Intermolecular acylation

The acylpalladium complex formed from acyl halides undergoes intramolecular alkene insertion. 2,5-Hexadienoyl chloride (894) is converted into phenol in its attempted Rosenmund reduction[759]. The reaction is explained by the oxidative addition, intramolecular alkene insertion to generate 895, and / -elimination. Chloroformate will be a useful compound for the preparation of a, /3-unsaturated esters if its oxidative addition and alkene insertion are possible. An intramolecular version is known, namely homoallylic chloroformates are converted into a-methylene-7-butyrolactones in moderate yields[760]. As another example, the homoallylic chloroformamide 896 is converted into the q-methylene- -butyrolactams 897 and 898[761]. An intermolecular version of alkene insertion into acyl chlorides is known only with bridgehead acid chlorides. Adamantanecarbonyl chloride (899) reacts with acrylonitrile to give the unsaturated ketone 900[762],... 

Chiral Lactones and Polyesters. Similar to intermolecular reactions described previously. Upases also catalyze intramolecular acylations of hydroxy acids the reactionsults in the formation of lactones. 

The acid-catalyzed rearrangements of substituted pyrroles and thiophenes consequent on ipso protonation have been referred to previously (Section 3.02.2.4.2). There is some evidence that these rearrangements are intramolecular in nature since in the case of acid-induced rearrangement of 2-acylpyrroles to 3-acylpyrroles no intermolecular acylation of suitable substrates could be demonstrated (Scheme 10) (8UOC839). 

Acyl derivatives of azoles containing two different environments of nitrogen atoms can rearrange. For example, 1-acyl-1,2,3-triazoles are readily isomerized to the 2H-isomers in the presence of triethylamine or other bases the reaction is intermolecular and probably involves nucleophilic attack by N-2 of one triazole on the carbonyl group attached to another (74AHC(16)33). 

A well-known example of non-prototropic tautomerism is that of azolides (acylotropy). The acyl group migrates between the different heteroatoms and the most stable isomer (annular or functional) is obtained after equilibration. In indazoles both isomers are formed, but 2-acyl derivatives readily isomerize to the 1-substituted isomer. The first order kinetics of this isomerization have been studied by NMR spectroscopy (74TL4421). The same publication described an experiment (Scheme 8) that demonstrated the intermolecular character of the process, which has been called a dissociation-recombination process. 

As with intermolecular catalysis, the form of the rate equation may not decisively indicate the meehanism of the catalysis because of kinetic equivalences. Consider a substrate containing the acyl function -COX and an ionizable catalytic function -YH. 

The mechanisms available to intramolecular reactions are the same as those of intermolecular reactions. The same problems of kinetic equivalence of rate terms may arise, and Table 6-3 shows some kinetically equivalent mechanisms for intramolecular reactions of the acyl function. The efficiency of intramolecular reactivity may be difficult to assess. One technique, described above as a method for the detection of an intramolecular reaction, is to make a comparison with an analog incapable of the intramolecular process. Thus p-nitrophenyl 5-nitrosalicylate, 17, hydrolyzes about 2500 times faster than p-nitrophenyl 2-methoxy-5-nitrobenzoate, 18. 

Bifunctional molecules undergo intermolecular cyclizations with enamines through simple alkylations 112-114) and acylations 115). For example, the reaction between l-(N-pyrrolidino)cyclopentene and 1,4-diiodobutane produces, after hydrolysis, ketospirans 92 and 93 113). 

In Corey and Chaykovsky s initial investigation, a cyclic ylide 79 was observed from the reaction of ethyl cinnamate with ylide 1 in addition to 32% of cyclopropane 53. In a similar fashion, an intermolecular cycloaddition between 2-acyl-3,3-bis(methylthio)acrylnitrile 80 and 1 furnished 1-methylthiabenzene 1-oxide 81. Similar cases are found in transformations of ynone 82 to 1-arylthiabenzene 1-oxide 83 and N-cyanoimidate 84 to adduct ylide 85, which was subsequently transformed to 1-methyl-lX -4-thiazin-l-oxide 86. ... 

Bischler-Napieralski reactions of N-acyl tryptamine derivatives 16 are believed to proceed via a related mechanism involving the initial formation of intermediate spiroindolenines (17) that rearrange to the observed 2-carboline products (18). The presence of these intermediates has been inferred by the observation of dimerized products that are presumably formed by the intermolecular trapping of the spiroindolenine by unreacted indole present in the reaction mixture." ... 

Rapid exchange of positions was observed for acyl and amidoyl groups in the NMR spectra of compounds 36 in 1-chloronaphthalene solution at high temperatures (170-215°C) (Scheme 18). [72JCS(CC)709]. Crossover experiments clearly indicated the intermolecular exchange. The value of the free-energy barrier was determined as AG = 100 kJ mol at the coales-... 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

In contrast to the acyl- and sulfonylnitrenes described in this section, arylnitrenes produced thermally or photolytically from aryl azides, including those bearing strongly electron-withdrawing substituents (e.g., CN, N02, CF3), fail to promote ring expansion of arenes to 1H-azepines, although intermolecular substitution of electron-rich substrates, e.g. mesitylene and A.TV-dimethylaniline, have been noted.167... 

As to the question of intra- or intermolecularity of the rearrangement there are three opinions, one which states that the reaction is completely intermolecular148, another supports a concurrent intra- and intermolecular mechanism149, whilst a third claims that the reaction is completely intramolecular150. Evidence for the intermolecular mechanism is based on trapping experiments such as the reaction of meta-tolyl acetate (CVIII) in the presence of we/a-chlorobenzoyl chloride (CIX) when the acylation product (CX) is formed rather than the products of... 

The exact mechanism has still not been completely worked out. Opinions have been expressed that it is completely intermolecular, completely intramolecular, and partially inter- and intramolecular. " One way to decide between inter- and intramolecular processes is to run the reaction of the phenolic ester in the presence of another aromatic compound, say, toluene. If some of the toluene is acylated, the reaction must be, at least in part, interraolecular. If the toluene is not acylated, the presumption is that the reaction is intramolecular, though this is not certain, for it may be that the toluene is not attacked because it is less active than the other. A number of such experiments (called crossover experiments) have been carried out sometimes crossover products have been found and sometimes not. As in 11-14, an initial complex (40) is formed between the substrate and the catalyst, so that a catalyst/substrate molar ratio of at least 1 1 is required. 

Mermerian AH, Fu GC (2003) Catalytic enantioselective synthesis of quaternary stereocenters via intermolecular C-acylation of silyl ketene acetals dual activation of the electrophile and the nucleophile. J Am Chem Soc 125 4050-4051... 

A classical procedure for fusing a six-membered ring to an aromatic ring uses succinic anhydride or a derivative. An intermolecular acylation is followed by reduction and an intramolecular acylation. The reduction step is necessary to provide a more reactive ring for the second acylation. 

Deuteration experiments suggested an intra- as well as an intermolecular migration of the acyl group. / -Methoxybenzoyl- and / -nitrobenzoylimidazole did not undergo acyl migration upon irradiation. Af-Crotyl- and TV-geranylimidazoles are stable to irradiation. 

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

Lipids from marine products have been studied less frequently. The detection of co-(o-alkylphenyl)alkanoic acids with 16,18 and 20 carbon atoms together with isoprenoid fatty acids (4,8,12-trimethyltetradecanoic acid and phytanic acid) and substantial quantities of bones from fish and molluscs has provided evidence for the processing of marine animal products in vessels [58 60]. C16, C18, and C20 co-(o-alkylphenyl)alkanoic acids are presumed to be formed during the heating of tri-unsaturated fatty acids (C16 3, C18 3 and C20 3), fatty acyl components of marine lipids, involving alkali isomerization, pericyclic (intermolecular Diels-Alder reaction) and aromatization reactions. 

The progress of the deprotection and acylation was monitored by recording MALDI-TOF spectra of the crude products. In this particular case, microwave irradiation not only accelerated the palladium(0)-catalyzed deprotection and the ensuing amide formation, but also led to cleaner reactions. Apparently, the microwave heating breaks up any hindrance to the reaction sites such that the intermolecular reaction sites prevail and competing reactions are suppressed [46]. 

Intermolecular nucleophilic acyl substitution is a fundamental carbon—carbon bondforming reaction. In spite of its high synthetic potential, however, its intramolecular version, that is, intramolecular nucleophilic acyl substitution (INAS) is rather rare because of the intrinsic difficulties involved in carrying it out. One difficulty associated with the INAS reaction is that a reactive nucleophilic species must be generated in the presence of carbonyl functionality, and at the same time this nucleophile is expected to react only with... 

Many conformations were sampled by the usual MC procedure. The result is of course that there is no preferred orientation of the molecule. Each conformation can, however, be characterised by an instantaneous main axis this is the average direction of the chain. Then this axis is defined as a director . This director is used to subsequently determine the orientational order parameter along the chain. The order is obviously low at the chain ends, and relatively high in the middle of the chain. It was found that the order profile going from the centre of the molecules towards the tails fell off very similarly to corresponding chains (with half the chain length) in the bilayer membrane. As an example, we reproduce here the results for saturated acyl chains, in Figure 10. The conclusion is that the order of the chains found for acyl tails in the bilayer is dominated by intramolecular interactions. The intermolecular interactions due to the presence of other chains that are densely packed around such a chain,... 

Besides the intramolecular acyl-transfer reactions, electrophilic activation is shown to occur with intermolecular Friedel-Craft-type reactions.18 When the simple amides (45a,b) are reacted in the presence of superacid, the monoprotonated species (46a,b) is unreactive towards benzene (eq 18). Although in the case of 45b a trace amount of benzophenone is detected as a product, more than 95% of the starting amides 45a,b are isolated upon workup. In contrast, amides 47 and 48 give the acyl-transfer products in good yields (eqs 19-20). It was proposed that dications 49-50 are formed in the superacidic solution. The results indicate that protonated amino-groups can activate the adjacent (protonated) amide-groups in acyl-transfer reactions. 

Many of these reactions are not observed at all when the relevant groups are allowed to come together in bimolecular processes in aqueous solution. For mechanistic work involving intermolecular reactions, therefore, it is necessary to use activated substrates. Much of what we know about the relevant reactions of esters, for example, comes from studies using aryl esters like p-nitrophenyl acetate, or acyl-activated compounds like ethyl trifluoroacetate (Bruice and Benkovic, 1966 Jencks, 1969 Bender, 1971). 

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