Carbon-nitrogen bonds intramolecular amidation

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 hydroamination/cyclization, the addition of an N-H bond across an intramolecular carbon-carbon unsaturated bond, offers an efficient, atom economical route to nitrogen-containing heterocyclic molecules (Equation 8.37). Numerous organolanthanide complexes were found to be efficient catalysts for this transformation [124, 125]. The real active intermediates are organolanthanide amides, which are formed by the rapid protonolysis reactions of precatalysts with amine substrates. The proposed catalytic cycle of hydroamination/cyclization of aminoalkenes is presented in Figure 8.37 [124]. 

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. 

General discussion of intra- and intermolecular interactions 3 van der Waals interactions 3 Coulombic interactions 5 Medium effects on conformational equilibria 5 Quantum mechanical interpretations of intramolecular interactions 7 Methods of study 8 Introduction 8 Nmr and esr spectroscopy 8 Microwave spectroscopy (MW) 12 Gas-phase electron diffraction (ED) 12 X-ray crystallographic methods 13 Circular-dichroism spectroscopy and optical rotation 14 Infrared and Raman spectroscopy 18 Supersonic molecular jet technique 20 Ultrasonic relaxation 22 Dipole moments and Kerr constants 22 Molecular mechanic calculations 23 Quantum mechanical calculations 25 Conformations with respect to rotation about sp —sp bonds 27 Carbon-carbon and carbon-silicon bonds 28 Carbon-nitrogen and carbon-phosphorus bonds 42 Carbon-oxygen and carbon-sulphur bonds 48 Conformations with respect to rotation about sp —sp bonds Alkenes and carbonyl derivatives 53 Aromatic and heteroaromatic compounds 60 Amides, thioamides and analogues 75 Conclusions 83 References 84... 

Sargeson and his coworkers have developed an area of cobalt(III) coordination chemistry which has enabled the synthesis of complicated multidentate ligands directly around the metal. The basis for all of this chemistry is the high stability of cobalt(III) ammine complexes towards dissociation. Consequently, a coordinated ammonia molecule can be deprotonated with base to produce a coordinated amine anion (or amide anion) which functions as a powerful nucleophile. Such a species can attack carbonyl groups, either in intramolecular or intermolecular processes. Similar reactions can be performed by coordinated primary or secondary amines after deprotonation. The resulting imines coordinated to cobalt(III) show unusually high stability towards hydrolysis, but are reactive towards carbon nucleophiles. While the cobalt(III) ion produces some iminium character, it occupies the normal site of protonation and is attached to the nitrogen atom by a kinetically inert bond, and thus resists hydrolysis. 

The critical feature of the Edman degradation is that it allows the N-terminal amino acid to be removed without cleaving any of the other peptide bonds. Let s see how this occurs. The mechanism of the reaction is shown in Figure 26.3. First the nucleophilic nitrogen of the N-terminal amino acid attacks the electrophilic carbon of phenyl isothiocyanate. When anhydrous HF is added in the next step, the sulfur of the thiourea acts as an intramolecular nucleophile and attacks the carbonyl carbon of the closest peptide bond. II is the intramolecular nature of this step and the formation of a five-membered ring that result in the selective cleavage of only the N-terminal amino acid. The mechanism for this part of the reaction is very similar to that for acid-catalyzed hydrolysis of an amide (see Section 19.5). However, because no water is present, only the sulfur is available to act as a nucleophile. The sulfur is ideally positioned for intramolecular attack at the carbonyl carbon of the N-terminal amino acid, so only this amide bond is broken. 

The cyclization of 4,5-hexadienamines and -amides, catalyzed by palladium salts in the presence of copper(II) chloride under a carbon monoxide atmosphere, afforded 2-(2-pyrrolidinyl)acrylates. A different mechanism is operating here, which does not involve the intramolecular addition of nitrogen nucleophile to a rt-complex, but, instead, the addition of PdX2 to a double bond, followed by SN2 or S 2 displacement in the cyclization step28. 

An a-helix can form only if there is rotation about the bonds at the a carbon of the amide carbonyl group, and not all amino acids can do this. For example, proline, the amino acid whose nitrogen atom forms part of a five-membered ring, is more rigid than other amino acids, and its C(, N bond cannot rotate the necessary amount. Additionally, it has no N-H proton with which to form an intramolecular hydrogen bond to stabilize the helix. Thus, proline cannot be part of an a-helix. 

Because of this principal structural divergence from coded peptides, peptoids lack amide protons. This property precludes the formation of the intramolecular H-bonds that contribute largely to the stabilization of the most common helical structures of a-peptides. Unlike that of a-peptides, the peptoid backbone is inherently achiral (as it is based on Gly residues). However, it has been reported that sufficient bias to form stable helices of a specific screw sense can be provided by side chains with an a-chiral carbon atom (that is linked directly to nitrogen) (32, 33). The extraordinary resistance of these helices to loss of their ordered secondary structure is another intriguing property of peptoid molecules. 

An intramolecular example of this type of addition, involving an amide and a C=C triple bond, is afforded by the reaction of o-acetamidophenylacetylenes (equation 29). The product may arise by transfer of a hydrogen from the amide nitrogen to the acetylenic carbon, followed by ring closure to the amide oxygen . 

Cyclization. Intramolecular oxidative addition of an amidic nitrogen atom and a ip -hybridized carbon to a double bond is effected by the Cu(I) carboxylate. This type of reaction has been accomplished by Cu(OAc)2 on unsaturated sulfonamides. 

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