Amidation, Intramolecular

Intramolecular amidation provides a useful way to directly install a new C-N bond at a designated position and is a powerful method for introducing new synthons. 

Generally, hydrocarbons tethered with sulfamate esters or carbamates are suitable substrates and afford five- or six-membered ring products through intramolecular C-H amidation. For reasons not yet understood, carbamates and sulfamate esters prefer to form five- and six-membered rings, respectively. In general, this important and useful selectivity can avoid formation of product mixtures, a major drawback for similar organic transformations. 

After successful application of the silver catalyst shown in olefin aziridination (Section 6.1.1), He and coworkers showed that intramolecular amidation was possible with both hydrocarbon-tethered carbamates and sulfamate esters.24 They found that only the Bu3tpy silver complex could catalyze efficient intramolecular amidation, while other pyridine ligands gave either dramatically lower yields or complicated product mixtures. In an interesting control study, both copper and gold were also tested in this reaction. Both the copper and gold Bu tpy complexes can mediate olefin aziridination, but only silver can catalyze intramolecular C-H amidation, indicating that the silver catalyst forms a more reactive metal nitrene intermediate. 

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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-... 

Intramolecular amide formation has also been used recently to obtain new pentacyclic ring systems, e.g. 408a. 

Many examples of retention of activity in the face of replacement of benzene by thiophene have been noted so far. Application of this stratagem to a clozapine-like antipsychotic constitutes yet another example where activity is retained. The seven-membered ring of the compound in question is established by intramolecular amide formation on intermediate 102. Treatment of amide 103 with N-methylpiperazine in the presence of titanium tetrachloride affords flumezapine (104) [20]. 

Another synthesis of diazepines (tricyclic) was carried out by reaction of an amino chloropyridine 258 and anthranilic acid [163]. First, a nucleophilic substitution occurred (Scheme 95) followed by an intramolecular amidation on compound 259 by microwave irradiation to give structure 260. The reaction was carried out at 100 °C for more than 2 h, a remarkably long time for a microwave-assisted reaction. 

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

Several syntheses of thienobenzazepines have been reported in the literature however, they generally require the use of reagents and/or reaction conditions which present challenges on a preparative scale. In this manuscript we describe a new and efficient synthesis of the thieno[2,3-c]benzazepine tricycle that involves a key selective reduction-intramolecular amidation cyclization process and enables large-scale preparation of these important compounds. 

In our second approach, we considered reversal of these functional group transformations, wherein reduction of the nitro group followed by palladium-mediated intramolecular amidation would provide the desired tricylcic lactam (Scheme 6.6). One concern with this approach, however, was to identify reaction conditions that would selectively reduce the nitro functionality and not lead to... 

In summary, we have described a novel and efficient synthesis of thienobenzazepine derivatives in which the key transformation includes a telescoped process involving a selective intro reduction followed by palladium-mediated intramolecular amidation. The process developed is quite amenable for preparative scale (multi-gram) and presents significant advantage to those reported previously with respect to overall yield (e.g., 50% vs. 17% overall yield), total number of synthetic transformations (4 vs. 9), and reagents and/or conditions that are suitable for large-scale synthesis. 

Benzodiazocines 182 and 183 were obtained through a sequence of Ugi-depro-tection-carbonylation/intramolecular amidation using ort/io-iodobenzaldehyde and a bifunctional acid or amine [146] (Fig. 36). This cyclocarbonylation was carefully optimized and succeeded in affording 8-membered lactams, which are typically difficult to obtain, in good yields. 

Vasudevan A, Verzal MK (2005) A post-Ugi carbonylation/intramolecular amidation approach toward the synthesis of macrolactams. Tetrahedron Lett 46 1697-1701... 

Reduction of nitro compound 31 with hydrazine hydrate/Raney nickel affords an amine, which produces pyrrolo-benzazepine 32 under intramolecular amide bond coupling (Equation (5) (1996BCF251). 

The most straightforward method for the synthesis of the sulfonamide class of 1,2-thiazines is the intramolecular amidation reaction between a sulfonyl chloride and an amine. Preparation of the sulfonyl chloride moiety via the oxidation of thiol acetate 179 and subsequent deprotection and cyclization afforded sulfonamide 180, an intermediate for the synthesis of the matrix metalloproteinase inhibitor 38 (Scheme 22) <2004JME2981>. 

Intramolecular acylation 1-21 Intramolecular amidation of aromatic rings... 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Path A involves N-formylation of anthranilic acid, condensation of the resultant 2-formaminobenzoic acid with the amine followed by intramolecular amidation of the intermediate amidine to form the product. On the other hand, the amine instead of anthranalic acid may be formylated and go through the known Niementowski reaction (path B). When the reaction of 2-formamidobenzoic acid with aniline and the condensation of formanilide with anthralic acid were conducted under microwave irradiation, the desired 3-phenylquinazolin-4(3 JT)-one was obtained in both cases in a few minutes in 68-87% yield. 

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. 

Here we give an example of this method. The resin-bound 229 was treated with 0-bcnzotriazolyl-/V,/V,/V, /V -tetramethyluronium hexafluorophosphate (HBTU) in anhydrous dichloromethane, and intramolecular amide bond formation occurred to afford resin-bound nitrobenzothiazepine 230 (Equation 19) <1999TL4939>. 

Ketopiperazines, 2,5-Diketopiperazines and Quinoxalines by Ugi-4CR with N-Deprotection and Intramolecular Amide Bond Formation... 

A less common approach to 2,5-diketopiperazine was reported by Marcaccini et al. [79] who used a Ugi-4CR between amines, aldehydes, isocyanides, and chloroacetic acid to get adducts 140. Treatment of 140 with ethanolic potassium hydroxide led to an intramolecular amide N-alkylation reaction, giving 2,5-diketopiperazines 141... 

Sulfamate indan-2-yl ester 145 is oxidized by iodobenzene diacetate to give condensed 1,2,3-oxathiazole di-A-oxides 146 (Equation 35). Various rhodium <2001JA6935, 2004HCA1607>, manganese(m) Schiff base <2005TL5403>, and ruthenium porphyrin <2002AGE3465> catalysts can be used for this transformation. Enantioselective intramolecular amidation is achieved with good yields. 

The aziridination of olefins, which forms a three-membered nitrogen heterocycle, is one important nitrene transfer reaction. Aziridination shows an advantage over the more classic olefin hydroamination reaction in some syntheses because the three-membered ring that is formed can be further modified. More recently, intramolecular amidation and intermolecular amination of C-H bonds into new C-N bonds has been developed with various metal catalysts. When compared with conventional substitution or nucleophilic addition routes, the direct formation of C-N bonds from C-H bonds reduces the number of synthetic steps and improves overall efficiency.2 After early work on iron, manganese, and copper,6 Muller, Dauban, Dodd, Du Bois, and others developed different dirhodium carboxylate catalyst systems that catalyze C-N bond formation starting from nitrene precursors,7 while Che studied a ruthenium porphyrin catalyst system extensively.8 The rhodium and ruthenium systems are... 

The vase conformation can be stabilized by a seam of eight intramolecular amide hydrogen bonds forming a macrocyclic ring (compound 33) that surrounds the open... 

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