Meerwein cyclizations

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

Cyclizations of aromatic diazonium salts138 (intramolecular Meerwein arylations) are pieparatively related to atom transfer reactions because a radical cyclization is terminated by the transfer of an atom or group other than hydrogen. However, the two methods are not mechanistically related. In the atom transfer method, the atom that is transferred to the cyclic product always derives from the radical precursor, but in the cyclizations of aryldiazonium salts, die atom or group transferred derives from an added reagent. This means that many different products can be prepared from a single diazonium precursor, but it... 

The reaction path depicted in Scheme 5.14 involves Wagner-Meerwein shifts of the methyl group prior to cyclization followed by hydride shift to a number of cationic intermediates. The second scheme (Scheme 5.15) depicts ring closure before methyl migration. The first step involves protolysis of the C—H bond next to the methyl-bearing carbon. The corresponding ion can then rearrange by a 1,2-methyl shift and yield 1,16-dimethyldodecahedrane 28 by hydride abstraction from a hydride donor. 

Cyclization reactions of GGPP mediated by car-bocation formation, plus the potential for Wagner -Meerwein rearrangements, will allow many structural variants of diterpenoids to be produced. The toxic principle taxine from common yew (Taxus baccata Taxaceae) has been shown to be a mixture of at least eleven compounds based on the taxadiene skeleton which can be readily rationalized as in Figure 5.43, employing the same mechanistic principles as seen with mono- and sesqui-terpenes. 

Cyclization of squalene is via the intermediate squalene-2,3-oxide (Figure 5.55), produced in a reaction catalysed by a flavoprotein requiring O2 and NADPH cofactors. If squalene oxide is suitably positioned and folded on the enzyme surface, the polycyclic triterpene structures formed can be rationalized in terms of a series of cycliza-tions, followed by a sequence of concerted Wag-ner-Meerwein migrations of methyls and hydrides... 

The unsaturated lactam ester 62 was also employed in a modified synthesis of ( )-lycorine (1) (109). In the event, O-ethylation of 62 with excess Meerwein reagent followed by reduction of the resulting imidate 77 with either sodium borohydride/stannic chloride dietherate (111) or sodium borohydride/stannous chloride gave an intermediate secondary amine, which cyclized on heating in methanol containing K2C03 to provide the lactam 78 (Scheme 5). When 78 was... 

In order to transform the spirocyclic enone 445 to ( )-elwesine (439) and ( )-epielwesine (449), it was treated with boron trifluoride and dimethylsulfide to cleave the Al-carbobenzyloxy protecting group, and cyclization of the resulting amino enone spontaneously ensued to produce ( )-dihydrooxocrinine (447). Reduction of carbonyl function of 447 with sodium borohydride afforded ( )-3-epielwesine (449), which was converted to ( )-elwesine (439) by inversion of the hydroxyl function at C-3 via a Mitsunobu protocol using diethyl azodicarboxylate, triphenylphosphine, and formic acid. Attempted reduction of 447 directly to 439 by a Meerwein-Ponndorf-Verley reduction or with bulky hydride reagents gave only mixtures of 449 and 439 that were difficult to separate. 

For intramolecular Meerwein reactions, compounds of type 1 can serve as attractive test systems for new initiators, reaction conditions, and trapping reagents, which are finally responsible for the substituent Y in the cyclized product 2 (Scheme 1) [16, 17]. 

As in other fields of organic chemistry, the use of microreactors represents a new method to accelerate reactions significantly. Within a larger study on tin hydride and tris(trimethylsilyl)silane-mediated reactions, the continuous flow system has also been applied to conduct an intramolecular Meerwein reaction. The cyclization of bromide 6 to indane 7 was completed in less than 1 min (Scheme 3) [39]. 

In comparison to the cyclization reactions shown above, intermolecular Meerwein arylations are often more difficult to conduct. Since the aryl radical addition to the alkene is no longer favored by the close proximity of the reacting centers, the probability for a direct recombination of the aryl radical with scavengers Y is significantly increased (Scheme 17). To maintain the desired reaction course from 44 to 45 including steps (1) and (2) [89, 90], Meerwein arylations have for a long time mostly been conducted with activated alkenes, such as acrylates (R = COOR ), vinylketones (R = COR ), styrenes (R = Ph), or conjugated dienes [91,92]. These types of alkenes are known for fast addition of aryl radicals. 

Mixed bis-lactim ethers of type (20) are best prepared by the following route, outlined for the bis-lactimether (20a) of Cyclo(L-Val-Ala). L-Val, the chiral auxiliary, is converted with phosgene into its N-carboxyanhydride (L-Val-NCA, Leuchs anhydride) (17)l5). This gives with D,L-Ala-OCH3 the dipeptide (18) which on heating in toluene cyclizes to the diketopiperazine (19). This is converted into the bis-lactim ether (20a) [(3RS, 6S)-2,5-dimethoxy-6-isopropyl-3-methyl-3,6-dihydropyra-zine] with methyl Meerwein s salt. 

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