Isocyanoacetates, cycloaddition

Pyrrolyl)-4,5-dihydroisoxazole derivatives 402 have been synthesized (Scheme 1.48) in good yields (66%-78%) by regioselective 1,3-dipolar cycloaddition of nitrile oxides to 1-phenylsulfony 1-1,3-dienes, followed by Barton-Zard pyrrole annulation using ethyl isocyanoacetate anion (444). 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

The oxidation of the alcohol was performed with supported perruthenate (8.48, Fig. 8.46) to produce clean aldehydes 8.91 after filtration. The Henry reaction was performed in the presence of a commercially available, supported strong base 8.92 and an excess of volatile nitroalkenes, giving clean nitroalcohols 8.93 after filtration and evaporation. The reaction mixtures from the trifluoroacetylation/elimina-tion steps were purified with commercially available amino PS resin 8.58 to scavenge the trifluoroacetates and with acidic ion-exchange resin 8.76 to remove the TEA-derived salts. Again, the nitrostyrenes 8.94 were obtained cleanly after filtration and evaporation. Cycloaddition with isocyanoacetate was promoted by the commercially available, supported guanidine base 8.95, while the subsequent N-alkylation of the pyrroles 8.96 was performed with an excess of halide in the presence of the commercially available, supported phosphazene 8.97. In this case, the excess halide was removed by treatment with supported 8.58, and filtra-... 

Organoaluminum and Sn(IV) Lewis acid-mediated [3 + 2] cycloadditions of oxa-zoles and aldehydes or diethyl ketomalonate have been observed [116]. The reactions are highly regioselective, with stereoselectivity highly dependent upon the Lewis acid used (Eq. 76). For example, the (BINOL)AlMe-promoted reaction between benzal-dehyde and the oxazole furnishes the oxazoline with a transicis ratio of 2 98. The selectivity is reversed with SnCU which results in a transicis ratio of 85 15. trans-5-Sub-stituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes [117]. 

Grigg and coworkers have recently shown that AgOAc is a catalyst of choice for the cycloaddition of isocyanoacetates with olefins possessing conjugated electron-withdrawing groups to give <5 - or <5 -pyrrolines [14], For instance, the reaction of... 

Imidazole-4-carboxylates have been made from amidines derived from or-ainino acids (see Section 2.2.1 and Table 2.2.1), by Claisen rearrangement of the adduct formed when an arylamidoxime reacts with a propiolate ester (see Section 2.2.1 and Scheme 2.2.6), from a-aminocarbonyls with cyanates or thiocyanates (see Section 4.1 and Table 4.1.1), from a-oximino- 6-dicarbonyl compounds heated with an aUcylamine (see Section 4.1 and Scheme 4.1.7), and by anionic cycloaddition of an alkyl isocyanoacetate to diethoxyacetonitrile (see Section 4.2 and Scheme 4.2.11 see also Scheme 4.2.12). A further useful approach is to use an appropriate tricarbonyl compound with an aldehyde and a source of ammonia (see Chapter and Scheme 5.1.1). Irradiation of 1-alkenyltetrazoles bearing an ester substituent may have applications (see Section 6.1.2.3). 

Ruthenium(ll)-catalyzed cycloaddition reactions of Y-sulfonylimines 1308 with methyl isocyanoacetate 1309 gave /ra r-2-imidazolines 1310 stereoselectively in 75-90% yields under neutral, mild conditions [R = phenyl, substituted phenyl, 2-furyl, lrans-PhCH=CH, tert-Bu R = tosyl, PI1SO2] (Scheme 333) < 1997JOG1799>. In contrast, the same reaction catalyzed by 1 mol% AuCl(( -HexNG) provides 4-methoxycarbonyl-5-alkyl-2-imidazolines 1321 with over 98% -selectivity (Scheme 333) <1996TL4969>. 

Similarly, the anionic cycloaddition of methyl isocyanoacetate to diethoxyacetonitrile gives methyl... 

Cycloadditions. 1,3-Dipolar cycloadditions of isocyanoacetic esters are catalyzed by AgOAc. In the absence of dipolarophiles, the esters dimerize to give imidazole-4-car-... 

Imidazolines and isoxazolines. 1,3-Dipolar cycloaddition of isocyanoacetic esters and amides with 7/-tosylimines and aldehydes, respectively, furnishes the five-membered heterocycles. Interestingly, cis-imidazolines and frans-oxazolines are major products. Since trans-imidazolines are obtained on base-catalyzed isomerization of the cts-isomers, both erythro- and threo-a,P-diamino acids are accessible. 

Base-induced cycloaddition of TosMlC 37 to N-sulfonylaldimines 36 affords 4(5)-monosubstituted imidazoles 38 from which the parent imidazoles 39 can be prepared <97T11355>. This type of chemistry has been extended to reaction with arylazosulfones <97T2125>. N-Sulfonyl-2-imidazolines are derived from the ruthenium complex catalyzed reaction between isocyanoacetate and analogs of 36 <97JOC1799>. Cycloaddition of ylide 40 with trifluoroacetonitrile gives trifluoromethyl substituted imidazolines <97TL4359>. 

A quite new route to unsaturated fused 1,2,4-triazines 19 and 20 includes the first [3 + 3]-cross-cycloadditions ofa-acidic ethyl isocyanoacetate with 1,3-dipo-lar azomethine imines 21 or Af-irninoisoqiiinoliniurn ylides 22 with significant regiochemical control under mild catalytic reaction conditions (140L4004). 

Gribble and Pelkey adapted the Barton-Zard pyrrole synthesis [84] to 3-nitroindoles and ethyl isocyanoacetate (and tosylmethyl isocyanide) to give 2,4-dihydropyrrolo [3,4-T [indoles (Scheme 15, equation 1) [85, 86], In complementary work, Gribble and cowoikers synthesized pyrrolo[3,4-fc]indoles from the 1,3-dipolar cycloaddition of 2- and 3-nitroindoles with miinchnones (1,3-oxazo-lium-5 elates) (eqnations 2, 3) [87, 88]. The mesoionic miinchnones were generated in situ from the appropriate Af-benzyl-Af-acylamino acids. Gribble and Kishbaugh... 

Cooperative catalysis using cinchona alkaloid derivatives in combination with metals such as silver have also been widely developed. On the basis of this concept, Escolano et al. have disclosed an enantioselective domino Michael-cyclisation reaction. This formal [3 + 2] cycloaddition occurred between isocyanoacetates and enones in the presence of a combination of a chiral hifunctional cinchona alkaloid, such as cupreine, and AgNOs to provide the corresponding chiral 2,3-dihydropyrroles in low to high yields and... 

Silver acetate catalyses the cycloaddition of methyl isocyanoacetate with electron-deficient alkenes to produce A - or A -pyrrolines in good yields. The reaction of 3-acetoxy-l-methylallylsilane with A-chlorosulfonyl isocyanate at 0°C produces the... 

Fluorinated pyrroles have been studied intensively in recent years. As a resnlt, a significant number of synthetic approaches to these compounds was elaborated. The most general methods involve direct fluorination/trifluoromethylation of the parent pyrroles, both the [3 -1- 2]- and the [4H-2]-cycloaddition reactions, the applications of carbonyl compounds as well as TOSMIC and isocyanoacetates. Thongh variety of methods are already known, the elaboration of novel preparative pathways towards fluorinated pyrrole derivatives is still ongoing, which is due to the manifold of biological activities of this structural motive and the use as precursors for porphyrins synthesis. It is no doubt, that this branch of synthetic organic chemistry will enjoy a much attention, giving rise to sustainable flow of novel convenient pathways to the synthesis of fluorinated pyrroles. 

Yuan described the synthesis of A -substituted 5-trifluoromethylimidazole-4-carboxylates via the base-induced cycloaddition of ethyl isocyanoacetates to trifluo-roacetimidoyl chlorides followed by aromaticity-driven intramolecular cyclization via 1,1-addition of the amino group to the isocyano functionality (Scheme 39) [53]. A wide variety of 5-trifluoromethylimidazole carboxylates, bearing an alkyl or aryl group at iV-1, was prepared using this method. Moreover, the electronic nature of the aryl group did not significantly affect the course of reaction. 

Wu and coworkers developed a Cu(I)-catalyzed three-component reaction of 2-(2-ethynylphenyl)oxiranes 111, sulfonyl azides 112, and ethyl a-isocyanoacetate (113) to afford 3 5 -dihydro-l//-spiro[benzo[d]oxepme-2,4 -imidazoles] 114 as a single diastereomer (Scheme 4.24) [44]. The reaction was initiated by a Cu(I)-catalyzed [3+2] cycloaddition between azide and alkyne to generate the intermediate 115. Subsequent release of nitrogen would provide the reactive ketenimine species 116. An intramolecular nucleophilic attack of epoxide to the ketenimine afforded the intermediate 117, which underwent fragmentation to provide 118. Finally, a [3+2] cycloaddition of 118 with a-isocyanoacetate 113 afforded the observed product 114. 

Silver nitrate is used for the ring-opening of 2-nitrothiophene by amines, and for the asymmetric formal [3+2] cycloaddition reaction of isocyanoacetates to a. unsaturated ketones. Silver nitrate is also used for the separation of homopropar-gylic alcohols from allenic alcohols and for the purification of a rra i, /rans-2,4-hexadienol from its stereoisomers. ... 

The asymmetric formal 3 + 2-cycloaddition reaction of a-isocyanoacetates with A-aryl maleimides produced optically active, substituted l,3fl,4,5,6,6a-hexahydropyrrolo[3,4-cjpyrrole derivatives in high yields, high diastereoselectivities, and good to excellent enantioselectivities. A cinchona-derived squaramide/AgSbFg catalyst (68) was used in this reaction. 

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