFONYL)IMINES, 529... 

This Pd-catalyzed transformation uses two imines an acid chloride and CO. Mechanistically, this reaction is proposed to proceed via Pd addition to the activated imine, followed by CO insertion. Reductive elimination of Pd with HCl provides the ketene, which undergoes formation of the Munchnone. Miinchnones are known to undergo cycloaddition reactions with electron-deficient imines to yield cycloaddition adducts, which lose CO2 and TsH to yield imidazole. 

A novel synthesis of 2-aryl-4-piperidones by Mannich cy-clization of imino acetals, initiated by methylation of the imine, has been described. MeOTf has been used in the generation of a munchnone for cycloaddition. Pinally, methylation of 1-lithio-2-/ butyl-l,2-dihydropyridine with MeOTf gives 2-butyl-5-methylpyridine in 42% yield. ... 

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