Cyclization-elimination sequence

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

In the improved synthesis of Ifetroban described above, environmental concerns due to special handling of copper bromide waste and hazards associated with hexa-methylene tetramine (HMT) on manufacturing scale led to further perfection of the synthesis. Mechanistic considerations suggested that an oxidized form of aminoamide B (Scheme 4) would eliminate the necessity for a late-stage copper-mediated oxidation. This was indeed accomplished. The cyclization-elimination sequence was initiated by a Lewis acid and completed by base-mediated elimination to afford the Ifetroban penultimate. In addition to eliminating the need for copper bromide and HMT, this modification helped to reduce the cost of the product by an additional 15%. 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

The Bi2-catalyzed electrolysis of acetoxy bromo acetal 19a in DMF at -1.0 V alforded the diastereomeric acetal 20 as a product of a cyclization-elimination sequence. Starting from a chiral cyclopentene bromoacetal (19b) and l-octyn-3-one, a prostaglandin p2a precursor (21) containing all the structural features from C(, to C20 with SR, 11/ , and 12/ chirality, is obtained by the one-step formation of two carbon-carbon bonds in the B -catalyzed radical cyclization addition sequence (Scheme 7) [10]. 

In a similar manner, these researchers have also synthesized [48] a C-8 side-chain analog 60 of domoic acid using a cobalt-mediated cyclization-elimination sequence on the iodide 59 (Scheme 22). They extended this methodology to an enantiospecific total synthesis of acromelic acid A 64, a potent neurotoxin obtained from poisonous mushrooms [46]. The cornerstone of their synthetic strategy was a cobalt-mediated radical cyclization of the substrate 61 which was prepared from the epoxy alcohol in optically pure form. Treatment of 61 with cobalt(I) afforded 62, which was converted to the natural product 64 via pyridone 63 using routine functional group manipulation (Scheme 23). 

Treatment of the alkynes 190 with Hg(OTf)2 in acetonitrile afforded the spiroacetals 191 in excellent yield. In cases where both 5-exo-dig and 6-exo-dig cyclization was possible (m = 2, n — 2), 6-exo-dig was favored, giving only 6,6-spiroacetals as the product. However, in substrates where both 6-exo-dig and 5-endo-dig cyclizations were possible m = 1, = 1,2), 5-endo-dig was favored. The unsaturated spiroacetals 193 could be accessed from triol alkynes 192 in similarly excellent yield via a cyclization/elimination sequence upon treatment with Hg(OTf)2. Deslongchamps et al. [105] had also used this method in their synthesis of hippuristanol, where treatment of 194 with Hg(OTf>2 afforded 195 in excellent yield. 

A5-hexenyl substituent, extensive cyclization occurs to yield the cyclopentylcarbinyl product from the yields of uncyclized and cyclized products for A5-hexenylmercury chloride, the rate constants for equation 50 have been estimated (vide supra). The SH2 reaction 49 has also been invoked to be the key step in the alkylation of -substituted styrenes by a free-radical addition-elimination sequence, namely96... 

The multistep radical elimination may involve the generation of discrete intermediates, which for instance could be formed by a cyclization process7) such as 15- 16- 17e). Alternatively, there may be no intermediate involved in the elimination sequence, but the actual transition states 19, 22 are substantially lower in energy due to the anchimeric assistance of suitable functional groups9,10) (4). 

As shown in Scheme 14, a sulfuric acid-catalyzed dehydration-cyclization-elimination domino sequence starting from protonation of the secondary hydroxy group of the indolo[2,3- ]quinolizidine 112 led to the isolation of the pentacyclic compound 113 in good yield <1999EJ03429>. 

A more elaborate spiroquinolizidine unit 463 was obtained by simply heating a basic thiophenoxide solution of thioether 461, presumably by addition-elimination of thiophenoxide to give 462, which then cyclized by a second addition-elimination sequence involving the piperidine nitrogen atom, giving 463, an advanced intermediate, in a total synthesis of ( )-halichlorine (Scheme 110) <2004PNAS12079>. 

Fig. 8.22. 2-[(Acyloxy)methyl]benzamides (8.187) as double prodrugs of active amines. Activation is by cyclization-elimination in a two-step sequence, namely hydrolase-catalyzed hydrolysis of the carboxylate moiety followed by an intramolecular nucleophilic substitution with...

The mechanism was proposed to involve the formation of a nickel metallacycle by the oxidative cyclization of Ni(0) with the aldehyde and alkyne, followed by conversion of the metallacycle to product by a transmetalation/reductive elimination sequence. If R possesses a P-hydrogen, then P-hydride elimination after the transmetalation step generates the product with R = H in some instances. The mechanism was shown to be ligand dependent, and the mechanism depicted below is undoubtedly oversimplified. ... 

Reaction of 4-(ethoxymethylene)-2-phenyl-5(47f)-oxazolone 542 with a hydra-zide gives l-acyl-3-hydroxy-17/-pyrazoles 544 via an addition-elimination sequence to generate 543 followed by cyclization as shown in Scheme 7.171. ... 

Diyne cyclization/hydrosilylation catalyzed by 4 was proposed to occur via a mechanism analogous to that proposed for nickel-catalyzed diyne cyclization/hydrosilylation (Scheme 4). It was worth noting that experimental evidence pointed to a silane-promoted reductive elimination pathway. In particular, reaction of dimethyl dipropargylmalonate with HSiMc2Et (3 equiv.) catalyzed by 4 led to predominant formation of the disilylated uncyclized compound 5 in 51% yield, whereas slow addition of HSiMe2Et to a mixture of the diyne and 4 led to predominant formation of silylated 1,2-dialkylidene cyclopentane 6 (Scheme 5). This and related observations were consistent with a mechanism involving silane-promoted G-H reductive elimination from alkenylrhodium hydride species Id to form silylated uncyclized products in competition with intramolecular carbometallation of Id to form cyclization/hydrosilylation products (Scheme 4). Silane-promoted reductive elimination could occur either via an oxidative addition/reductive elimination sequence involving an Rh(v) intermediate, or via a cr-bond metathesis pathway. 

Treatment of the symmetrical triaminopyrimidine (50-1) with sulfuryl chloride ties up the two adjacent amines in a thiadiazole ring, protecting those groups from attacks in subsequent reactions. Reaction of the product (50-2) with ortho difluorinated benzylamine (50-3) results in the replacement of the pyrimidine amino group by that in the reagent most hkely by an addition-elimination sequence to afford (50-4). That amino group is then converted to the formamide (50-5) with formic acid. Exposure of the product to Raney nickel leads to a loss of sulfur and the formation of the transient intermediate (50-6). This cyclizes to a purine... 

Not only acetylene derivatives do undergo palladium catalysed intarmolecular carbon-nitrogen bond formation with amines. The similar reaction of olefins in a Wacker-type process also leads to ring closure. (0-Aminopentenes bearing a suitable leaving group in the 4-position were converted to pyrroles in a cyclization-isomerisation-elimination sequence (3.65.),82... 

An addition-elimination sequence was proposed for the intramolecular aromatic cyclization of a series of 4-aryl-alkenyl iodonium salts which were converted into dihydronaphthalenes [44] ... 

In fact, the enol ether of this compound is easily made from diethyl malonate and ethyl orthoformate [HC(OEt)3]. The aromatic amine reacts with this compound by an addition-elimination sequence giving an enamine that cyclizes on heating. This time there is no worry about the geometry of the enamine. 

Trapping of the cyclized a-alkylpalladium species by carbon monoxide (2 atm) is exemplified by Scheme 51. Again the use of acetic acid as a solvent was essential for the cyclization of the butadiene telomer (245) giving initially a-Pd species (246). Subsequent C— Pd/CO insertion (246) —> (247) + (248) was followed more readily an alkene/acylpalladium insertion-p-elimination sequence (248 -> 251) when the two adjacent moieties were cis disposed, whereas the trans intermediate (247) mainly provided the rran5-vinylcyclopentane acetic acid (249) (50% from 245). Ligand variations have so far failed to increase the diastereoselectivity of these cyclizations. 

The nickel/chromium-catalyzed cyclizations of 1,2,7-trienes (270) to (272) were postulated to proceed via a metal hydride addition to the allene unit of (270X generating an allylmetal intermediate (271) which undergoes a metallo-ene/p-elimination sequence. It is worth noting that these cyclizations can be stereocontrolled by the presence of resident stereogenic centers, as demonstrated by the transformations (273) (274) and (275) (276) (Scheme 57). 

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