Boron Trifluoride Etherate cyclizations

CYCLIZATION Boron trifluoride etherate. Dibenzoyl peroxide. Dimethylcopperlithi-um. Dimethylformormide dimethyl acetal. Mercuric tiifluoroacetate. Polyphos-phoricacid. Sodium hydride. Sodium methylsulfinyUnethylide. Sulfuric acid. Tris( triphenyl phosphine)chlororhodium. 

Treatment of the indole derivative 290 with trifluoroacetic acid gave the addition product 291 that upon cyclization afforded the pyridoindole derivative 292 (81H713). Treatment of 290 which has a dioxopiperazine ring on C-3 with boron trifluoride etherate gave a mixture of pyrroloindole 293... 

An indolo[3,2-7]quinoliziniuru salt, 399, can be synthesized by a Lewis acid-induced intramolecular cyclization of compound 398 upon treatment with boron trifluoride etherate (Equation 145) <1999T11563>. 

Reaction of the benzotriazole-linked aminopyridine 503 with 2,3-dihydrofuran and boron trifluoride etherate results in cyclization to the furopyridopyrimidinium salt 504 with loss of benzotriazole (Equation 221) <1998S704>. 

The tetracyclic alcohol 179 is produced by the action of boron trifluoride etherate or tin(IV) chloride on the oxirane 178 (equation 85)95. A similar cyclization of the oxirane 180 yields DL-<5-amyrin (181) (equation 86)96. In the SnCLt-catalysed ring-closure of the tetraene 182 to the all-fraws-tetracycle 183 (equation 87) seven asymmetric centres are created, yet only two of sixty-four possible racemates are formed97. It has been proposed that multiple ring-closures of this kind form the basis of the biosynthesis of steroids and tetra-and pentacyclic triterpenoids, the Stork-Eschenmoser hypothesis 98,99. Such biomimetic polyene cyclizations, e.g. the formation of lanosterol from squalene (equation 88), have been reviewed69,70. 

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes by acid-mediated intramolecular annelation reactions. For example, treatment of alcohol 96 with trimethylsilyl triflate promoted a Friedel-Crafts acylation and subsequent dehydration giving benzo[b]thiophene 97, a potential analgesic <00JMC765>. Treatment of ketone 98 with p-toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene 99 <00T8153>. Another variant involved the cyclization of epoxide 100 to fused benzo[f>]thiophene 101 mediated by boron trifluoride-etherate . 

Nakagome and co-workers effected the successful cyclization of N-ethyl-N-arylaminomethylenemalonates (749) in poly phosphoric acid, prepared from orthophosphoric acid and phosphorus pentoxide in polyphosphate ester (PPE), prepared from phosphorus pentoxide and anhydrous diethyl ether in chloroform in phosphoryl chloride on the action of boron trifluoride etherate on the action of acetic anhydride and concentrated sulfuric acid or on the action of phosphorus pentoxide in benzene [71GEP2033971, 71JHC357 76JAP(K) 18440]. Depending on the work-up process, l-ethyl-4-oxoquinoline-3-carboxylates (750, R1 = Et), l-ethyl-4-oxoquinoline-3-carboxylic acids (750, R2 = H) and 3-ethoxycarbonyl-4-chloroquinolinium iodides (751) were obtained. Only the cyclization of... 

Diethyl 7V-ethyl-A-[6-(4-ethoxycarbonyl-l-piperazinyl)-5-fluoro-2-pyri-dyl]aminomethylenemalonate (1027) was cyclized on the action of boron trifluoride etherate complex in diphenyl ether at 228-231 °C for 30 min to give the 1,8-naphthyridine derivative (1028) in 90% yield [84JAP(K)80683]. 

Reduced furans 93 with /3-methylene groups are obtained by an intramolecular reaction of unsaturated alcohols 91 with PhEOBFa (generated in situ from iodosobenzene and boron trifluoride etherate). This cyclization may proceed via intermediate 92 (85CPB989). 

Tetrahydrofuran itself can be opened using either the stoichiometric or the catalytic version of arene-promoted lithiation, but both cases need the activation by boron trifluoride. The catalytic reaction was performed by treating the solvent THF 324 with the complex boron trifluoride-etherate and a catalytic amount (4%) of naphthalene. The intermediate 325 was formed. Further reaction with carbonyl compounds and flnal hydrolysis yielded the expected 1,5-diols 326 (Scheme 95), which could be easily cyclized to the corresponding substituted tetrahydropyrans under acidic conditions (concentrated FlCl). 

Two transannular cyclizations have been reported which lead to isomers of 677. Thus, treatment of 677 or 678 with boron trifluoride etherate gives rise to capnellene (679) Also, conversion of humulene 6,7-oxide (680) to tricyclic epoxide 681 has provided the opportunity for trimethylsilyl triftate-promoted... 

Epoxides can also serve as effective carbocyclization promotors, either through a polyene cyclization, as in the biomimetic epoxy-olefin cyclization of 100 in the presence of boron trifluoride etherate <99CC325>, or by a Friedel-Crafts approach, as exemplified by the cycli-alkylation of arylalkyl epoxides 102 under the influence of solid acid catalysts <99EJOC837>. 

Mercury salts, such as mercury(II) acetate,521-525 mercury(II) oxide,524,526-528 metcury(II) trifluoroace-tate,529,530 mercury(II) sulfate524,531 and mercury(II) phosphate531 catalyze the addition of carboxylic acids to alkynes. Acetic anhydride in the presence of boron trifluoride etherate can also be effectively used in this reaction (equation 292).521,522 Alkynoic acids undergo mercury-catalyzed cyclization to lactones (equation 293).523,532,533... 

A number of tosylhydrazones containing an alkene have been shown to undergo intramolecular cycloaddition in the presence of acid.103 96 Boron trifluoride etherate appears to be the acid of choice.103 Bridged, rather than fused, bicyclic pyrazolines are formed under these conditions. The mechanism almost certainly involves cationic intermediates. Thus, tosylhydrazone (192a) cyclized in 87% yield to the... 

Upon addition of boron trifluoride etherate, acetoxylactam 8 eliminates an acetoxy group to produce A-acyliminium ion 9. The indo-lizidinone 10 is formed diastereomerically pure in an iminium-ion-ini bated cyclization reaction of the Overman type ending in a vinyl-silane.14... 

In connection with a ciguatoxin synthesis, a cyclization (Equation 18) of stannane derivatives like 50 with tetrabutylammonium periodate followed by boron trifluoride etherate to give oxepanes, for example, 51, are... 

Boron trifluoride etherate-mediated cyclization (Equation 24) of the pyran derivative 62 (prepared from D-glucose) is used in the synthesis of AB ring system of ciguatoxine <1997T3057>. 

Diazo ketone cyclizathn. Some years ago Mander and his group1 demonstrated that the protonated diazomethylcarbonyl group can initiate cyclizations in unsaturatcd systems. In the case of phenolic diazo ketones, formation of spirodienones can predominate over competing side reactions (dienone-phenol rearrangement). Tetra-fluoroboric acid or boron trifluoride etherate can be used, but trifluoroacetic acid is usually the acid of choice. 

Cyclization of the phenol 415 (R = H) in the presence of 2,2-dimethoxypropane and boron trifluoride etherate gave the acetonide 416 (R = H) and this was reduced in the presence of ruthenium(m) chloride and Aliquat 336 to provide 417 (R = H) as a single isomer in 65-70% yield (Scheme 14). Although the corresponding 5-methoxy tricyclic compound 416 (R = OMe) was obtained, it could not be converted to the corresponding fully reduced ring system <1999EJO3067>. 

Cyclohexanone (202) was converted to compound (203) whose transformation to cyclohexanone (204) was accomplished in three steps. It underwent cyclialkylation with boron trifluoride etherate affording the cyclized product (205) (R=R,=OMe) in 64% yield along with naphthalene (206) (R=Ri= H,H). Compound (205) on heating under reflux with DDQ in benzene produced ketone (207) whose tosylhydrazone on treatment with sodium cyanoborohydride afforded reduced product (208). Deprotection of the aryl methyl ethers and oxidation with ceric ammonium nitrate led to the formation of miltirone (197). 

Reports) was converted (by a modified Curtius reaction) into the corresponding isocyanate, which was cyclized in 70—90% yield into the lactam (26), using boron trifluoride etherate. Since these represent new conditions for effecting such a reaction, generalization to a number of substituted phenethyl isocyanates was carried out. Compound (26), upon successive acetoxybromination, dehydro-bromination, and hydrolysis, gave the target compound (27), whose quasi-axial a-OH configuration was deduced from n.m.r. data. 

The regiospecific cyclization of the dimethyl derivative 48 in the presence of boron trifluoride etherate has been detailed.82 ... 

With catalytic amounts of rare earth metal triflates, heterocarbonyl compounds, e.g. acylhy-drazones, are also successfully activated. From the latter and silyl enolates (Scheme 4), the coupling products are obtained directly or in a one-pot synthesis in the presence of 5 mol% of Sc(OTf)3 or Yb(OTf)3 in 45-96% yield. For example, compound 17 was isolated in 92 % yield and was subsequently cyclized with base to the corresponding pyrazolone (Scheme 4) [16]. In comparison with typical Lewis acids, such as SnCl4, (10% yield) and boron trifluoride etherate (42 % yield), Sc(OT03 proved to be superior. 

NAZAROV CYCLIZATION Aluminum chloride. Benzylchlorobis(triphenylphos-phine)palladium. Bis(acetonitrile)-dichloropalladium(II). Boron trifluoride etherate. Tetrakis(triphenyl-phosphine)paIladium. 

Barton oxidation was the key to form the 1,2-diketone 341 in surprisingly high yield, in order to close the five-membered ring (Scheme 38). The conditions chosen for the deprotection of the aldehyde, mercuric oxide and boron trifluoride etherate, at room temperature, immediately led to aldol 342. After protection of the newly formed secondary alcohol as a benzoate, the diketone was fragmented quantitatively with excess sodium hypochlorite. Cyclization of the generated diacid 343 to the desired dilactone 344 proved very difficult. After a variety of methods failed, the use of lead tetraacetate (203), precedented by work performed within the stmcmre determination of picrotoxinin (1), was spectacularly successful (204). In 99% yield, the simultaneous formation of both lactones was achieved. EIcb reaction with an excess of tertiary amine removed the benzoate of 344 and the double bond formed was epoxidized with peracid affording p-oxirane 104 stereoselectively. Treatment of... 

In another attempt to mimic the in vivo cyclization of humulene, Mlotkiewicz et have shown that treatment of humulene 4,5-epoxide (272) with boron trifluoride etherate leads to the formation of the two tricyclic alcohols (273) and (274) in 70% yield. The carbon skeleton of these two compounds is exactly that found in africanol (276) and the more recently isolated keto-angelate (275). Further elaboration of the alcohol (273) has in fact resulted in a biomimetic synthesis of the keto-alcohol corresponding to (275). This work constitutes the first example of the direct conversion of a humulene derivative into a naturally occurring compound. 

Some noteworthy intramolecular nucleophilic ring openings have been reported in the recent literature, which can be used to prepare functionalized heterocycles of synthetic interest. For example, the highly oxygenated epoxide 100 undergoes rearrangement induced by boron trifluoride etherate, whereby anchimeric assistance from the pendant phenylthio substituent leads to an intermediate episulfonium ion 101 which subsequently suffers 5-e o-tet cyclization to form the tetrahydrofiiran derivative 102 <03TL5547>. 

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