Heterocycles, acylation metalation

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

Enehydroxylamines (102) are invoked as intermediates in the rearrangement of O-vinyl, acyl or aryl oximes (101) (equation 31). Varlamov and coworkers demonstrated that the heterocyclization of ketoximes (103) with acetylene in snper basic medium and in the presence of metal hydroxides proceeds by a [3,3]-sigmatropic rearrangement of the enehydroxylamine 105 of the corresponding oxime vinyl ethers 104 (equation 32). The unreactivity of 3-methyl-2-azabicyclo[3.3.1]nonan-9-one oxime (106) in the same reaction conditions was explained by its inability to isomerize to the corresponding enehydroxylamine. 

The successful acylation of ferrocene set off a vigorous research effort that has resulted in the establishment of the present field of metallocene chemistry, ir- Cyclopentadienyl compounds of ruthenium, osmium, manganese, vanadium, and chromium also exhibit certain aromatic-type reactions in varying degrees. These metallocenes thus represent a new class of heterocyclic compounds in which transition metals, akin to nitrogen, oxygen, and sulfur in classical heterocycles, not only are an integral part of the structure but actually participate directly in many reactions. 

Strong Brpnsted acids are also available to induce acylations.3,8,9 Perfluoroalkane-sulfonic acids were shown to be highly effective. Certain metal powders, such as Zn, Cu, Al, and Fe, were also found to effect acylations with acyl chlorides. The de facto catalysts are the in situ formed corresponding metal halides.3,8 A number of other catalysts were developed over the years however, many of these are effective only for the acylation of highly reactive aromatics, such as heterocycles.9... 

The most important use of 1,3-dithianes (792) stems from their ability to function as acyl anion equivalents (794 Scheme 184). Metallation of this heterocycle followed by alkylation of the anion and cleavage of the dithiane group produces a carbonyl compound. Since such aspects of dithiane chemistry have been extensively documented (69S17 75JOC231), only a few of the more current applications of these heterocycles are highlighted. We again note here that the application of heterocycles to the synthesis of carbonyl compounds has been the sole subject of an extensive review (77H(6)73l). 

To expand the diversity of their libraries Brill et al.16 also modified various heterocycles by alkylation, acylation, or metal-mediated coupling reaction prior to resin capture. A remaining chloro substituent was still available for nucleophilic displacement or a palladium-mediated coupling reaction with anilines, phenols, and boronic acids on solid phase [see Fig. 10 for the preparation of purine derivative (62)]. 

N-Tfa- and iV-Fmoc-a-amino ketones have been synthesized56 by reaction of some N -heterocycles or benzene with chiral AM Tfa- and Fmoc-a-aminoacyl)benzotriazoles [e.g. (49)] in the presence of aluminium trichloride. Full preservation of chirality was reported. Aromatic side-chains in some of the (a-amineacyl)benzotriazole compounds gave a competitive intramolecular cyclization, again with retention of chirality [e.g. (49) to (50)]. A full report57 on the intramolecular acylation of aromatics with Meldrum s acid derivatives catalysed by metal trifluoromethanesulfonates under mild reaction conditions has appeared [e.g. (51) to (52)]. The method tolerates many functional groups and was extended to the synthesis of 1-tetralones, 1-benzosuberones and donepezil (53). 

While there are several reports concerning electrophilic substitution on to (5,5)-fused heterocycles, very few of these involve a study with the parent system. The ir-excessive systems (50), (51), (52) and (53) were found to be susceptible to attack by electrophilic reagents at the positions indicated, leading to alkylation, formylation (Vilsmeier-Haack reaction), acylation, tritylation, metalation, tricyanoethylation, halogenation, thiocyanation, nitrosation, nitration and diazo coupling (77HC(30)l). 

Heterocyclic derivatives of a range of metals other than lithium have received considerable attention, especially as precursors for coupling reactions. These derivatives can be prepared either directly from halo compounds or from the lithio compounds. Thus, direct formation of the pyrrolylzinc compounds can be effected under very mild conditions by treatment of an iodide with a zincsilver couple deposited on graphite. The zinc reagents are formed in excellent yields and can be converted into acylated or allylated products (Scheme 140). For further discussion on this theme, see Section 3.3.3.8.8. 

Acyl chlorides obtained from aromatic, heterocyclic, or dibasic aliphatic acids allowed us to obtain acyl derivatives from NaMn(CO)5 or NaRe(CO)5-Their decarbonylation gave the respective o-aryl, o-heterocyclic, or substituted-alkyl derivatives, allowing studies as to how a substituent influenced a CO group through a benzene ring (or an alkyl chain) and a metal bonded thereto (241-244). 

A different type of metallation, directed by an acyl group at either the pyridine 3- or 4-position, uses a catalytic ruthenium complex and results in a reductive Heck-type substitution, as illustrated below. The mechanism involves insertion of the metal into a C-H bond. The process is non-polar and works equally well with electron-rich heterocycles, for example indole. ... 

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