Amine displacement reactions

Amine Displacement Reactions. Miller and Muetterties I4), Dupont, and Moews (f5), working in the laboratories of the University of Michigan, demonstrated base displacement processes independently. Base displacement processes involve the displacement of a given donor molecule by a stronger donor molecule and may be represented by the general equation ... 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

Various sources of fluoride ion have been investigated, of which highly nucleophilic tetraalkylammonium fluorides ate the most effective Thuf, fluoro alkyl halides and N (fluoroalkyl)amines are efficiently synthesized by treatment of the corresponding trifluoromethanesulfonic esters with tetrabutylammonium fluoride trihydrate in aprotic solvents [5fl] (equation 34) The displacement reactions proceed quantitatively at room temperature within seconds, but tail with hydrogen fluoride-pyridine and give reasonable yields only with hydrogen fluo ride-alkylamine reagents... 

A bifunctional autocatalytic effect of azinones in general is possible in certain nucleophilic reactions such as amination. Zollinger has found that 2-pyridone is the best catalyst for anilino-dechlorination of various chloroazines. It seems likely that examples of autocatalysis will be found when the substrate contains an azinone moiety. The azinone hy-products of displacement reactions may also function in this way as catalysts for the main reaction. 

Benzazepin-2-amines can be obtained by nucleophilic displacement reactions on a variety of substrates. For example, the benzazepin-2-amine 22 is formed by treating the thiolactam 21, obtained from the benzazepinone 20 with phosphorus pentasulfide in pyridine or triethylamine solution, with ammonia.61... 

The nucleophilic displacement reactions with azide, primary amines, thiols and carboxylatc salts arc reported to be highly efficient giving high (>95%) yields of the displacement product (Table 9.25). The latter two reactions are carried out in the presence of a base (DBU, DABCO). Radical-induced reduction with tin hydrides is quantitative. The displacement reaction with phenolates,61j phosphines,6M and potassium phthalimide608 gives elimination of HBr as a side reaction. 

The preparation of purine derivatives substituted at the C-2 position via amine displacement of a halogen is known as a difficult reaction step requiring several days of reaction time. However, Al-Obeidi and coworkers have recently prepared 2,6,9-trisubstituted purines on soUd-phase by employing a synthetic route in which the critical step was performed with microwave irradiation (Fig. 37) [62]. PS resin-bound 2-iodosubstituted purine was treated with diethanolamine or propanolamine in NMP with microwave irradiation at 200 °C for 30 min. Trifluoroacetic acid-mediated cleavage resulted in the 2-amino substituted purines in 45-59% yields and 77-89% purities. 

The second step introduces the side chain group by nucleophilic displacement of the bromide (as a resin-bound a-bromoacetamide) with an excess of primary amine. Because there is such diversity in reactivity among candidate amine submonomers, high concentrations of the amine are typically used ( l-2 M) in a polar aprotic solvent (e.g. DMSO, NMP or DMF). This 8 2 reaction is really a mono-alkylation of a primary amine, a reaction that is typically complicated by over-alkylation when amines are alkylated with halides in solution. However, since the reactive bromoacetamide is immobilized to the solid support, any over-alkyla-tion side-products would be the result of a cross-reaction with another immobilized oligomer (slow) in preference to reaction with an amine in solution at high concentration (fast). Thus, in the sub-monomer method, the solid phase serves not only to enable a rapid reaction work-up, but also to isolate reactive sites from... 

An interesting iridium-catalysed 5-CH boronation of 2,3-dimethylpyrazine was reported incidentally in a paper mainly devoted to the reaction of pyridines. The product 89 was used in a Suzuki coupling <06AG(I)489>. Selective mono coupling of 2,6-dichloropyrazine with boronic acids, followed by amine displacement of the second chlorine has been used to prepare potential anti-cancer compounds <06JMC407>. A full paper has been published on the chelation-driven selective Suzuki coupling of the pyridinium ylides 90 <06TL6457>. 

Fluorobenzene-type compounds have been used as functional groups in homobifunctional crosslinking agents (Chapter 4, Section 4). Their reaction with amines involves nucleophilic displacement of the fluorine atom with the amine derivative, creating a substituted aryl amine bond (Reaction 9). Detection reagents incorporating reactive aryl chemistry include 2,4-dinitrofluorobenzene and trinitrobenzenesulfonate (Eisen et al., 1953). These compounds form... 

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.

BioH14 is a mdo-polyborane, therefore, it is expected that it forms adducts with Lewis bases. This is indeed the case but with concomitant loss of hydrogen as shown in Eq. (51). These adducts of the type BioHi2-2L (L = amines, pyridine, phosphines, nitriles, dialkylsulfides inter alia) proved to be versatile reagents. For instance, when triethylamine is used to replace acetonitrile from the adduct not only does the expected replacement occur but in preference also a proton shift (most likely prior to the base displacement reaction) with cluster closure to the decahydro-doso-decaborate(2—) (Eq. 52) ... 

Aryloxy groups are much easier to displace compared to primary and secondary alkox-ide anions and so, aryl ethers are generally more useful in displacement reactions. Amine nucleophiles react with unsymmetrical aryl ethers to form the amine of the heavier nitrated moiety.Accordingly, 2,4,6-trinitrodiphenyl ether reacts with ammonia to expel phenoxide... 

The A-acetyl derivatives of the 2-alkylthio-l,3-thiadiazol-4-imines (124, R = SR, R = Ac) undergo nucleophilic displacement reaction with amines (benzylamine, cyclohexylamine, morpholine, or aniline) giving the 2-amino derivatives (124, R = NRj, R = Ac). The salt (126, R = R = Ph, R = R = H, X = Cl) reacts with aniline at room temperature giving 4-anilino-2-phenyl-l,3-thiazole (128), presumably by a mechanism involving cleavage of the heterocyclic ring. ... 

Compound 26, likewise, undergoes a series of displacement reactions (Scheme 34). Whereas reaction with copper(I) cyanide replaces only one chlorine atom to yield 136, all are displaced by reactions with ammonia and isopropylamine, diethyl(trimethylsilyl)amine, water, and thiols to give, respectively, 137-140. Some additional transformations are also shown. 

There are three common approaches to the displacement of amine substituents from purines. First, diazotization and dediazoniation have been used to replace amine substituents, primarily with hydrogen or hydroxyl, carboxyl, and halide functionalities. Second, the S Ar reactions of quaternary ammonium substituents have provided useful synthetic adjuncts to the displacement reactions of halopurines. Finally, of increasing importance has been the conversion of aminopurines (or oxopurines) to N-linked 1,2,4-triazoles (and other azoles), which function as pseudohalogens and can be displaced by nucleophiles or take part in transition metal-catalyzed reactions. 

A one-pot procedure for the transformation of 6-thiopurine nucleosides to 6-aminopurines was developed using DMDO as the oxidant in the presence of a stoichiometric amount of various amines <1996T6759>. For example, 6-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)purine was readily converted to the 6-alkylamino derivatives (6-amino, 75% yield 6-methylamino, 55% yield). Similarly, A -6-acetyl-8-thio-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine was converted to A -6-acetyl-8-methylamino-9-(2, 3, 5 -tri-0-acetyl-/3-D-ribosyl)adenosine (DMDO, methylamine, CH2CI2, 25 °C, 83% yield). Less nucleophilic 2-mercaptopurine derivatives did not undergo the displacement reaction, however, and only the products of dithiane formation and desulfurization were isolated. 

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