Side-products mechanistic studie

Despite the synthetic utility of this transformation, nearly eighty years elapsed between the discovery of the Bischler-Napieralski reaction and the first detailed studies of its mechanism. " Early mechanistic proposals regarding the Bischler-Napieralski reaction involved protonation of the amide oxygen by traces of acid present in P2O5 or POCI3 followed by electrophilic aromatic substitution to provide intermediate 5, which upon dehydration would afford the observed product 2. However, this proposed mechanism fails to account for the formation of several side products that are observed under these conditions vide infra), and is no longer favored. 

Although many early synthetic studies employed HMPA as a cosolvent, its mechanistic role remained unclear. Its role was later clarified by Molander, who studied the influence of HMPA concentration on the product distributions from the Sml2-mediated reductive cyclisations of unactivated olefinic ketones.16 The addition of HMPA was required to promote efficient ketyl-alkene cyclisation, and correlations between the concentration of HMPA, product ratios and diastereoselectivities were apparent (Scheme 2.6). In the absence of HMPA, attempted cyclisations led to the recovery of starting material 1, reduced side-product 3 and desired cyclisation product 2. Addition of 2 equiv of HMPA provided 2 and only a small fraction of 3. Further addition of HMPA (3-8 equiv) provided 2 exclusively (Scheme 2.6). 

In addition, the protocol for the transformation of 3 to 4 has been modified from our original publication. We have found that the use of EtgNH instead of triethylamine (Et3N) as base gives a more reproducible reaction and, at the same time, all but eliminates the formation of biaryl material as a side product. The synthesis of 4 with Et3N as base has been the subject of a mechanistic study and our results have been communicated.21 Whether or not the mechanism is as we propose when Et2NH is employed is not known. 

Norrish Type I fission of the side chain carbonyl group again at C-4. - Laser flash irradiation has been used as a aethod for the production of n-butylkotene from cyclohexanone. The chemistry of this ketene was studied in detail. The cyclohexanones (9a) undergo both Norrish Type I and II processes on irradiation. The fluorinated compounds (9b) showed a preference for Norrish Type II behaviour. Within the Norrish Type II biradical fluorine substitution leads to a preference for cyclization rather than cleavage. The Norrish Type I biradical afforded a ketene rather than an alkenal. A study of the photochemical reactivity of the diones (10) has shown that both Norrish Typo I and Type II reactivity can take place. The Typo I Type II product ratio is dependent upon ring size. Thus dione (10a) affords the Type II products (11) and (12) while dione (10c) yields the Norrish type I products (I3c-15c) and low yields of the Norrish Type II products (11) and (12). Compound (10b) is intermediate between these results affording a Type I Type II ratio of 0.3. A mechanistic study of the reactions was carried out. - ... 

The predominance of nuclear methoxylation over competing alkyl side-chain oxidation processes for these systems was largely attributed to an intramolecular attack by the appended side-chain alkoxy radical on the anodically generated aromatic radical cation in the usual EEQCp mechanism [99]. A more recent mechanistic study of anodic oxidation of chiral alkoxynaphthalene derivative (LXXXIX) sheds some additional light on this process [Eq. (46)] [100]. The isolation of a 2 1 mixture of enantiomeric methoxylated products indicated that intramolecular attack by the appended alkoxy radical on the aromatic radical cation (path B) was disfavored at —7S°C (a nearly 1 1 mixture of enantiomers was obtained at 25 C), since the intermediate cyclic ketal resulting from such a process would be a meso form that would lead to a racemic mixture of methoxylated products. Note that the chirality of the appended hydroxyether side-chain disappears upon cycliza-tion to the acetal. 

The acetamidation of alkylaromatics has been partly discussed [Eq. (11)]. Methyl-substituted benzenes are particularly good substrates for side-chain acetamidation, and they have featured in numerous product and mechanistic studies [9-12,21-23,160-162] ethylbenzene and isopropylbenzene give other products predominantly [163]. Hexamethylbenzene has been a favored substrate for mechanistic investigations of acetamidation [160,164], and in this case there is evidence [165] that on the time scale of conventional cyclic voltammetry, proton loss is rapid from hexamethylbenzene radical cation but relatively slow from hexaethylbenzene. 

Reduction of the cinnoline nucleus was a side reaction in the stannous chloride reduction of the nitro group in 4-carboxamido-3-nitrocinnoline, but was minimized by the careful use of just three equivalents of the reductant <84JOC289>. A mechanistic study of the electroreduction of benzo[c]-cinnoline has shown that the ArNHNAr radical is an intermediate which breaks down by disproportionation to give benzo[c]cinnoline and 5,6-dihydrobenzo[c]cinnoline. The latter is the product obtained after two-electron reduction by electrolysis at —1.1 V in aqueous medium <88JOC5781>. 

In the two separate, initial reports on the reactivity of Fischer carbenes with enynes, one study found cyclobutanone and furan products [59], while the other found products due to olefin metathesis [60]. These products have turned out to be the exceptions rather than the rule, as enynes have since been found to react with Fischer carbenes to produce bicyclic cyclopropanes quite generally. The proposed mechanistic pathway is included as part of Bq. (28), in which vinylcarbene 10, produced by insertion of the alkyne into the metal carbene, may then cyclize with the pendant olefin to metallacyclobutane 11, leading to product. The first reported version of this reaction suffered from extreme sensitivity to olefin substitution [Eq. (28) compare R=H, Me] often producing side-products due to metathesis (through 11 to yield dienes) and CO insertion (into 10 to yield cyclobutanones and furans) [61]. Since then, several important modifications have been developed which improve yield, provide greater tolerance for alkene substitution, and increase chemoselectivity for the bicyclic cyclopropane... 

Mechanistic studies performed by Wennemers and coworkers revealed that the presence of water significantly reduces the reaction rate of peptide-catalysed Michael additions. In order to make the reaction water compatible, the group of Wennemers studied the asymmetric Michael addition in aqueous emulsions supported by tripeptides equipped with alltyl moieties that are supposed to provide a hydrophobic environment for catalysis, similar to the behaviour of enzymes. While the parent peptide 15b showed, under these conditions, low conversion rates and a decreased enantiomeric excess of 73%, the insertion of hydrophobic allqrl side ehains improves the catalyst s performance (21, Scheme 13.14c) by shielding the catalytically active peptide from the surrounding water allowing the addition to proceed in a hydrophobic microenviroment, as previously assumed. The prepared addition products were isolated in good yield and with excellent diastereo- and enantioselectivity." " ... 

An iridium-mediated synthesis of pyrroles 17 was reported which was enabled by the development of Ir catalyst 18. This method allows for the smooth coupling of alcohols 16 and amino alcohols 15 through a dehy-drogenative process. Detailed mechanistic studies were conducted to identify all of the intermediates, side-products, and by-products of the reaction. It was proven that the catalytic cycle is base-promoted and hydrogen transfer shuttles are active in the system. It is important to note that this reaction can also be carried out under Ru catalysis albeit with lower reactivity (14JA4974). 

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