Cycloadditions forming furans

The [3 + 2] cycloaddition of furan proceeds in the reaction of 5M in protic solvent (HFIP), where deprotonation from the initially formed intermediate 28 does not take place and intramolecular cyclization predominates in the termi-... 

If 2-camphanyloxyacrylonitrile (15 R = C8H 02C00) is taken for cycloaddition, diastereoisomeric cycloadducts can be separated, and the basic system, 7-oxabicyclo-[2.2.1]hept-5-en-2-one 17, can be obtained in optically pure form [36]. Another way of obtaining enantiomeric ketones is based on crystallization of a brucine complex obtained from the corresponding cyanohydrines (see Sec. III). Ketone 17 can be converted [e.g., by cis-hydroxylation (—>18), protection of the diol system, and Baeyer-Villiger oxidation] to lactone 19, the opening of which leads to furanuronic acid 20. A new development in this field is based in cycloaddition between furan and 2-chloro- or 2-bromoacrolein in the presence of 5 mol% chiral oxazaborolidine 21 as catalyst [37],... 

The only other dipolar species that has been added to thiophene is the carbonyl ylide (287). Thus tetracyanoethylene oxide, as the carbonyl ylide, reacts with thiophene to form the adduct (288) in 70% yield (65JA3657, 68T2551). Several monosubstituted thiophenes have been used in this reaction. From competitive experiments it has been shown that the rate of cycloaddition to furan and benzo[6]furan is greater than that to thiophene and benzo[6]thiophene respectively (75ACS(B)441). 

A number of different furan-based approaches to the synthesis of 7-membered ring systems were reported in 2003. In the novel example shown below, the furan participated in an intramolecular [4+3] cycloaddition with nitrogen-stabilized chiral oxyallyl cation to form polycyclic structures <03JA12694>. Attempts to construct the [4.4.1] bicychc BC ring system of ingenol via a type-II intramolecular [4+3] cycloaddition between furan and an oxyallyl cation produced the desired product but only in 14% yield <03JOC7899>. 

Enantiomerically enriched products can also be obtained by employing a dienophile bearing a chiral controller group [13]. For example, the use of the camphanate ester derivative (S)-3b (also available in the (R) form) in the cycloaddition with furan gave a 29% yield of diastereomer 4 b after purification, along with other endo and exo isomers, Eq. 2. Saponification afforded the chiral ketone (+)-2. Reactions of 4b and 2 have been reported to occur with high regio-and stereocontrol (vide infra). 

The bicyclic intermediate arising from Diels-Alder reaction of oxazoles with alkynes extrudes nitriles (comprised of the nitrogen atom and C4 of the oxazole) to form furans as the ultimate product of the cycloaddition. The same regioselectivity seen in alkene Diels-Alder reactions is noted here. 

Sol 15. The majority of Diels—Alder reactions yield endo products. In most of the cases, the exo product is thermodynamically more stable, but the endo adduct forms much more rapidly (kinetic control). However, [4 + 2] cycloaddition of furan and maleic anhydride gives predominantly exo adduct. Such a stereochemistry of the furan-maleic anhydride adduct is due to the fact that the initially formed endo compound readily reverses into the reactants whereas the exo cycloaddition gives a relatively stable adduct that is the product of the thermodynamic control. 

Six-membered Rings.— The versatility of 1,3-dipolar cycloadditions and of hetero-Diels-Alder reactions is, once again, used to great effect for the synthesis of 1,2-oxazine derivatives. Useful, multifunctionalized heterocycles are obtained by reaction of nitrile oxides with sulphoxonium allylides, followed by conversion of the initially formed furans (257) to oxazines (258) by treatment with tosic acid. Treatment with NEts causes migration of the alkoxycarbonyl group forming the pyrrolone (259). 

The experimental observations and outcomes of the cycloadditions of oxyallyl cations, which are the same except for the identity of M, are compared in Table 18.1. Over a series of cycloadditions with furan as the common diene, the lithium oxyallyl cation (5, M = Li), formed from chloroke-tone la under basic conditions, was not highly electrophilic. 

Craft and Gung developed a paUadium-catalyzed transannular [4+3] cycloaddition route in which all of the rings of cortistatins are prepared in one step from a single macrocyclic precursor (Scheme 19.50) [114]. Exposure of macrocyclic allene 233 to a catalytic amount of palladium (II) acetate in the presence of excess lithium bromide resulted in the formation of 238 as a single isomer in 37% yield. This is the first report of a transannular [4+3] cycloaddition. The proposed mechanism is shown in Scheme 19.50. The formation of allene-palladium complex 234 affords a a-allylpalladium intermediate, which rapidly isomerizes to the 7i-allylpalladium intermediate 235. This can then undergo intramolecular cycloaddilion via an endo (compact) transition strucmre 236 to give bromonium ion 237. The loss of a proton results in the formation of the observed product 238. Cycloadduct 238 was readily converted into the tetracyclic core skeleton of cortistatins 239 by selective reduction of the olefin formed by cycloaddition with furan, followed by reductive debromination. 

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

Give the structure of the cycloaddition product formed when benzyne is generated in the presence of furan (See Section 11 22 if necessary to remind yourself of the structure of furan )... 

The addition of p-quinone to enamines normally produces furan derivatives, especially when the enamine possesses a 3 hydrogen (see Section III. A). 1,2 Cycloaddition is claimed to take place to give a cyclobutane derivative when p-quinone and an enamine with no jS hydrogens are allowed to react at low temperatures (51). However, little evidence is reported to verify this structural assignment, and the actual structure probably is a benzofuranol (52). Reaction of a dienamine (formed in situ) with p-quinone in the presence... 

Adduct 100 is formed from the 1,4 cycloaddition of o-quinone (99) with the morpholine enamine of cyclohexanone (125). Treatment of styrene oxide with cyclic enamines at elevated temperatures (about 230°C) produces O.N-ketals possessing a furan nucleus (125a). 

Substituted TMM complexes also cycloadd to aldehydes in the presence of a tin cocatalyst such as MesSnOAc and MesSnOTs [31]. Reaction of 2-heptenal with methyl precursor (6) gave a mixture of methylenetetrahydrofurans (68) and (69). This regioselectivity is reversed with 10-undecenal and methyl precursor (5), where adduct (70) now predominates over (71). As in the carbocyclic system, the phenylthio group also functions as a regiocontrol element in reaction with cyclohexyl aldehyde. The initially formed adduct (72) eliminates the element of thio-phenol on attempted allyl rearrangement, and the overall process becomes a cycloaddition approach to furans (Scheme 2.21) [20]. 

Further mechanistic evidence comes from trapping experiments. When bromobenzene is treated with KNH2 in the presence of a diene such as furan, a Diels-Alder reaction (Section 14.5) occurs, implying that the symmetrical intermediate is a benzyne, formed by elimination of HBr from bromobenzene. Ben-zyne is too reactive to be isolated as a pure compound but, in the presence of water, addition occurs to give the phenol, in the presence of a diene, Diels-Alder cycloaddition takes place. 

The insertion of alkynes into a chromium-carbon double bond is not restricted to Fischer alkenylcarbene complexes. Numerous transformations of this kind have been performed with simple alkylcarbene complexes, from which unstable a,/J-unsaturated carbene complexes were formed in situ, and in turn underwent further reactions in several different ways. For example, reaction of the 1-me-thoxyethylidene complex 6a with the conjugated enyne-ketimines and -ketones 131 afforded pyrrole [92] and furan 134 derivatives [93], respectively. The alkyne-inserted intermediate 132 apparently undergoes 671-electrocyclization and reductive elimination to afford enol ether 133, which yields the cycloaddition product 134 via a subsequent hydrolysis (Scheme 28). This transformation also demonstrates that Fischer carbene complexes are highly selective in their reactivity toward alkynes in the presence of other multiple bonds (Table 6). 

When benzyne is generated in the absence of another reactive molecule it dimerizes to biphenylene.132 In the presence of dienes, benzyne is a very reactive dienophile and [4+2] cycloaddition products are formed. The adducts with furans can be converted to polycyclic aromatic compounds by elimination of water. Similarly, cyclopentadienones can give a new aromatic ring by loss of carbon monoxide. Pyrones give adducts that can aromatize by loss of C02, as illustrated by Entry 7 in Scheme 11.9. 

Diterpenoids related to lambertianic acid were prepared by intramolecular cyclization of either an alkene or an alkyne with a furan ring <2005RJ01145>. On heating amine 101 with allyl bromide, the intermediate ammonium ion 102 was formed which then underwent [4+2] cycloadditions in situ to give the spiroazonium bromides 103 and 104 (Scheme 13). These isomers arose from either endo- or co-transition states. The analogous reaction was also carried out with the same amine 101 and propargyl bromide. The products 105 and 106 contain an additional double bond and were isolated in 58% yield. The product ratios of 103 104 and 105 106 were not presented. 

Ethyl diazopyruvate, under copper catalysis, reacts with alkynes to give furane-2-carboxylates rather than cyclopropenes u3) (Scheme 30). What looks like a [3 + 2] cycloaddition product of a ketocarbenoid, may actually have arisen from a primarily formed cyclopropene by subsequent copper-catalyzed ring enlargement. Such a sequence has been established for the reaction of diazoacetic esters with acetylenes in the presence of certain copper catalysts, but metallic copper, in these cases, was not able to bring about the ring enlargement14). Conversely, no cyclopropene derivative was detected in the diazopyruvate reaction. 

MCP (1) is not known to undergo [4 + 2] cycloadditions. The substitution of two, or more, ring protons with fluorine atoms, however, seems to improve dramatically the dienophilic reactivity of the exocyclic double bond. 2,2-Di-fluoromethylenecyclopropane (5) is a quite reactive dienophile in Diels-Alder cycloadditions. With cyclopentadiene (6) and furan (7), it formed two isomeric adducts (Scheme 1) [9]. In both cases the adduct with the endo CF2 group is the major isomer. 

The 2-phenylsulfinylester 94, which had been prepared in racemic form, rapidly eycloadded to furan (7) at room temperature, albeit with low stereoselectivity [19], The effect of Lewis acids on the stereoselectivity of the cycloaddition has not been tested (Scheme 19). 

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