Munchnone intermediate

The intramolecular cycloaddition of munchnone intermediates (derived from the cyclodehydration of A-acyl amino acids) with 1,3-dipolarophiles was employed to construct the mitomycin skeleton. Thus, heating alkynyl acids 23 with acetic anhydride forms the intermediates 24 which undergo cyclization with loss of carbon dioxide to afford the 4-oxo-tetrahydroindoles 25 <96TL2887>... 

Acetylation of the amide (128) produced a fused tricyclic pyrrole in 17% yield (Scheme 39).64 A munchnone intermediate was postulated and could be trapped via intermolecular cycloaddition with diethyl acetylenedicarboxylate. Presumably the direct cyclization product lost carbon dioxide, a known reaction of munchnone cycloadducts.65 An homologous munchnone with an o-(propenyl)phenyl group, rather than o-(butenyl)phenyl group, failed to cyclize, although it could again be trapped with diethyl acetylenedicarboxylate. 

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>. 

The munchnone (66) reacts by [3+2] cycloaddition with dimethyl acetylenedicarboxylate to give an intermediate which spontaneously loses carbon dioxide (Scheme 21) (72JOC3111). 

This cycloaddition takes place to give the exo cycloadduct, rather than the more common endo cycloadduct, as the major product. Presumably this is a consequence of the intermediate munchnone 131 being locked in an anti orientation as compared to the commonly favored syn orientation (as in 24). 

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). 

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>. 

In yet another variation of TFAA reactions of in situ-generated munchnones, Kawase" described a novel synthesis of 2-trifluoromethyltetrahydro-3-benzazepi-nones 77 from tetrahydroisoquinoIine-1-carboxylic acids 76 (Table 4.3). This novel conversion is thought to involve an oxazolium intermediate, which is formed from the corresponding munchnone (see Scheme 4.5). Addition of TFA followed by a... 

The authors propose a pathway to these novel sprrolactones as involving munchnone ring opening to ketene 131 followed by condensation with acetic anhydride and alkyl vinyl ketone in some fashion to give intermediate 132 (Fig. 4.47). Loss of acetic acid leads to spirolactone 130. Pinho e Melo and colleagues also found that acrylonitrile reacts with this munchnone to afford a 1 1 mixture of epimers 133 in very low yield (3%) (Fig. 4.48). Oxidation with DDQ gave the aromatic pyrrole 134. 

The proline-derived munchnone 153 reacts with electron-deficient alkenes to afford pyrrolizines 207 (Fig. 4.72). The intermediate adducts 206 can be isolated. 

Maryanoff and Turchi pursued a detailed theoretical study of the reaction between 1,2-dicyanocyclobutene 279 and munchnone 280, prepared by cyclodehydration of 278 and acetic anhydride (Fig. 4.100). The results from these AMI molecular orbital calculations led to the conclusions that the transition state leading to the exo cycloadduct 281 is favored electrostatically and that azomethine ylide 282 is a discrete intermediate in the formation of dihydroazepine 283. More recently, Turchi reported cycloaddition reactions between munchnone 285 and 279 to afford dihydroazepine 286 in high yield. Further cyclization of 286 gave tricycle 287. Likewise, diester 288 reacts with munchnone 42 to give dihydroazepine 289. 

Rodriguez and co-workers found that munchnone 52 reacts with nitrosoben-zene in hot xylene to give //-benzoyl-iV -phenylbenzamidine 346 (Fig. 4.114). At room temperature, the intermediate oxadiazoline 347 can be isolated. 

Apparently independently, Markl and Regitz " discovered that 1,3-dipolar cycloaddition reactions of munchnones and phosphaalkenes or phosphaalk-ynes provide a direct synthesis of 1,3-azaphospholes 353 (Table 4.21). The intermediate cycloadducts cannot be isolated. The various phosphaalkynes were generated from phosphaalkenes or, in the case of methylidynephosphane 352... 

A series of 3- and 4- pyridyl substituted pyrroles was prepared from N-acylated amino acid under microwave irradiation (Harju et al., 2009). In this synthesis, dehydration of the acylated amino acids gave cyclic intermediates (munchnones or azlac-tones), which were further treated in situ with alkynes in 1,3-dipolar cycloadditions. 

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