Amines nucleophilicity

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

Q Addition to the ketone or aldehyde carbonyl group by the neutral amine nucleophile gives a dipolar tetrahedral intermediate. 

We can explain the observed pH dependence of imine formation by looking at the individual steps in the mechanism. As indicated in Figure 19.8, an acid catalyst is required in step 3 to protonate the intermediate carbinolamine, thereby converting the —OH into a better leaving group. Thus, reaction will be slow if not enough acid is present (that is, at high pH). On the other hand, if too much acid is present (low pH), the basic amine nucleophile is completely protonated, so the initial nucleophilic addition step can t occur. 

The pattern of base catalysis of reactions with amine nucleophiles provides additional evidence. These reactions are catalyzed by bases only when a relatively... 

The reaction of 2-bromo-5-nitrothiazole with weakly basic secondary aliphatic amines gave the expected 2-amino products. The isomeric 5-bromo-2-nitrothiazole with such amines gave mixtures of the expected 5-amino products along with 2-aminated 5-nitrothiazole rearrangement products. A mechanism was proposed which involves the slow thermal isomerisation of the 5-bromo-2-nitrothiazole to the much more reactive 2-bromo isomer which competes, in the case of relatively weak amine nucleophiles, with direct but slow displacement of the 5-bromo group to form the normal displacement product <96JHC1191>. 

An amino alcohol can be formed in situ by the reaction of an iV-formylpiperizine 79 with epoxide 78 which then can be induced to cyclize to give the spiroaziridinium salt 80 (Equation 17) <2004TL4175>. The spiroaziridinium was not isolated but instead trapped by reaction with an amine nucleophile (cf. Section 12.20.6.1). 

The selective replacement of chlorine in cyanuric chloride by the 3,7-dioxa-r-l-azabicyclo[3,3,0]oct-5-yl-methoxy group through the Williamson method has been described <06T7319>. The reactions of cyanuric chloride with some amine nucleophiles have been described under very mild conditions <06H807>. 

Figure 1.48 Cytosine bases are susceptible to bromination at the C-5 double bond position, resulting in active intermediates capable of reacting with amine nucleophiles.

Carbodiimides are used to mediate the formation of amide or phosphoramidate linkages between a carboxylate and an amine or a phosphate and an amine, respectively (Hoare and Koshland, 1966 Chu et al., 1986 Ghosh et al., 1990). Regardless of the type of carbodiimide, the reaction proceeds by the formation of an intermediate o-acylisourea that is highly reactive and short-lived in aqueous environments. The attack of an amine nucleophile on the carbonyl group of this ester results in the loss an isourea derivative and formation of an amide bond (see Reactions 11 and 12). The major competing reaction in water is hydrolysis. 

Figure 3.1 EDC reacts with carboxylic acids to create an active-ester intermediate. In the presence of an amine nucleophile, an amide bond is formed with release of an isourea by-product.

Figure 3.11 Woodward s reagent K undergoes a rearrangement in alkaline solution to form a reactive ketoket-enimine. This active species can react with a carboxylate group to create another active group, an enol ester derivative. In the presence of amine nucleophiles, amide bond formation takes place.

Figure 3.14 Carbonyl groups can react with amine nucleophiles to form reversible Schiff base intermediates. In the presence of a suitable reductant, such as sodium cyanoborohydride, the Schiff base is stabilized to a secondary amine bond.

Carboxylate groups activated with NHS esters are highly reactive toward amine nucleophiles. In the mid-1970s, NHS esters were introduced as reactive ends of homobifunctional crosslinkers (Bragg and Hou, 1975 Fomant and Fairbanks, 1976). Their excellent reactivity at physiological pH quickly established NHS esters as viable alternatives to the imidoesters predominating at the time (Section 2, this chapter). 

Figure 25.2 mPEG may be derivatized with succinic anhydride to produce a carboxylate end. A reactive NHS ester can be formed from this derivative by use of a carbodiimide-mediated reaction under nonaqueous conditions. The succinimidyl succinate-mPEG is highly reactive toward amine nucleophiles. 

Figure 27.3 The reaction of cytosine with bisulfite in the presence of an excess of an amine nucleophile (such as a diamine compound) leads to transamination at the N-4 position. This process is a route to adding an amine functional group to cytosine residues in oligonucleotides.

Figure 27.4 Reaction of guanine bases with N-bromosuccinimide causes bromination at the C-8 position of the ring. Amine nucleophiles can be coupled to this active derivative by nucleophilic displacement. Reaction of diamine compounds results in amine-terminal spacers that can be further modified to contain detectable components.

Figure 27.5 Oligonucleotides containing a 5 -phosphate group can be reacted with EDC in the presence of imidazole to form an active phosphorimidazolide intermediate. This derivative is highly reactive with amine nucleophiles, forming a phosphoramidate linkage. Diamines reacted with the phosphorimidazolide result in amine-terminal spacers that can be modified with detectable components.

The formation of a phosphorimidazolide intermediate provides better reactivity toward amine nucleophiles than the EDC phosphodiester intermediate if EDC is used without added imidazole. The EDC phosphodiester intermediate also has a shorter half-life in aqueous conditions due to hydrolysis than the phosphorimidazolide. Although EDC alone will create nucleotide phosphoramidate conjugates with amine-containing molecules (Shabarova, 1988), the result of forming the secondary phosphorimidazolide-activated species is increased derivatiza-tion yield over carbodiimide-only reactions. 

The same research group has shown that the 5-fluorophenyl-l,2,4-oxadiazoles 73 (Scheme 6) form the triazoles 74 as the major products in the presence of amine nucleophiles, together with varying amounts of side products 75-77, with product 76, for example, being formed by the competitive addition of the methanol solvent to the N-O-cleaved photolytic product <2005H(65)387>. The formation of quinazolin-4-ones 75 has been studied separately, and has been optimized to allow good yields as shown by the example in Equation (6) <1999JOC7028>. 

Although the Capdevielle reaction for one-pot conversion of aldehydes to nitriles is a very convenient and widely applicable synthetic procedure, 3-substituted furoxans appear to be susceptible to rearrangement when substitutions with amine nucleophiles are attempted, even under relatively mild conditions (Scheme 29) <1999JOC8748>. The formation of the final product 107 in this reaction was explained via phenyl abstraction by carbamoyl radical cation from the second molecule of intermediate product 106 < 1999JOC8748>. 

Nucleophilic substitution of thiophene can also be enabled by the presence of electron withdrawing groups (e.g., -CHO <00SC1359>, -COMe <00T7573>, -NO2 <00JCS(P1)1811>) on carbon. The regioselectivity of the addition of amine nucleophiles onto 3,5-dibromothiophene-2-carboxaldehyde (54) has been studied and found to be independent of reaction conditions (para product 55 favored over ortho product 56) <00SL459>. 

An alternative approach (Scheme 2) to polyoxyfunctionalised azepines (eg. 9) involves cyclooctatetraene as a starting material via its la, 2a, 5a, 6a -diepoxy-3(3,4(S-diol 7, and subsequent amine nucleophilic attack to give 8 followed by ozonolysis with reductive work up to afford 9 <00TL5483>. 

This cascade has been exemplified with both carbon nucleophiles and primary amine nucleophiles. We have also carried out these processes... 

The proposed catalytic cycle of the ruthenium-catalyzed intermolecular Alder-ene reaction is shown in Scheme 21 (cycle A) and proceeds via ruthenacyclopentane 100. Support for this mechanism is derived from the observation that the intermediate can be trapped intramolecularly by an alcohol or amine nucleophile to form the corresponding five-or six-membered heterocycle (Scheme 21, cycle B and Equation (66)).74,75 Four- and seven-membered rings cannot be formed via this methodology, presumably because the competing /3-hydride elimination is faster than interception of the transition state for these substrates, 101 and 102, only the formal Alder-ene product is observed (Equations (67) and (68)). 

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