By Nucleophilic Displacement

2 By Nucleophilic Displacement. - The Amadori compound 7 was synthesized by reaction of 2,3 4,5-di-0-isopropylidene-D-fructopyranose 1-triflate with the requisite primary amine, followed by acid-catalysed deprotection. Syntheses of 2-azido-2-deoxy-a-D-glucopyranosides of myo-inositol, involving either inversion at C-2 of the corresponding a-mannoside 2-triflate or direct glycosylation with a pentenyl donor, are further detailed in Chapter 10.  

5- amino-group in 16 was introduced by reaction of a 5-hydroxy-derivative under Mitsunobu conditions [PhaP, DEAD, (PhO)2PN3]. Syntheses of 5 -deoxy-5 -dialkylamino-derivatives of a spiro-cyclic nucleoside inhibitor of HIV-1 reverse transcriptase are covered in Chapter 19. The disaccharide scaffold 18, based on tunicamycin and required for further elaboration into bioactive compounds, was made by glycosylation of a nucleoside derivative followed by introduction of a 

3 By Nucleophilic Displacement - Reaction of 2,3 4,5-di-0-isopropylidene-P-D-fructopyranose 1-triflate with tyrosine benzyl ester gave an Amadori-type 

All four isomeric 5-amino-5-deoxy-D-pentono-1,5-lactams have been prepared. D-Xylose and D-arabinose were converted into 5-azido-5-deoxy-l,2-0-isopropyli-dene derivatives via 5-tosylate intermediates. Oxidation and reduction of the free 

3-hydroxy group gave the corresponding D-ribose and o-lyxose isomers. Hydrolysis, bromine oxidation and catalytic hydrogenation gave the lactams.  

3-Amino-3-deoxy-sucrose has been synthesized from sucrose by sequential oxidation at C-3 by Agrobacterium tumefaciens (40% yield), peracetylation, reduction of the C-3 ketone to an a//o-configured product (H2, Pt), trifluoro-methanesulfonylation, displacement by azide with inversion, deacetylation and hydrogenation. 4-Amino-4-deoxy-sucrose was obtained from a sucrose hepta-pivaloate by double inversion at C-4 by sequential triflate displacement reactions, first with nitrite then azide ion. Various 4-alkylamino-2,4-dideoxy-L-r/ireo-pentopyranosides 15, components of the calicheamicins, were synthesized from 

The 3 -amino-3 -deoxy-derivative 26 of iV-acetyl-lactosamine was synthesized using a known 3 -azido-3 -deoxy-galactosyl donor for construction of the disaccharide. It was an inhibitor (Ki=104 pM) of the glycosyltransferase that 

Reagents i, BnNH2, MeOH ii, TbdpsCl, imidazole, DMF iii, LiN SiMe3 2 then EtI or M62CO 

Reagents i, Bu OaCCINa, AgNOa, OSO4, MeCN ii, OSO4, chloramine T, Bu OH, H2O iii, BU4NF  

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Substitution reactions on dialkyl peroxides without concurrent peroxide cleavage have been reported, eg, the nitration of dicumyl peroxide (44), and the chlorination of di-/ fZ-butyl peroxide (77). Bromination by nucleophilic displacement on a-chloro- or a-hydroxyalkyl peroxides with hydrogen bromide produces a-bromoalkyl peroxides (78). 

Amines also react with diacyl peroxides by nucleophilic displacement on the oxygen—oxygen bond forming an ion pair iatermediate (187) ... 

A.mina.tlon. Amination describes the introduction of amino groups into aromatic molecules by reaction of ammonia or an amine with suitably substituted halogeno, hydroxy, or sulfonated derivatives by nucleophilic displacement. Although reaction and operational conditions vary, the process always involves the heating of the appropriate precursor with excess aqueous ammonia or amine under pressure. 

Three selective methods to remove protective groups are receiving much attention assisted, electrolytic, and photolytic removal. Four examples illustrate assisted removal of a protective group. A stable allyl group can be converted to a labile vinyl ether group (eq. 4) a /3-haloethoxy (eq. 5) or a /3-silylethoxy (eq. 6) derivative is cleaved by attack at the /3-substituent and a stable o-nitro-phenyl derivative can be reduced to the o-amino compound, which undergoes cleavage by nucleophilic displacement (eq. 7) ° ... 

In a penicillin synthesis the carboxyl group was protected as a p-bromophenac ester that was cleaved by nucleophilic displacement (PhSK, DMF, 20°, 30 mil... 

The parent ligand forms complexes of the type [M(CO)5(HNSO)][AsF6] (M = Mn, Re) (Eq. 9.11). ° The rhenium complex can also be prepared by nucleophilic displacement of F from coordinated NSF using MesSnOH as the source of... 

In a penicillin synthesis, the carboxyl group was protected as a / -bromophenacyl ester that was cleaved by nucleophilic displacement (PhSK, DMF, 20°, 30 min, 64% yield). Hydrogenolysis of a benzyl ester was difficult (perhaps because of catalyst poisoning by sulfur) basic hydrolysis of methyl or ethyl esters led to attack at the /3-lactam ring. ... 

Grignard reagents are rapidly hydrolysed by water or acid to give the parem hydrcxatbon, RH, but this reacdon is rarely of synthedc importance. Hydrocarbons can also be syndiesized by nucleophilic displacement of halide ion from a reacdve alkyl halide, e.g. 

A similar reaction is probably involved in the reaction of 4-nitrophthalodi-nitrile (27) with dimedone (28), which provided under milder condition compound 29 and at a higher temperature tricyclic compound 30 (87ZOR2629). Similarly as in the vicarious nucleophilic reactions, intermediate 29 is formed by nucleophilic displacement of the ort/io-hydrogen atom in 27 (Scheme 3). 

Cefonicid (55) is synthesized conveniently by nucleophilic displacement of the C-3 acetoxy moiety of with the appropriately substituted tetrazole thiol (54).The mandelic acid amide C-7 side chain is reminiscent of cefamandole. 

Interestingly, the photolysis of methyl 3-azido-2.6-difluorobenzoate (61) in diethylamine yields, in addition to the two expected 3//-azepines 62 and 63, a third azepine 64 formed by nucleophilic displacement of allylic fluorine from the 3-position by diethylamine.188 Displacement of allylic halogen from haloazepines has been noted previously.177... 

Ring expansions of 3-aryl-7-azido-2-chloroquinolines, e.g. 21, in potassium methoxide-meth-anol/dioxane yield mixtures of the expected 3-aryl-2-chloro-7-methoxy-9//-pyrido[2,3-f]pyrid-ines, e.g. 22, and the 2,7-dimethoxy derivatives, e.g. 23, formed by nucleophilic displacement of the 2-chloro group.154 ... 

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 synthesis of polyether quinoxaline by nucleophilic displacement discussed in Section 5.4.2.2 has also been used for the preparation of hyperbranched polyquinoxaline based on AB2 or A2B monomers. In the AB2 monomer the focal point is a single fluoro group (Fig. 5.42)172 in the A2B the focal point is a single... 

Recently, Baneijee et al. prepared a series of difluoro monomers with pendent trifluoromethyl groups using a Pd(0)-catalyzed cross-coupling reaction (Scheme 6.32).242,243 These monomers were converted to poly(arylene ether)s by nucleophilic displacement of the halogen atoms on the benzene ring with several... 

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... 

Dihalocarbene complexes are useful precursors to new carbenes by nucleophilic displacement of the chlorine substituents. This has been nicely illustrated for Fe(TPP)(=CCl2) by its reaction with two equivalents of Re(CO)5J to give the unusual /t-carbido complex Fe(TPP)=C=Re(CO)4Re(CO)5 which also contains a rhenium-rhenium bond. " The carbido carbon resonance was observed at 211.7 ppm in the C NMR spectrum. An X-ray crystal structure showed a very short Fe=C bond (1.605(13) A, shorter than comparable carbyne complexes) and a relatively long Re=C bond (1.957( 12) A) (Fig. 4, Table III). " ... 

The tetracyclines are important antibiotics often effective against organisms showing penicillin resistance. In 1980, a synthesis of some sulphur containing tetracyclines ° required thiol (14) as an intermediate. The SH group could be introduced by nucleophilic displacement of a diazonium salt (guideline 4) so amine (IS) is an essential intermediate. 

Considerable interest has been focused on the efficient and rapid synthesis of 2-deoxy-2-[ F]fluoro-D-gIucose, a popular imaging agent for positron-emission tomography (see Section III, 1). However, introduction of a fluorine atom at C-2 by nucleophilic displacement is generally not easy on account of the weak nucleophilic character of the fluoride ion. One possible... 

A very mild method that is useful for compounds that are prone to allylic rearrangement involves prior conversion of the alcohol to the tosylate, followed by nucleophilic displacement with halide ion. 

Nucleophilic substitution reactions, to which the aromatic rings are activated by the presence of the carbonyl groups, are commonly used in the elaboration of the anthraquinone nucleus, particularly for the introduction of hydroxy and amino groups. Commonly these substitution reactions are catalysed by either boric acid or by transition metal ions. As an example, amino and hydroxy groups may be introduced into the anthraquinone system by nucleophilic displacement of sulfonic acid groups. Another example of an industrially useful nucleophilic substitution is the reaction of l-amino-4-bromoanthraquinone-2-sulfonic acid (bromamine acid) (76) with aromatic amines, as shown in Scheme 4.5, to give a series of useful water-soluble blue dyes. The displacement of bromine in these reactions is catalysed markedly by the presence of copper(n) ions. 

The mechanism of the dehydrocyclization reaction is not completely understood. Two alternatives were proposed (11), one which proceeds via a silaimine mechanism, exemplified by reaction (25), and one wherein ring closure occurs by nucleophilic displacement of hydrogen, reaction (26). 

There has been significant emphasis on the use of pyrimidine thio ethers for further selective functionalisation by nucleophilic displacements of either the alkylthio or alkylsulfone and general syntheses of pyrimidines often include methylthio as one of the representative substituents. 

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.

Chloromethylphosphonamide 104 has been alkylated with diastereoselectivities up to >95%. The corresponding azido compounds 106 were obtained by nucleophilic displacement, with partial to full stereospecificity <2000HA528>. This two-step process can lead to aminophosphonic acids after reduction of the azido group and hydrolysis of the chiral appendage (Scheme 7). 

A suitable example is Cl Acid Blue 27 (6.37 X = NHCH3), which is made from 4-bromo-l-methylaminoanthraquinone by nucleophilic displacement followed by sulphonation. Some commercial acid dyes based on 1,4-diaminoanthraquinone contain substituents in both the 2- and the 3-positions. Thus, for example, Cl Acid Violet 41 (6.38) is produced by the condensation of l,4-diamino-2,3-dichloroanthraquinone with phenol in the presence of sodium sulphite and manganese dioxide. 

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