Amides intramolecular

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

Insertion of carbenes into other bonds, particularly O—H and N—H bonds, has found worthwhile application in organic synthesis. Both inter- and intramolecular reactions are possible to give ethers, amines or amides. Intramolecular O—H insertion of the carbene, generated from the diazoketone 105, gave rise to the seven-membered cycUc ether 106 (4.84). In a synthesis of the -lactam antibiotic thienamycin, intramolecular N—H insertion of the carbene, formed from the diazoketone 107, was a key step to give the -lactam 108 (4.85). 

It is known that the oxidative addition of aryl or vinyl halides to a low-valent palladium complex produces an aryl- or vinylpalladium complex, which reacts with carbon monoxide to afford an acylpalladium complex. If alcohol and amine are added to this reaction system, we can obtain ester or amide. " Intramolecular reactions of aryl or... 

Sodium bis(trimethylsilyl)amide Intramolecular C-alkylation with mesylates s. 23, 904 suppl. 29... 

Cyclosporine A (16) is a natural product which serves as the quintessential Beyond Rule-of-5 macrocycle, able to overcome the disadvantages of high MW (1203 Daltons) and polarity (11 amide bonds) and achieve excellent absorption (Fa = 0.86). It appears able to do this by a combination of N-methylation (seven Ai-methylated amides), intramolecular hydrogen bonding (four observed in the crystal structure), a compact 3D structure incorporating p turns, and a preponderance of hydrophobic sidechains. This same feature set is seen in many of the designed orally bioavailable macrocycles in Tables 10.7 and 10.8 and perhaps most closely adopted in the design of 24. 

The "zip-reaction (U. Kramer, 1978, 1979) leads to giant macrocycles. Potassium 3- ami-nopropyl)amide = KAPA ( superbase ) in 1,3-diaminopropane is used to deprotonate amines. The amide anions are highly nucleophilic and may, for example, be used to transam-idate carboxylic amides. If N- 39-atnino-4,8,12,16,20,24,28,32,36-nonaazanonatriacontyl)do-decanolactam is treated with KAPA, the amino groups may be deprotonated and react with the macrocyclic lactam. The most probable reaction is the intramolecular formation of the six-membered ring intermediate indicated below. This intermediate opens spontaneously to produce the azalactam with seventeen atoms in the cycle. This reaction is repeated nine times in the presence of excess KAPA, and the 53-membered macrocycle is formed in reasonable yield. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

An intramolecular version offers useful synthetic methods for heterocycles. The total syntheses of a- and 7-lycoranes (373 and 374) have been carried out by applying the intramolecular aminochlorination of the carbamate of 5-(2-aminoethyl)-l,3-cyclohexadiene (372) as a key reaction[312,313]. Interestingly, the 4,6- and 5,7-diene amides 375 and 377 undergo the intramolecular amina-tion twice via x-allylpalladium to form alkaloid skeletons ofpyrrolizidine (376) and indolizidine (378), showing that amide group is reactive[314]. 

The reaction of alkenyl mercurials with alkenes forms 7r-allylpalladium intermediates by the rearrangement of Pd via the elimination of H—Pd—Cl and its reverse readdition. Further transformations such as trapping with nucleophiles or elimination form conjugated dienes[379]. The 7r-allylpalladium intermediate 418 formed from 3-butenoic acid reacts intramolecularly with carboxylic acid to yield the 7-vinyl-7-laCtone 4I9[380], The /i,7-titisaturated amide 421 is obtained by the reaction of 4-vinyl-2-azetidinone (420) with an organomercur-ial. Similarly homoallylic alcohols are obtained from vinylic oxetanes[381]. 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

The Madelung Synthesis and Related Base-Catalyzed Condensations. The Madelung cyclization involves an intramolecular condensation of an o-aLkylanilide. A classic example of the Madelung synthesis is the high temperature condensation of o-methylacetanihde [120-66-1] to 2-methylindole [95-20-5] by sodium amide. 

The reverse reaction is an intramolecular acidolysis of amide group by the o-carboxyhc acid to reform anhydride and amine. This unique feature is the result of an ortho neighboring effect. In contrast, the acylation of an amine with ben2oic anhydride is an irreversible reaction under the same reaction conditions. The poly(amic acid) stmcture (8) can be considered as a class of polyamides. Aromatic polyamides that lack ortho carboxylic groups are very... 

Ring closure resulting from attack of a heteroatom on a carboxyl group or its equivalent is merely a case of intramolecular esterification or amide formation. The y-butyrolactones or pyrrolidones obtained from such reactions are usually regarded as the province of aliphatic chemistry, so only a few examples are offered by way of illustration in Scheme 15. 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

In contrast to the above additions A-allyl- and substituted A-allyl-amides, -urethanes, -ureas and -thioureas undergo intramolecular cyclization only in 6(3-96% sulfuric acid to give the corresponding oxazolinium and thiazolinium salts. Treatment of these cations with base yields 2-oxazolines and 2-thiazolines in moderate to good yields. The reaction is illustrated by the conversion of A-2-phenylallylacetamide (342) into 2,5-dimethyl-5-phenyl-2-oxazoline (343) in 70% yield 70JOC3768) (see also Chapter 4.19). 

S-Substituted thiiranium ions react with secondary amines to give ring-opened products. Nitriles also react with thiiranium ions, probably via an open carbenium ion whose formation is favored by increasing the polarity of the medium by the addition of lithium perchlorate (Scheme 79) (79ACR282). An intramolecular displacement by an amide nitrogen atom on an intermediate thiiranium ion has been invoked (80JA1954). 

A series of amides has been prepared as protective groups that are cleaved by intramolecular cyclization after activation, by reduction of a nitro group, or by activation by other chemical means. These groups have not found much use since the first edition of this volume and are therefore only listed for completeness. The concept is generalized in the following scheme ... 

This compound undergoes hydrolysis of the amide group intramolecularly catalyzed by the neighboring carboxylic acid group. The rate equation, in the pH range 1—... 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

In this series of amides, hydrolysis or aminolysis of a simple ester, cleavage of a silyl groups a cis/trans isomerization, or reduction of a quinone to a hydro-quinone exposes an alcohol that then induces deprotection by intramolecular addition to the amide carbonyl. 

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