Nucleophiles amine formation

Based on the above-mentioned stereochemistry of the allylation reactions, nucleophiles have been classified into Nu (overall retention group) and Nu (overall inversion group) by the following experiments with the cyclic exo- and ent/n-acetales 12 and 13[25], No Pd-catalyzed reaction takes place with the exo-allylic acetate 12, because attack of Pd(0) from the rear side to form Tr-allyl-palladium is sterically difficult. On the other hand, smooth 7r-allylpalladium complex formation should take place with the endo-sWyWc acetate 13. The Nu -type nucleophiles must attack the 7r-allylic ligand from the endo side 14, namely tram to the exo-oriented Pd, but this is difficult. On the other hand, the attack of the Nu -type nucleophiles is directed to the Pd. and subsequent reductive elimination affords the exo products 15. Thus the allylation reaction of 13 takes place with the Nu nucleophiles (PhZnCl, formate, indenide anion) and no reaction with Nu nucleophiles (malonate. secondary amines, LiP(S)Ph2, cyclopentadienide anion). 

The methodology did not work for secondary amines, thus suggesting the formation of an isocyanate as intermediate (Scheme 27, MX2 = Pdl2, [OX] = (1/2) O2]. However, by reacting a primary amine in the presence of a secondary nucleophilic amine, a general and selective synthesis of trisubstituted ureas has been achieved, through trapping of the isocyanate intermediate by the secondary amine (Eq. 52) [274,275]. 

Allylammonium ylides can undergo 2,3-sigmatropic rearrangement [1234]. With weakly nucleophilic amines, C-H bond insertion or hydride abstraction can compete efficiently with ammonium ylide formation. 

Scheme 6 Formation of hyperbranched thin film nanocomposites using an electrophilic polymeric reagent 14 and a nucleophilic amine-functionalized PAMAM dendrimer 15...

In addition, acid cocatalysts can assist the formation of the enamine. With very basic, nucleophilic amines, such as pyrrolidine and its derivatives, acid catalysis is not necessarily required for enamine formation. However, with less basic amines, Brpnsted or Lewis acids are often used to assist in enamine formation (Scheme 7). 

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

Amines may also behave as nucleophiles (Lewis bases). Primary amines are stronger nucleophiles than secondary amines, which, in turn, are stronger nucleophiles than tertiary amines. As nucleophiles, amines attack acid chlorides to form amides. Later in this chapter you see that they re important in the formation of sulfonamides. 

Amines are generally prepared by nucleophilic amination, which is a coupling of carbon electrophiles with a nucleophilic amination reagent, NR2, and Ni and Pd catalyzed reaction of aryl halides with arylamines (Hartwig-Buchwald amination) . Thus, the direct C—N bond formation between carbon nucleophiles and electrophilic nitrogen functionality R2N+ constitutes an example of the umpolung methodology. 

Pathway 2 of Scheme 9 corresponds to one of the most interesting developments in the Beckmann rearrangement chemistry. By trapping of the electrophilic intermediate with a nucleophile (Nu ) other than water, an imine derivative 227 is produced that may be used for further transformations. Carbon or heteroatom nucleophiles have been used to trap the nitrilium intermediate. Reducing agents promote the amine formation. More than one nucleophile may be added (for example, two different Grignard reagents can be introduced at the electrophilic carbon atom). Some of the most used transformations are condensed in Scheme 11. 

Many researchers have investigated the use of amines and alcohols as initiators for the ROP of lactones. As a rule, amines and alcohols are not nucleophilic enough to be efficient initiators, and it is then mandatory to use catalysts to perform the polymerization successfully. Nevertheless, highly reactive p-lactones exhibit a particular behavior because their polymerization can be initiated by nucleophilic amines in the absence of any catalyst. As far as tertiary amines are concerned, the initiation step implies the formation of a zwitterion made up of an ammonium cation and a carboxylate anion, as shown in Fig. 20. Authors coined the name zwitterionic polymerization for this process [80]. Nevertheless, this polymerization is not really new because the mechanism is mainly anionic. Interestingly, Rticheldorf and coworkers did not exclude the possibility that, at least at some stage of the polymerization, chain extension takes place by step-growth polycondensation [81]. 

Addition of primary amines to carbonyl groups follows the pattern we have established for other nucleophiles with formation of a carbinolamine (Equation 8.49). These compounds are sufficiendy stable to be isolated in some cases,87... 

On the other hand, some evidence for the longer life-time of the intermediate formed with amines may be inferred from the formation of small amounts of (116a) from piperidine and /J-chloroacrylonitrile, in addition to the main substitution product. (116a) is also the sole substitution product with aniline (R1=Ph, R2 = H) but no such products were reported for reactions with oxygen or sulphur nucleophiles. For formation of (116a) the initially-formed carbanion should be long-lived enough as to attack another j8-chloroacrylonitrile molecule (Scotti and Frazza, 1964). 

This weakly basic amine (pK 4.05) is a superior catalyst for reactions involving deprotonation a to a carbonyl group. It is more effective than other weakly basic amines because of ease of iminium ion formation. Thus the decalone 1 is converted into 2 more rapidly by this amine via a than by other weakly basic nucleophilic amines. ... 

Extension of acetal arKi aminal formation into examples where the intermediate is trapped by i different nucleophile. 

In the example shown below, the regiochemistry of attack of the nucleophilic amine at the six-member ring favors, for steric reasons, formation of a five-member heterocyclic ring. ... 

The formation of carbon—nitrogen bonds on a pyridazine nucleus is usually done via direct nucleophilic substitution (addition-elimination) with an amine on the corresponding halopyridazine derivative [2a, 3]. Less frequently, other leaving groups such as alkoxy, alkylsulfanyl, and alkylsulfonyl groups have been used successfully. However, for less nucleophilic amines, such as arylamines, such a strategy usually does not lead to the desired pyridazinamines and the success depends on the electron density of the pyridazine substrate as well as on the nucleophilicity of the arylamine used [99]. 

The mechanism of nucleophilic amination presented by Eq. (73) seems very unlikely at first because of the instability of the azolyl cation and the low basicity of the N-amino group in Af-aminoazoles. However, the previously mentioned formation of arylazides from 1-aminobenzimidazole and aryldiazonium salts [Eq. (64)] is concerned, in fact, with such a process. Probably, the course of this reaction is governed also by the elimination of the azolyl fragment as the anion, which is due to the primary deprotonation of tetrazene 260. 

The reaction medium, especially the pH, determines the constants for a given pair of reactants. To obtain an equilibrium that is shifted in favor of peptide product formation the ionization equilibrium must be manipulated. One efficient method is the addition of water-miscible organic solvents to the aqueous reaction mixture thereby lowering the dielectric constant of the medium, reducing the acidity of the carboxyl group, and to a lesser extent the basicity of the amino group of the nucleophilic amine component[100 1011 The use of biphasic systems (for a review... 

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