Miinchnone

Diethylamino-4-(4-methoxyphenyl)-isothiazole 5,5-dioxide 6 is (95T(51)2455) a highly reactive partner in 1,3-dipolar cycloadditions with several dipoles. Azomethine yhdes, such as oxazolones 7 and miinchnones 8, afforded with 6 bicychc pyrrolo[3,4-d]isothiazole 5,5-dioxides 9, 10, 11 in satisfactory yield. The regioselectivity of the reaction was excellent. The thermal behavior of these new bicychc systems was investigated. When heated at their melting point or shghtly above, triarylpyrroles 12, 13 were obtained through SOj and AtiV-diethylcyanamide ehmination. 

Arndtsen and coworkers [154] described the first Pd-catalyzed synthesis of miinchnones 6/1-318 from an imine 6/1-316, a carboxylic acid chloride 6/1-317 and CO. The formed 1,3-dipol 6/1-318 can react with an alkyne 6/1-319 present in the reaction mixture to give pyrroles 6/1-321 via 6/1-320, in good yields. The best results in this four-component domino process were obtained with the preformed catalyst 6/1-322 (Scheme 6/1.83). 

The reaction of 5(4H)-oxazolones (32) and miinchnones with triphenylvinylphos-phonium bromide (33) provides a mild synthesis of substituted pyrroles (34) (Scheme 11). The cycloaddition-elimination reactions of 5-imino-l,2,4-thiadiazolidin-3-ones with enamines and ester enolates produce 2-iminothiazolidines. " Chiral isomtinchnone dipoles show jr-facial diastereoselectivity with IV-phenyl- or A -methyl-maleimide in refluxing benzene. ... 

In the presence of various metal ions, 2-(fluoroenone)benzothiazoline has been found to rearrange to A-2-mercaptophenylenimine, while a free radical mechanism involving the homolysis of C-S and C-N bonds has been invoked to explain the formation of 3-phenyl-1,2,4-triazole derivatives from the thermal fragmentation and rearrangement of 2-(arylidenehydrazino)-4-(5//)-thiazolone derivatives. The cycloadducts (36) formed from the reaction of 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxide (34) with nitric oxides or miinchnones (35) have been found to undergo pyrolytic transformation into a, jS-unsaturated nitriles (38) by way of pyrrole-isothiazoline 1,1-dioxide intermediates (37). 

A mechanism has been proposed involving a meso-ionic 1,3-oxazol-5-imine (miinchnone imine) intermediate for the acid-catalyzed forma-... 

The traditional synthesis of miinchnones involves the cyclodehydration of N-acylamino acids usually with acetic anhydride or another acid anhydride. Potts and Yao (3) were apparently the first to employ dicyclohexylcarbodiimide (DCC) to generate mesoionic heterocycles, including miinchnones. Subsequently, Anderson and Heider (4) discovered that miinchnones can be formed by the cyclodehydration of N-acylamino acids using Ai-ethyl-Ai -dimethylaminopropylcarbodiimide (EDC) or silicon tetrachloride. The advantage of EDC over DCC is that the urea byproduct is water soluble and easily removed, in contrast to dicyclohexylurea formed from DCC. Although the authors conclude that the traditional Huisgen method of acetic anhydride is still the method of choice, these two newer methods are important alternatives. Some examples from the work of Anderson and Heider are shown. The in situ generated miinchnones (not shown) were trapped either with dimethyl acetylenedicarboxylate (DMAD) or ethyl propiolate. 

During a peptide synthesis study, Slebioda (5) apparently independently observed the formation of miinchnone (12) from A -benzoylphenylalanine and DCC. He was able to isolate and fully characterize this crystalline miinchnone along with oxazolone 13. The tautomerization of 13 to 12 as a function of base and solvent is best effected with triethylamine in DMF (68% yield). 

Wilde (9) generated N-acyl mtinchnones for the first time via the acylation and desilylation of 5-siloxyoxazoles. Thus, for example, exposure of 17 to acetyl chloride in the presence of DMAD affords A-acetylpyrrole (19) via A-acetyl-miinchnone 18. Other trapping agents (thiocarbonyls, A-phenylmaleimide) failed and the analogous trimethylsiloxyoxazoles were unusually labile and gave lower yields of pyrroles (13-15%). Ethyl chloroformate was also used in this sequence and gave, for example, pyrroles 20-21. 

The relatively sensitive acylamino chromium complexes (e.g., 43) can be prepared in situ from stable amino carbene complexes (e.g., 42) as shown for the generation of miinchnone 44 and conversion to pyrrole 45 with DMAD (Scheme 10.5) (21). 

In the full account of this work, Padwa et al. (41) demonstrated that the 1,3-dipolar cycloaddition is an endo cycloaddition and the regiochemistry is consistent with that of a HOMO-dipole controlled process as judged from the products 91 and 92 that arise from the reaction between isomiinchnone 90 and methyl propiolate and phenyl vinyl sulfone, respectively (Scheme 10.15). Iso-miinchnone 90 is also trapped with DMAD to give the expected furan in 41% yield. 

The statement made in 1986 by Gingrich and Baum (10), with regard to miinchnones, that the most important reactions (of mtinchnones) from a synthetic point of view are 1,3-dipolar cycloaddition reactions, certainly applies to all mesoionic heterocycles and is more true today than it was in 1986. Although the factors governing the regioselectivity of unsymmetrical mesoionic cycloadditions are not always completely understood, the synthetic utility of this chemistry is enormous and indisputable. 

Yamanaka and co-workers (74) effected the 1,3-dipolar cycloaddition between miinchnones 134 and polyfluoro-2-alkynoic acid esters to afford the corresponding 4-(polyfluoroalkyl)pyrrole-3-carboxylates (135). The reaction proceeds rapidly at low temperature and the various miinchnones (134) were generated from 1,3-oxazolium perchlorates 133 using the method of Boyd and Wright (6,7). Under... 

Padwa et al. (75) found that the unsymmetrical miinchnone 137, which was generated from A-acetyl-7/-benzylglycine (136) and refluxing acetic anhydride, reacts with methyl propiolate to give an 8 1 mixture of pyrroles 138 and 139. The same product ratio is obtained from the reaction of methyl propiolate and the azomethine ylide derived from 7/-benzyl-A(-(a-cyanoethyl)-A(-[(trimethylsilyl)-methyl] amine. 

Similarly, Toupet et al. (76) determined the structures of the pyrrole adducts from the cycloaddition of several miinchnones with methyl phenylpropionate by X-ray crystallography. These highly regioselective cycloadditions are in accord with FMO predictions. This same French team (77) studied the cycloaddition reactions of miinchnones with methyl propiolate and methyl 3-phenylpropiolate to... 

Coppola et al. (81) extensively studied the dipolar cycloaddition of methyl propiolate with unsymmetrical miinchnones. In addition to their own results (Table 10.3), these investigators summarized much previous data on these cycloadditions. In the authors words No single criterion can successfully be used to correlate the experimental observations regarding the regioselectivity in milnch-none cycloaddition reactions. Steric and electronic effects must be considered in... 

Despite the uncertainties regarding regiochemistry, the reaction of propiolates with miinchnones has found use in synthesis. Kane and co-workers (84) synthesized the calcium channel activator FPL 64176 (161) using a mtinchnone cycloaddition protocol. Thus, reaction of amino acid 158 with acetic anhydride in the presence of acetylenic dipolarophUe 159 gave pyrrole 160 in 49% yield. Base-induced elimination of the 4-nitrophenethyl protecting group afforded FPL 64176 (161) in 85% yield. 

Pinho e Melo et al. (89) employed an intramolecular miinchnone cycloaddition to constmct several l/7-pyrrolo[l,2-c]thiazole derivatives from N-acylthiazolidines and acetic anhydride. Martinelli and co-workers (90,91) employed an intramolecular miinchnone cycloaddition to craft a series of 4-keto, 5,6,7-tetrahydroindoles (168-171) in two steps. The requisite acetylenic precursors were prepared from glutaric anhydride (or 3-methylglutaric anhydride). The overall sequence is illustrated for the synthesis of 168. An electrophilic acetylenic unit appears to be necessary for successful intramolecular 1,3-dipolar cycloaddition. 

Nan ya et al. (97) also reported the synthesis of isoindolediones by the reaction of miinchnones with 1,4-benzoquinones. Reactions with an unsymmetrical mtinchnone were not regioselective. Several groups have examined the reactions of miinchnones with unsaturated nitriles, including 2-chloroacrylonitrile (98), cinna-monitrile (78,99) and fumaronitrile (78) to give unexpected products in several cases. Eguchi and co-workers (100) smdied the cycloaddition of several mtinch-nones with electron-deficient trifluoromethylated olehns. Thus, miinchnones 176... 

The higher reactivity of ring-strained olefins has been exploited by several workers in 1,3-dipolar cycloaddition reactions of milnchnones. Thus, Kato and co-workers (112) reported that miinchnone 38 reacts with 1,2,3-triphenyl-1//-phosphirene (202) to give l-methyl-2,3,4,5-tetraphenylpyrrole (203) (45% yield). Control experiments demonstrated that phosphirene 202 does not decompose to diphenylacetylene appreciably under the reaction conditions. Moreover, the reaction of diphenylacetylene and miinchnone 38 afforded only a 21% yield of pyrrole 203. 

Unfortunately, this same group found that miinchnone 38 gave only complex product mixrnres upon reaction with benzocyclopropene, in an unsuccessful attempt to synthesize a methanoazonine (113). As is presented later, a similar reaction was successful with an isomilnchnone. Likewise, Kato et al. (114) were unable to induce milnchnones 38 and 190 to react cleanly with benzocyclobutadiene. 

Martin et al. (115) found that miinchnone 38 reacts with isopropyhdenecyclo-butenone (204) to form dihydroazepine 205. At room temperature the two bis(adducts) 206 and 207 were isolated, although the regiochemistry of the cycloaddition has not been established. 

Turchi (118) also reported cycloaddition reactions between milnchnones 215 and 209 to afford dihydroazepine 216 in high yield. Further cyclization of 216 gave tricycle 217. Likewise, diester 218 reacts with miinchnone 38 to give dihydroazepine 219. 

Kato et al. (119) explored reactions of fulvenes with a variety of mesoionic heterocycles. Unfortunately, reactions of miinchnone 38 with several fulvenes afforded complex mixtures in each case, and no identifiable products were reported, although Friedrichsen and co-workers (120-122) previously reported the reaction between mtinchnones and fulvenes to give cycloadducts. Kato et al. (123) also studied the cycloaddition reactions of tropone with several mesoionic heterocycles. Despite heroic efforts, the reaction of tropone with miinchnone 38 was complex and could not be unraveled. However, as described later, the reaction of tropone with isomtlnchnones was successful. Wu et al. (124) effected the cycloaddition between a miinchnone and fullerene-60 (Ceo) to give the corresponding dihydropyrrole in excellent yield. 

The father of miinchnone chemistry, Rolf Huisgen, reported (130) the 1,3-dipolar cycloaddition of miinchnone 38 with p-nitrophenyldiazonium salt 226 to give the triazolium salt 227. This reaction would appear to be an important new route to these heterocycles. 

The miinchnones were generated in situ by the cyclodehydration of their N-acylamino acid precursors with DCC in toluene (25-60°C). 

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