Carbon-nitrogen bond formation intramolecular reactions

Efficient preparative sequences involving radical decarboxylation followed by carbon-nitrogen bond formation are rare. Acyl nitrates decompose at elevated temperatures to give nitroalkanes (equation 46), but are unfortunately explosive and have to be prepared in situ and stored in solution. A noteworthy exception is found in the thermal or photochemical decarboxylation of tetrahydro-l,2-oxazine-3,6-diones leading to -lactams (equation 47). Doubtless a key factor in this reaction, considered to proceed via a radical cage mechanism, is the intramolecular nature of the carbon-nitrogen bond formation. 

Intramolecular carbon-nitrogen bond formation can be used to assemble a range of nitrogen-containing aromatic heterocycles (e.g., indoles, benzimidazoles, pyrro-zoles, quinolines, etc.). An early example of the application of this chemistry to indoles vas reported by Watanabe, in the intramolecular cyclization of hydrazones with ortho-chloroarenes (Scheme 6.36) [46]. This reaction can be considered to... 

Iron salts have recently attracted considerable attention as inexpensive and environmentally friendly agents in a wide range of selective processes in organic synthesis. Over the past decade, FeCls 6H2O has shown to be an effective catalyst in the formation of carbon-carbon or carbon-nitrogen bonds, in intramolecular Friedel-Craft reactions and in the reduction of ketones or allylic alcohols. ... 

Intramolecular carbon-nitrogen bond formation is possible utilizing a catalytic system derived from Pd2(dba)3/P(2-tolyl)3, which gives enantiomerically enriched amine and amide products with either endocyclic or exocyclic chiral centers, e.g., 15 to give 16 (eq 15). Note that no decrease in enantiomeric excess is observed from substrate to product. In contrast, the intermolecular variant, e.g., reaction of 17 and 18 to give 19, conducted under identical reaction conditions, leads to products that are partially or fully racemized. Key to the success of the intermolecular process is the employment of bidentate ligands such as roc-BINAP or DPPF (eq 16). 

Intramolecular carbon-nitrogen bond formation may result from the Ullmann coupling of l,3-bis(2-iodoaryl)propan-2-amines catalysed by copper. Using (i )-BINOL, l,l -Bi-2-naphthol, ligands, the enantioselective formation of indolines and 1,2,3,4-tetrahydroquinolines was achieved. Copper catalysis has also been used in the intramolecular formation of imidazobenzimidazole derivatives. The reaction is likely to involve the formation of intermediates, such as (16), which on aerobic oxidation yield the product. There is evidence for an intramolecular 0- -N Smiles rearrangement, as... 

Many approaches to y-lactams have been dependent on cyclization by acyl-nitrogen bond formation [22]. Cyclization involving carbon-carbon bond formation is an alternative route however, until recently, this potential methodology has received little attention. Mori and co-workers reported a palladium-catalyzed cyclization of A -allyl iodoacetamides, in which the intramolecular addition reaction of the carbon-iodine bond to an olefinic linkage is a key step [23]. 

Scheme 192. Reaction of Alkenyl Epoxides and Aziridines Producing Heterocycles via Carbon-Heteroatom Bond Formation by (a) Intramolecular Allylation of Oxygen and Nitrogen Nucleophiles and (b) Intermolecular [3 + 2]-Cycloaddition with Heterocumulenes...

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

The palladium-catalyzed synthesis of functionalized indoles through intramolecular nitrogen-carbon(sp ) bond formation has been reported (Scheme 3.55) [61], This was an oxidative cycloisomerization process, and the authors found that molecular oxygen (1 atm) was an effective oxidant for the process. The substrate scope for this reaction was quite... 

Lithiation of aryltriazenes followed by treatment with an electrophile provides a new approach to benzylamines. The regioselectivity of the reaction can be controlled by means of the substituents on the aryl group. The reaction consists of an intramolecular carbon-carbon bond formation with the aryl ring of a lithiated alkyl group on a 3-nitrogen atom, a 1,2-proton shift, demonstrated by deuterium substitution, and the subsequent release of nitrogen gas.15... 

The nitrile group in cyanopyridine can participate in intramolecular reactions. The presence in chalcone 118 of an ortho-hydroxyl substituent can lead to its addition to a carbon-nitrogen triple bond, with the formation of the 2/7-pyran-2-iminic moiety (compound 119) [126, 127] (Scheme 3.36). 

Formation of aminocyclopropanes in a carbene cycloaddition to a carbon-carbon double bond containing no nitrogen function requires an amino-substituted carbene as counterpart. Such a type of reaction was observed with special nitrile ylides possessing a suitable double bond within the molecule Thus, nitrile ylides (193) generated from the precursors 191 or 192, underwent intramolecular [2-f-l] or [2-I-3]cycloaddition yielding 194 and 195 respectively (Scheme 4). 195 was easily hydrolyzed to aminocyclo-propane (196). The preferential direction of the cycloaddition was influenced by the nature... 

In these reactions, the nitrogen nucleophile is typically an amide, carbamate, or sulfonamide. Because of the low nucleophilicity of such nitrogen functions, no intermolecular 1,4-addition involving C—N bond formation is known. In all cases reported, the carbon-nitrogen coupling takes place in an intramolecular aminopalladation. 

Intramolecular reactions of species (69) with simple alkenes have been of great importance in the field of /V-acyliminium chemistry. In Section 4.4.2.2, the mechanistic principles of IV-acyliminium cycliza-tions using these ir-nucleophiles have already been treated. If the carbon-carbon double bond tethered to the nitrogen atom does not have an electronic bias, a considerable preference exists for the formation of a six-membered ring by way of a chair-like transition state. Some recent applications of this reaction type are the preparation of bicyclic imidazolidin-2-ones (equation 57) and a cyclization reaction proceeding via a tertiary iV-acyliminium intermediate generated by protonation of an enamide (equation 58). A third example (equation 59) leads to a bicyclic system that apparently prefers proton loss instead of formation of a tertiary formate. ... 

The reaction is useful in the synthesis of acycHc imines [122-124] and heterocumulenes [112-117] and in the intramolecular formation of carbon-nitrogen double bonds in heterocycHc synthesis [112-117]. On the other hand aza-Wittig type reactions of iminophosphoranes with carbon dioxides, carbon disulphides, isocyanates, isothiocyanates and ketenes render access to functionalized heterocumulenes as highly reactive intermediates able to undergo a plethora of heterocycUzation reactions [112-117]. 

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