Bifunctional nucleophiles

Certain bifunctional nucleophiles allow cyclization after ring opening. The formation of 2-thiazolium salts (71JHC40S) and the analogous production of 2-amino-2-thiazolines (191) from aziridines and thiocyanic acid fall into this category (72JOC4401). 

A proposed explanation of the reactivity of the 4-position versus that of the 2-position in pyridinium compounds has been advanced by Kosower and Klinedinst nucleophiles which are expected to form charge-transfer complexes will tend to substitute at the 4-position. However, it is not clear why this (usually unknown) property should govern the site of substitution, except for a bifunctional nucleophile such as hydrosulfite ion which can form a suitable bridge from the nitrogen to the 4-position. 

A bifunctional reagent such as ethanolamine can favor ortho substitution of azines due to hydrogen bonding as in 62. With a bifunctional nucleophile such as ethylene glycol anion, facilitation of... 

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). 

Perfluoro-2-methyl-2-pentene reacted with acyclic bifunctional nucleophiles such as 2-mercaptoethanol (89NKK1772) and ethylene glycol (86JAP61200983), in the presence of a base, to give 1,4-oxathiepin and dioxepin derivatives, respectively. Eight- and nine-membered heterocycles are obtained with 1,2-bifunctional benzenes such as salicyclic acid [81JFC(18)447]. 

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. 

Wu, M. H. Jacobsen, E. N. (1998) Asymmetric ring opening of meso-epoxides with thiols enantiomeric enrichment using a bifunctional nucleophile., J. Org. Chem., 63 5252-5254. 

The addition of other bifunctional nucleophiles also allowed the preparation, in moderate to high yields, of the five-, seven-, and eight-membered heterocyclic carbene species 55-58 (Fig. 9) which, in some cases, were formed along with minor amounts of other derivatives [63]. Related 1,2,3-diheterocyclizations involving (ethoxy)allenylidene complexes have been described, ethanol instead of HNMe2 being released in this case [62],... 

Seven-membered rings can also be formed across the 2,3-position by bifunctional nucleophiles having an amino and an active methylene group (169 Section IV,B,1). 

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. 

A typical example of such heterocyclization is the interaction of 3-phenyl-5-met-hoxy-l,2,4-triazine 182 with urea or A,A -dimethylurea in acetic or, better, in tri-fluoroacetic anhydride. The role of anhydride consists in converting starting molecule into a more electrophilic triazinium salt 183, which then reacts with a bifunctional nucleophile to form imidazotriazinone 184 (Scheme 54) (00MC58, 01JHC901). 

Palladium- or nickel-catalysed carbonylation polycondensation of dibromoar-enes with bifunctional nucleophilic monomers such as aromatic diamines and bisphenols in the presence of carbon monoxide appeared to be a new promising method for the synthesis of aromatic polyamides [scheme (15)] and polyesters [scheme (16)] respectively [162-170], The first successful example was the synthesis of high molecular weight polyaramide according to scheme (15) (Ar1 = m-C6H4-, Ar2 = p-C6H4 O C6H4 ) [162],... 

Another approach uses the interaction of perfluoroolefms with bifunctional nucleophiles, for example, with the derivatives of hydrazoic acid, in particular, with sodium azide. 

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. 

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