Reaction with bifunctional nucleophiles

Detailed study on the interaction of bifunctional nucleophilic reagents with 16 revealed an interesting behavior of this compound. While reaction with ethylene glycol in polar solvents (DMF, DMSO, HMTA, and acetonitrile) leads to the predominant formation of dioxolane 20, in solvents of lower polarity predominant formation of the corresponding 1,4-dioxepine 21 as major product is observed (Fig. 10.9).22... 

Recently, the above mentioned model reaction has been extended to polycondensation reactions for synthesis of polyethers and polysulfides [7,81]. In recent reports crown ether catalysts have mostly been used in the reaction of a bifunctional nucleophile with a bifunctional electrophile, as well as in the monomer species carrying both types of functional groups [7]. Table 5 describes the syntheses of aromatic polyethers by the nucleophilic displacement polymerization using PTC. 

Fluorinated alkenes and alkynes are highly activated toward nucleophilic attack and reaction with bifunctional nucleophiles is a fruitful area for the synthesis of heterocycles. A review on perfluoroalkyl(aryl)acety-lenes contains many examples (91RCR501). 

The synthesis of this ring system was achieved by the reaction of the ketene aminal 79 with 3-morpholino-l-ethyl-l,2,4-triazinium tetrafluoro-borate 78 to give 80 (89IZV494). Cyclization of 78 with the bifunctional nucleophile 81 gave the pyrrolo[3,2-e][l,2,4]triazinones 82 (88TL1431). This reaction represents the first example of orthocyclization onto the 1,2,4-triazine ring by the addition of dienophiles at C-5,6 (Scheme 20). 

A new variant of the Sn(ANRORC) substitutions was found in reactions of A-methylpyrimidinium salts with bifunctional nucleophiles, such as S-methylisourea, O-methylisourea, and cyanamide. 

The weak nucleophilic nature of polynitroaliphatic alcohols is also reflected in their slow reactions with isocyanates to yield carbamates. These reactions often need the presence of Lewis acids like ferric acetylacetonate or boron trifluoride etherate. The reaction of bifunctional isocyanates with polynitroaliphatic diols has been used to synthesize energetic polymers.33°... 

According to the available experimental data, it is impossible to distinguish between these mechanisms, but the second mechanism seems to be preferred [Scheme (7)] for, according to this Scheme, the reaction of amine addition proceeding through a cyclic transition state is completed in one step, whereas for the reaction to occur according to Scheme (2) or (6) it is additionally necessary to transfer the proton. Then, it is probable that the different mechanisms [Schemes (3) and (5)] may precede formation of one and the same transition state [Scheme (7)]. Note finally that the mechanism of bifunctional catalysis [Scheme (7)] is extremely popular in different reactions of nucleophilic substitution at the saturated carbon atom and reactions with participation of a carbonyl group32>. 

The halogenoacetyl derivatives of pyrrole and indole undergo normal nucleophilic substitution reactions and with bifunctional nucleophiles they yield the expected heterocyclic derivatives, as, for example, in the formation of the thiazolylindole from the reaction of 3-(chloroacetyl)indole with thioacetamide (77IJC(B)473>. 

Charushin, V. N., Chupakhin, O. N., van der Plas, H. C., Reactions of Azines with Bifunctional Nucleophiles Cyclizations and Ring Transformations, 43, 301. 

Betainic alkaloids and nucleobases, 85, 67 Bicyclic 6/5 ring-fused systems with bridgehead nitrogen, 49, 193 Bifunctional nucleophiles cyclizations and ring transformations on reaction of azines with, 43, 301... 

Cyclizations of this type are realized in substrates with two vicinal electron-deficient carbon atoms, one is unsubstituted and the other carries a good leaving group. Correspondingly, bifunctional nucleophiles are normally used in these reactions. The symbol SNH-SN ipso means that nucleophilic replacement of hydrogen precedes ipso substitution. Formally, an SnH-Sn ipso transformation has to be an AEA E -process that includes two pairs of addition-elimination steps. However, the AA E E sequence usually occurs and therefore cyclizations described in this section are attributed to the SnH-Sn ipso type in accordance with an actual result. 

These examples demonstrate the utility of bifunctional nucleophiles in reactions of perfluoroolefins with an internal multiple bond leading to various heterocyclic compounds with perfluoroalkyl substituents. 

The above examples demonstrate the possibilities for syntheses of various heterocyclic compounds with perfluoroalkyl groups using bifunctional nucleophiles in reactions of perfluoroolefins involving their double bonds. Chambers et al. (79JCS(P1)214) found that the reaction of perfhioro-3,4-dimethylhex-3-ene with ethylene glycol in tetraglyme forms a seven-membered heterocycle, 5-pentafluoroethyl-5,6,7-tris-(tri-fluoromethyl)-l,4-dioxacyclohept-6-ene 133, while with ethanolamine the product is 5-pentafhioroethyl-5,6,7-tris-(trifluoromethyl)-l-oxa-4-azacyclo-hept-6-ene 134. 

Reaction of 1,2,4-triazinium salts with amides of acetoacetic acid results in 1,4,4a,5,7,7a-hexa-hydro-6/7-pyrrolo[3,2-e]-l,2,4-triazin-6-ones via the diaddition of bifunctional nucleophiles at the C-5 and C-6 positions of the 1,2,4-triazine ring (Equation (2)) <88TL1431>. 

Bifunctional nucleophilic compounds can add to TV-alkylpyrazinium salts, and the benzo fused pyrazino[2,3-e][l,3,4]thiadiazine (471) as well as the benzo fused pyrazino[2,3-e]-l,2,4-oxadiazine (472) can be made by this method (Scheme 40). A closely related reaction is exemplified by the preparation of the pyrazino[2,3-e]-1,2,4-triazine (473) (Equation (94)) <87KGS557, 87KGS1118). The pyrimido[5,4-c][l,2,5]oxadiazine (475) can be prepared by treatment of the uracil derivative (474) with isoamyl nitrite (Equation (95)). Presumably the reaction proceeds by cyclization of an initially formed 5-nitrosopyrimidine intermediate (64ZC454). 

Reactions of Azines with Bifunctional Nucleophiles Cyclizations and Ring Transformations... 

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