Displacement product

Bromomethyl-5-methylthiophene gives normal displacement products with amines but it is isomerized on attempted reaction with copper(I) cyanide (Scheme 59) 48MI30200. Whereas 2-hydroxymethylthiophene reacts normally with hydrogen halides to give 2-halomethylthiophenes, reaction of 2-hydroxymethylfuran (2-furfuryl alcohol) with hydrochloric acid results in formation of laevulinic acid (151). 2-Furfuryl alcohol derivatives are... 

With secondary amines such as piperidine or dimethylamine the formal products (169) of cine substitution are obtained with primary amines e.g. /-butylamine), in addition to the displacement product (173), a rearranged product (174) is obtained in which the nitrogen-bearing methyl becomes exocyclic 80CC123). Earlier studies on the reaction of... 

In one example where a 2-Cl and 2 -F were present, only the chloride displacement product (548) was reported also the tetrafluoro-l,2-benzisoxazole (550) was prepared by heating the oxime (549) (Scheme 166) (79EUP2666, 71MI41600). 

The question of the occurrence of cine or aryne substitution in some of these reactions has been raised but not answered adequately. The normal product, 2-methoxynaphthalene was shown to be formed from 2-chloronaphthalene and methoxide ion, and the normal 6- and 8-piperidinoquinolines were proved to be products of piperidino-debromination of 6- and 8-bromoquinolines, all in unspecified yield. More highly activated compounds were then assumed not to react via the aryne mechanism. Even if the major product had been characterized, the occurrence of a substantial or predominant amount of aryne reaction may escape notice when strong orientation or steric effects lead to formation of the normal displacement product from the aryne. A substantial amoimt of concurrent aryne reaction may also escape detection if it yields an amount of cine-substituted material easily removed in purification or if the entire reaction mixture is not chromatographed Kauffman and Boettcher have demonstrated that activated compounds such as 4-chloropyridine do indeed react partially via the aryne mechanism (Section I,C,1). 

OKO-l,3,7-triazanaphthalene (450) forms acyloxy derivatives in situ with phosphorus oxychloride and pentasulfide which undergo nucleophilic displacement with chloride ion and with a complex sulfide ion, respectively, to form the 4-chloro and 4-thioxo derivatives. The 4-carboxymethylthio compoimd failed to undergo the ring-opening reaction (see below) characteristic of more activated azino- and diazino-pyrimidines, but it did yield about 10% of the 4-0X0 displacement product. 

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 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>. 

Modifications of the substituent at Cg are conveniently accomplished using sulfur nucleophiles to displace the acetoxy moiety which is present in the fermentation products. Cefamandole (26) is such an agent. Reaction of 7-aminocephalosporanic acid with thiotetrazole 24 gave displacement product 25,... 

The lithium salt of a substituted cyclopentadienyl anion has been used in reaction with phosphorus trichloride for carbon-phosphorus bond formation.70 The resultant simple displacement product ultimately undergoes dimerization and loss of four (from the dimer) equivalents of HC1 (Equation 4.25). 

A detailed study of the conversion of 3,4-dichloro-l,2,5-thiadiazole into 3,4-diamino-l,2,5-thia-diazole has been carried out <76JHC13>. Reaction with lithium or sodium amide produces only 4% of the diamine together with cyano-containing by-products, a consequence of direct attack on sulfur. Use of a less powerful nucleophile, ammonia or potassium phthalimide, resulted in an increased attack on carbon and produced the diamine in 24% and 66% yields, respectively. Secondary amines, e.g. morpholine <76JOC3l2l> and dimethylamine <72JMC315>, produce the normal displacement products. The reaction of dichlorothiadiazole with potassium fluoride in sulfolane gives a mixture of 3-chloro-4-fluoro and 3,4-difluoro-l,2,5-thiadiazole <82CB2135>. 

Cyclopropane ring formation has been brought about by Michael addition initiated ring closure (sometimes called MIRC). The reaction of methyl 4-bromocrotonate (3) with different nucleophiles either gives the SN2-displacement product 4 or the Michael addition intermediate 5 which finally forms the cyclopropane carboxylate 697 (the configuration of 6 has not been determined). This reaction has been studied with different nucleophiles in the solvent systems tetrahydrofuran-HMPA (20 1) and tetrahydrofuran the bromocrotonate 3 was reacted with 1 equivalent of a 1 M solution of the lithium enolates at —78 for 12 h at room temperature97. 

There is an important practical consideration based on the above observations. If mixed 2,6-disubstituted products such as 109 are desired, where one of the substituents results from displacement by ammonia or a primary amine, then that substituent should be introduced in the second step to avoid the exchange that would occur otherwise. This is illustrated in Scheme 39 for the preparation of the mixed di-displacement products 109 and 111 via the intermediates 108 and 110 (75USP3928351). 

One of the earlier second-generation quinolones indeed includes fluorine at the 6 position and a basic function at the 7 position, characteristic of the more potent drugs that also feature a broader spectmm of antibacterial activity. The starting material (39-3) for one of these agents is prepared by application of the same scheme as above to the substituted aniline (39-1). Nucleophilic aromatic displacement with A-methylpiperazine (39-4) proceeds at the 7 position due to activation by the carbonyl group para to the chlorine (39-5). Saponification of the displacement product leads to pefloxacin (39-6) [46]. 

Pentafluorophenyllithium readily reacted with electrophiles to give the pentafluorophenylated compounds in good yield [195,197,207-211]. The addition-elimination product was obtained instead of the displacement product when pentafluorophenyllithium was reacted with iodotrifluoroethylene [212] (Scheme 72). 

Bromomethyl-5-methylthiophene gives normal displacement products with amines but it is isomerized on attempted reaction with copper cyanide (347 — 348) (48MI30200). 

Mercury(II) chloride also forms a 1 1 complex with 3-methyloxa-diazole, which in a buffered solution forms a new complex with the electrophilic displacement product [Eq. (67)]. 

Subsequent cleavage of a C-O bond and loss of a proton yields a displacement product ... 

P-31 NMR studies also were carried out in a similar manner on rhodium complexes of two chelating bisphosphines—bis-l,3-diphenyl-phosphinopropane and bis-l,2-diphenylphosphinoethane. These complexes were generated in solution via ligand displacement from tris(tri-phenylphosphine)rhodium carbonyl hydride. For example, one of the possible displacement products of bis-l,3-diphenylphosphinopropane (F) is a cis-chelate (G) that can undergo dissociation to yield a chelating bisphosphine complex (H) ... 

In contrast, for the oxy and thio analogues 106 and 107 only 1 equivalent of PPh3 was necessary to produce the neutral, pyridine-displaced products 130 and 131.52 Reaction of the ketone derivative 115 with an equimolar amount of PPh3 gave the neutral complex 132 formed by displacement of the pyridine ligand, while with 2 equivalents of PPh3 in the presence of Na[BF4] the cationic bis(phosphine) complex 133 is obtained.58... 

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