Ether compounds cycloadditions

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

A chiral zinc(II) complex derived from Et2Zn and diisopropyl (/ ,/ )-tartrate as a chiral auxiliary is applied to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to an achiral allylic alcohol, giving the corresponding (R)-2-isoxazolines with high enantioselectivity. Addition of a small amount of ethereal compounds such as DME and 1,4-dioxane is crucial for achieving the high asymmetric induction in a reproducible manner [71] (Eq. 8A.47). 

The propensity of a-pyrones to undergo the Diels-Alder reaction makes them useful for syntheses of highly substituted aromatics and biphenyls. A practical method for the regioselective synthesis of the A-benzoyl-4-(polyfluoroalkyl)ani-lines 82 by thermal Diels-Alder cycloaddition of 71 with fluorostyrenes and acetylenes was described. Free 4-(polyfluoroalkyl)anilines were smoothly formed in good yields by DBU-assisted deprotection. In the case of the reactions of pyrone 71a with isobutyl vinyl ethers and cyclic vinyl ethers, compounds 83 and 84 were obtained, respectively [36] (Scheme 26). 

Endo adducts are usually favored by iateractions between the double bonds of the diene and the carbonyl groups of the dienophile. As was mentioned ia the section on alkylation, the reaction of pyrrole compounds and maleic anhydride results ia a substitution at the 2-position of the pyrrole ring (34,44). Thiophene [110-02-1] forms a cycloaddition adduct with maleic anhydride but only under severe pressures and around 100°C (45). Addition of electron-withdrawiag substituents about the double bond of maleic anhydride increases rates of cycloaddition. Both a-(carbomethoxy)maleic anhydride [69327-00-0] and a-(phenylsulfonyl) maleic anhydride [120789-76-6] react with 1,3-dienes, styrenes, and vinyl ethers much faster than tetracyanoethylene [670-54-2] (46). 

Bravo et al. studied the reaction of various ylides with monooximes of biacetyl and benzil. Dimethylsulfonium methylide and triphenylarsonium methylide gave 2-isoxazolin-5-ol and isoxazoles, with the former being the major product. Triphenylphosphonium methylide and dimethyloxosulfonium methylide gave open-chain products (Scheme 135) (70TL3223, 72G395). The cycloaddition of benzonitrile oxide to enolic compounds produced 5-ethers which could be cleaved or dehydrated (Scheme 136) (70CJC467, 72NKK1452). 

Two different alkenes can be brought to reaction to give a [2 -I- 2] cycloaddition product. If one of the reactants is an o, /3-unsaturated ketone 11, this will be easier to bring to an excited state than an ordinary alkene or an enol ether e.g. 12. Consequently the excited carbonyl compound reacts with the ground state enol ether. By a competing reaction pathway, the Patemo-Buchi reaction of the 0, /3-unsaturated ketone may lead to formation of an oxetane, which however shall not be taken into account here ... 

Schemes 16-19 present the details of the enantioselective synthesis of key intermediate 9. The retrosynthetic analysis outlined in Scheme 5 identified aldoxime 32 as a potential synthetic intermediate the construction of this compound would mark the achievement of the first synthetic objective, for it would permit an evaluation of the crucial 1,3-dipolar cycloaddition reaction. As it turns out, an enantioselective synthesis of aldoxime 32 can be achieved in a straightforward manner by a route employing commercially available tetronic acid (36) and the MEM ether of allyl alcohol (74) as starting materials (see Scheme 16).

Diene 265, substituted by a bulky silyl ether to prevent cycloaddition before the metathesis process, produced in the presence of catalyst C the undesired furanophane 266 with a (Z) double bond as the sole reaction product in high yield. The same compound was obtained with Schrock s molybdenum catalyst B, while first-generation catalyst A led even under very high dilution only to an isomeric mixture of dimerized products. The (Z)-configured furanophane 266 after desilylation did not, in accordance with earlier observations, produce any TADA product. On the other hand, dienone 267 furnished the desired macrocycle (E)-268, though as minor component in a 2 1 isomeric mixture with (Z)-268. Alcohol 269 derived from E-268 then underwent the projected TADA reaction selectively to produce cycloadduct 270 (70% conversion) in a reversible process after 3 days. The final Lewis acid-mediated conversion to 272 however did not occur, delivering anhydrochatancin 271 instead. 

Cycloalkenones and/or their derivatives can also behave as dienic partners in the Diels-Alder cycloaddition. It is well documented [41] that cyclic acetals, for example, can interconvert with ring-opened enol ether forms, in a reversible manner the latter compounds can then be trapped by various dienophiles. Thus dienes 119 and 120 reacted with [60]-fullerene (Ceo) at high pressure, affording highly thermally stable products [42] (Scheme 5.16). Ketones 123 and 124 could be directly obtained by cycloaddition of enol forms 121 and 122 of 2-cyclopen-ten-and 2-cyclohexen-l-one, respectively. 

The rhodium-mediated reaction of 69 with 2,3-dihydrofuran (a formal dipolar cycloaddition of a cyclic diazo dicarbonyl compound with a vinyl ether) yields 70. Corrqiound 70 can be transformed in a number of steps to 71 a,b <96TL2391>. 

The JV-phosphino-l-azadiene 66 undergoes cycloaddition with DMAD in ether at -20 °C to form the bridged structure 67 <96AG(E)896>. The new compound is thermally unstable and isomerises to the alternative bridged structure 68 at 25 °C. X-ray analysis data have been interpreted to suggest that the isomer 69 co-exists in the solid state. The same ring system is also formed by protonation at the sp carbon atom neighbouring phosphorus in 67 (Scheme 15). 

Reactions of 1 with epoxides involve some cycloaddition products, and thus will be treated here. Such reactions are quite complicated and have been studied in some depth.84,92 With cyclohexene oxide, 1 yields the disilaoxirane 48, cyclohexene, and the silyl enol ether 56 (Eq. 29). With ( )- and (Z)-stilbene oxides (Eq. 30) the products include 48, ( > and (Z)-stilbenes, the E- and Z-isomers of silyl enol ether 57, and only one (trans) stereoisomer of the five-membered ring compound 58. The products have been rationalized in terms of the mechanism detailed in Scheme 14, involving a ring-opened zwitterionic intermediate, allowing for carbon-carbon bond rotation and the observed stereochemistry. 

Giomi s group developed a domino process for the synthesis of spiro tricyclic nitroso acetals using a, 3-unsaturated nitro compounds 4-163 and ethyl vinyl ether to give the nitrone 4-164, which underwent a second 1,3-dipolar cycloaddition with the enol ether (Scheme 4.35) [56]. The diastereomeric cycloadducts formed, 4-165 and 4-166 can be isolated in high yield. However, if R is hydrogen, an elimination process follows to give the acetals 4-167 in 56% yield. 

The ring-opening of the cyclopropane nitrosourea 233 with silver trifiate followed by stereospecific [4 + 2] cycloaddition yields 234 [129]. (Scheme 93) Oxovanadium(V) compounds, VO(OR)X2, are revealed to be Lewis acids with one-electron oxidation capability. These properties permit versatile oxidative transformations of carbonyl and organosilicon compounds as exemplified by ring-opening oxygenation of cyclic ketones [130], dehydrogenative aroma-tization of 2-eyclohexen-l-ones [131], allylic oxidation of oc,/ -unsaturated carbonyl compounds [132], decarboxylative oxidation of a-amino acids [133], oxidative desilylation of silyl enol ethers [134], allylic silanes, and benzylic silanes [135]. 

Increasing use is being made of pyran syntheses based upon [4 + 2] cycloadditions of carbonyl compounds. The appropriate unsaturated aldehyde with ethyl vinyl ether yields 53 with peracids this affords an epoxide that undergoes ring contraction to the aldehyde 54 (Scheme 23) and rhodium catalyzed decarbonylation affords the required 3-alkylfuran with the optical center intact.116 Acetoxybutadiene derivatives add active carbonyl compounds giving pyrans that contract under the influence of acids to give... 

Enol ether additives were used to probe the protonation of 3-cyclopen-tenylidene (127). Treatment of A-nitroso-A-(2-vinylcyclopropyl)urea (124) with sodium methoxide generates 2-vinylcyclopropylidene (126) by way of the labile diazo compound 125 (Scheme 25). For simplicity, products derived directly from 126 (allene, ether, cycloadduct) are not shown in Scheme 25. The Skat-tebpl rearrangement of 126 generates 127 whose protonation leads to the 3-cyclopentenyl cation (128). In the presence of methanol, cyclopentadiene (130) and 3-methoxycyclopentene (132) were obtained.53 With an equimolar mixture of methyl vinyl ether and methanol, cycloaddition of 127 (—> 131)... 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

On the basis of available experimental data, it is impossible to choose a definite pathway of elimination of silanol. However, study of silylation of methyl P -nitropropionate (411) with BSA in the presence of trapping agents rigorously proved that silyl nitronate D is initially formed. This compound can be detected in the [3 + 2]-cycloaddition reaction with methyl acrylate product (413). If silylation of AN (411) is performed in the presence of ethyl vinyl ether, a-nitrosoalkene E can be successfully trapped in as heterodiene a Diels-Alder reaction. Dihydroox-azine (414) is formed, and its silylation affords isolable product (415). 

The copper complex of these bis(oxazoline) compounds can also be used for hetero Diels-Alder reactions of acyl phosphonates with enol ethers.43 5 A favorable acyl phosphonate-catalyst association is achieved via complexation between the vicinal C=0 and P=0 functional groups. The acyl phosphonates are activated, leading to facile cycloaddition with electron-rich alkenes such as enol ethers. The product cyclic enol phosphonates can be used as building blocks in the asymmetric synthesis of complicated molecules. Scheme 5-36 shows the results of such reactions. 

Intramolecular [4+2]-cycloaddition reactions, which involve base-induced isomerization of a propargyl ether to an allenyl ether, have been extensively studied. Treatment of 157 with a base caused an intramolecular Diels-Alder reaction of the intermediate allenyl ether to give tricyclic compounds 158 [131]. An asymmetric synthesis of benzofuran lactone 159 was achieved by an analogous procedure [132],... 

Similar intramolecular cycloadditions are encountered where an ether linkage has been incorporated into the met a or para linking groups 123. In these cyclizations the better yields were obtained from the para-attached systems. The yields obtained are again dependent on the chain length of the separator and are indicated below the appropriate structures (124)57. Other hetero-atom-substituted cyclophanes (125) can be obtained by irradiation of the divinyl compounds (126)58,59. The use of tin and germanium derivatives... 

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