Intramolecular C-N Bond-forming Reactions

Quinidine, a natural product epimeric with quinine at Cg and C9, was accessed through the diastereoisomeric trans epoxide prepared from 86 by SAD, in this case by using AD-mix a [2b, 41]. 

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was 

Synthesis of Complex Molecules by Ring-opening of Epoxides with C-Nudeophiles 

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The intramolecular C-N bond forming reactions proved to be more straightforward than their intermolecular counterparts [138]. The desired couplings often could be achieved using (Ph3P)4Pd as catalyst to form 5-, 6-, and 7-mem-bered nitrogen heterocycles, Eq. (171). 

Rhodium Catalysts Rhodium catalysts have been widely used in C—N bond formation via the Rh-nitrene intermediates. Du Bois and co-workers have developed various types of Rh-catalyzed intramolecular C—N bond-forming reactions (Equation 11.18) [44] and intermolecular C—N bond-forming reactions (Equation 11.19) [45]. The mechanism of these C—H amidation reactions proceeds via a concerted asynchronous two-electron oxidation pathway. 

Intramolecular Heck reaction of organomercurial 332 has been used to prepare unsaturated lactone 333 by a non-traditional strategy452. Sequential, regiospecific C—C and C—N bond-forming reactions via a novel Heck-type coupling have been developed453. 

The CUSO4-1,10-phenanthroline complex efficiently catalyzes amidation of alkynyl bromides to furnish ynamides, in both intermolecular and intramolecular manners (eq 25). This C-N bond forming reaction can be used for easy construction of macrocyclic ynamides (eq 26). ... 

Conjugated aza-addition to a,P-unsaturated compounds constitutes one of the most important methods in C-N bond forming reactions. It was not until 2007 that the highly stereocontroUed intramolecular aza-Michael addition was disclosed via iminium catalysis [15aj. The reaction of carbamates 31 bearing an ot,P-unsaturated aldehyde moiety took place with good yields and excellent ees by catalysis of Jorgensen s catalyst 30. This process provides an efficient way for the enantioselective preparation of several five- and six-membered heterocycles 32 (Scheme 36.9). 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

Aromatic amines have been shown to be intermediates in the metal catalyzed carbonylation of nitroaromatics to aryl carbamates. Previous research established that the novel bis(methoxycarbonyl) complex, Ru(dppe)(C0)2[C(0)0Me]2, was the most abundant species present during catalysis. In this study, the complete kinetic analysis of the reaction of p-toluidine with Ru(dppe)(C0)2[C(0)0Me]2 established that the C-N bond formed by nucleophilic attack on a metal carbonyl, and that the organic product was removed from the metal by an intramolecular elimination of aryl isocyanate. 

There were a few isolated examples of coupling reactions that form C—and C—S bonds.f Tunney and Stille had reported the Pd-catalyzed formation of the C—P bonds in aromatic phosphines, and several groups had reported the formation of C—S bonds in sulfides using catalysts based on both palladium and nickel. In addition there were suggestions that simple procedures for C—bond formation could be developed and that palladium complexes could act as catalysts for C—N bond-forming cross-coupling processes. For example, Boger and co-workers used stoichiometric amounts of palladium to form aromatic C—N bonds in a /3-carbolide natural product by an intramolecular process (Eq. 1). Perhaps more closely related to the work discussed in detail here. 

The insertion of CO into Pd-carbon bonds has also been employed in several tandem/cascade reactions that afford five-membered nitrogen heterocycles [97]. A representative example of this approach to the construction of heterocydes involves synthesis of isoindolinones via the Pd-catalyzed coupling of 2-bromobenzaldehyde with two equivalents of a primary amine under an atmosphere of CO [97bj. As shown below (Eq. (1.57)), this method was used for the preparation of 144 in 64% yield. The mechanism of this reaction is likely via initial, reversible condensation of 2-bromobenzaldehyde with 2 equiv of the amine to form an aminal 145. Oxidative addition of the aryl bromide to Pd° followed by CO insertion provides the acylpalladium spedes 146, which is then captured by the pendant aminal to afford the observed product. An alternative mechanism involving intramolecular imine insertion into the Pd—C bond of a related acylpalladium species, followed by formation of a paUadium-amido complex and C—N bond-forming reductive elimination has also been proposed [97b],... 

A similar approach was used by the Alcaide group [183] in the synthesis of tricyclic (3-lactams 6/1-391 from 6/1-390 (Scheme 6/1.99). In this domino process the primarily obtained it-allyl-Pd-complex reacts with the N-nucleophile of the urethane moiety to form a C-N-bond and a vinyl halide. The final step is then an intramolecular Heck-type reaction of the vinyl halide with the alkyne moiety and re-... 

N(2) of benzamidrazinium, the only product in the reaction with pentane-2,4-dione was 1,2,4-triazolinium iodide 79C. This isomer is formed by intramolecular NH-group addition to the C=N bond. The formation of a seven-membered 1,2,4-triazepine isomer has not been detected. 

Imine formation is an important reaction. It generates a C-N bond, and it is probably the most common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thns, cycliza-tion of 5-aminopentanal to A -piperideine is merely intramolecular imine formation. A further property of imines that is shared with carbonyl groups is their susceptibility to reduction via complex metal hydrides (see Section 7.5). This allows imines to be... 

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