Reactions with Binucleophiles

Phosgene and several of its equivalents react with 1,2-binucleophiles 1109 forming 2-oxo-five-membered heterocycles. Oxazolidin-2-ones (1110, Nu = NH, Nu = O), thiazolidin-2-ones (1110, Nu = NH, Nu = S), imidazolidin-2-ones (1110, Nu, Nu = NH), and lH-benzo[d][l,3]oxazine-2,4-diones (1110, Nu = COO, Nu = NH) are the most important classes of reaction products. 

Several synthetic methods were presented in Sections 4.3.2, 4.3.3, and 4.3.4, in which five-membered cyclic carbamates (oxazolidin-2-ones), cyclic carbonates (1,3-dioxolan-2-ones), and cyclic ureas (imidazolidin-2-ones), respectively, were constructed. General reviews of the synthesis and chemistry of 2-oxazolidinones and thiazolidin-2-ones [363, 364], reporting the reactions of N,0- and N,S-l,2-binu-cleophUic substrates with various carbonylating agents, are available. 

When the substrates 1109 are a-amino adds (1,1-binucleophiles having Nu H = COOH and Nu = NH), a spedal dass of mixed anhydrides, 2,5-dioxo- 

3-oxazoUdines, more commonly referred to as N-carboxy-a-amino acid anhydrides (NCAs), is formed. 

Aryl and allryl chloroformates, alkyl and aryl carbonates, diphosgene, and oxalyl dichloride are the most commonly employed reagents. For many reasons, as discussed in Section 4.3.2, reactions of vicinal amino alcohols with triphosgene [522-524, 526, 528] or l,l -carbonyldiimidazole [461-463, 467-483] have recently emerged as the preferred and most cited methods for preparing 2-oxazolidinones. 

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The conditions influence the direction of the reactions between the nucleophile and unsaturated carbonyl compounds as well. For example, the reaction of hydrazides of some organic acids with chalcone in the presence of acetic acid involves the carbonyl group of the unsaturated ketone, while basic catalysis (piperidine) promotes /3-addition [45]. An analogous influence of the acidity on the direction is observed in reactions with binucleophiles [46]. Numerous similar examples are given in the appropriate chapters of this book. 

One of the features of a,/3-unsaturated ketones is the presence of two electrophilic centers. Because of this feature, reactions with binucleophiles can proceed as a 1,2-addition or as a 1,4-addition. Regarding three-membered nitrogen-containing heterocycles formed from a,/3-unsaturated ketones and their derivatives, the unsaturated ketone acts either as a 1,2-bielectrophile (substituted ethylene), which leads to the formation of ethyleneimines, or as a 1,4-bielectrophile, giving rise to either bi- or tricyclic aziridines. Hence, the present chapter is divided into two parts, one which is entirely dedicated to aziridinyl ketones and the other to bi- and tricyclic aziridines. 

Vinylacetylenes or -diacetylenes, reactions with binucleophiles leading to N-heterocycles 81 UK 1252. 

Addition of a reactive group to the 2 position of the 1,3-dicarbonyl compound expands the traditional synthetic utility of these substances since their reactions with binucleophilic reagents form both the expected (benzodiazepine heterocycles) and the unexpected (quinoxalines) products. 

See Section 4.3 for isocyanates, carbamates, carbonates, ureas, and reactions with binucleophiles). 

Sufficient differences in the nature of these two electrophilic centers of enones are reflected in the high regioselectivity of their reactions with mono-and binucleophiles. This fact clearly discriminates a,/3-unsaturated carbonyls from other bielectrophilic compounds, for instance, /3-diketones. However, the application of this advantage requires the determination and subsequent systematization of the factors influencing the directions of the reactions. 

Another representative of urea-like binucleophiles is guanidine and its derivatives. There are dozens of publications devoted to their reactions with a,(3-unsaturated carbonyls, which are usually very simple processes. For example, routine magnetic stirring of guanidine 61 with chalcone 5 at room temperature in ethanol led to the formation of 1,6-dihydropyrimidin-2-ylamine 76 [78] with good yields (Scheme 3.24). But in several publications it was mentioned that such reactions may be complicated by side reactions and isolation of the target dihydropyrimidines is difficult. Very often among... 

Dihydropyridines containing at position 3 a carbonyl group similar to oc,(3-unsaturated ketones can be involved in cyclocondensation reactions with 1,2-binucleophiles. Dihydropyridine 376 treated with hydroxylamine yields isoxazoline derivatives 377 [363, 382, 383, 384, 385, 386] (Scheme 3.122). Dihydro-l,2,4-triazolo[l,5- ]pyrimidine 378 reacts with hydrazine and hydroxylamine in the same manner, giving the condensation products 379 [387]. 

II. Reactions of Binucleophilic Reagents with Terminal Perfluoroolefins. 137... 

Systemization of experimental data on the syntheses of heterocyclic compounds with perfluoroalkyl groups from perfluoroolefins is based on reactions with various 1,1-, 1,2-, 1,3-, and 1,4-binucleophilic reagents. While the main features of nucleophilic reactions are preserved, further transformations of the primary products (or adducts, or the products of substitution of the functional groups at the internal multiple bond) occur under the influence of the added functional group containing a heteroatom. Here one can expect dramatic differences in the effect of the nature of the nucleophilic reagent between cyclizations by new nucleophilic centers and centers already available in the molecule. Another important aspect is isomerization of the primary internal olefin into the terminal olefin or internal olefin with a different structure under the action of the nucleophilic agent. This may be critical to the structure of the heterocycle formed. 

Terminal perfluoroolefins have two fluorine atoms at the double bond. The carbon atoms of the latter bear a significant positive charge, and the nucleophilic agents easily replace the fluorine atoms at the multiple bond. The reactions of binucleophilic reagents with terminal perfluoroolefins form heterocyclic systems. The first step of the reaction involves a nucleophilic attack at the carbon atom of the double bond, generating a carbanion. The latter is stabilized by elimination of the fluoride ion and formation of a new double bond. Subsequent cyclization by the intramolecular attack of the nucleophilic center at the double bond leads to the formation of a heterocyclic system. For example, when a reaction mixture of hexafluoropropylene and sodium dialkylaminodithiocarbamate in dimethylacetamide is heated with aqueous sodium tetraphenylborate, one obtains the tetraphenylborate salt of 2-dialkylamino-4-trifluoromethyl-4,5-difluoro-l,3-dithiolan-2-yl (78JFC(12)193). This compound is formed by intramolecular cyclization of the S-nucleophilic center. 

Since primary alkylamines are binucleophilic reagents, both amino hydrogen atoms are lost in reactions with unsaturated compounds. However, it should be realized that these are rather strong bases catalyzing isomerization of perfluoroolefins. 

Table IV. Products of the Reaction of Perfluoro-2-methylpent-2-ene with Binucleophiles...

If the N,S- or Y,Y-binucleophile has an a-b-c triad, the character of the heterocyclic product depends on the nature of the nucleophile initiating the reaction with perfluoroolefins and perfluoroazaalkens (Table Y) (03PU1). 

Aromatic primary amines are not only binucleophiles at the amino group, but they also exhibit the properties of C,N-binucleophiles. Their reactions with internal perfluoroolefins lead to quinoline derivatives (98JFC(88)169, 94JCS(CC)134, 98T4949). Thus the reaction of aniline with 2//-heptafluorobut-2-ene yields phenyl(2-trifluoromethylquinolin-4-yl) amine (00ZOR109) when the reaction is carried out with the tetrafluoro-ethylene trimer, it leads to 2-trifluoromethyl-3-(l-N-phenylimino-2,2,2-trifluoroethyl)-4-(N-phenylamino)quinoline (98JFC(88)169). 

Reaction of the 1,3-dithiolanes 305 with binucleophiles such as hydrazine hydrate or ethanolamine afforded pyrazoles 306 and isoxazoles 307, respectively (Scheme 41) <1995SC3603>. 

The lA4,2,5-thiadiazole 1-oxide 4 undergoes ring transformation with binucleophiles, e g. imidamides, guanidines, isothiourea, to give 1,2,4,6-thiatriazinc 1-oxides 5.64 The reactions of the 1-oxide 4 with binucleophiles are conducted in methanolic solution at room temperature. Thus, 5 (R = Ph) is obtained in a 40% yield by reaction of the 1-oxide 4 with benzimidamide hydrochloride. 

Reaction of compound 65 with binucleophiles such as hydrazine, phenyl-hydrazine, or hydroxylamine, leads to bis-heterocyclic compounds 66 and 67 (95IZV762) (Scheme 73). 

Reactions with aromatic binucleophiles form fused ring heterocycles (00T7267). Thus, when the reaction is performed with 2-aminothiophenol, compound 99 is converted into 2-trifluoroacety 1-4/7-1,4-benzothiazine (identified by X-ray crystallography) (Scheme 106). In the case of thioethanolamine hydrochloride, the product is 2-trifluoroacetyl-47/-1,4-thiazine. 

Because of the convincing results even in penicillin chemistry, due to the smooth reaction conditions, carbodiimides and particndarly DCC became common coupling reagents in natural compound and peptide chemistry. In combination with binucleophiles, such as N-hydroxysuccinimide or N-hydroxybenzotriazole, the method is racemization-free [1248]. Other frequent applications are in esterifications and general dehydration reactions, and, more recently, in carbodiimide-mediated multicomponent reactions [1251] (see Section 4.S.3.5). All these reactions proceed through activated intermediates 1689. Thus, compounds with a carboxylic function 1688 can be coupled with a nucleophilic compound 1690 to afford the coupled product 1691 under extremely mild conditions. The resulting by-product dicydohexylurea 1693, however, is difficult to separate because of its ambivalent solubility properties, which usually complicate the whole work-up procedure. 

As it was mentioned previously, mesoionic oxazolones were used as dipolaro-philes in the synthesis of 2-CF3-pyrroles. A tandem addition of 1,2-binucleophiles to oxazolones also led to pyrroles, but bearing the CFs-group in 3-position. For instance, the reaction of the oxazolones 426 with aminomalonate 427 gave the pyrrolidine derivative 428, which formed 429 by reaction with acetic anhydride. Treatment of 429 with lithium hydroxide resulted in a decarboxylation giving the pyrrole 430 [140]. 

Certain ten-substituted aromatic diamines can act as NCCCN binucleophiles in reaction with fluorinated acid derivatives to give pyrimidines. In particular, fused pyrimidine derivatives 658,659 and 661 were obtained from amines 657 [397] and 660 [398] by reaction with fluorinated anhydrides (Scheme 136). 

In case of non-symmetrical binucleophiles, the reaction with 699 is regioselec-tive (although not always 100 %). Normally, it should start with attack of more nucleophilic nitrogen atom of the nucleophile at the fluoroalkyl-substituted carbonyl group of the electrophile (see, for example. Table 34, Entries 4 and 12). Nevertheless, the available data, reported mainly for the reactions of aminoazoles. 

A range of NCN binucleophiles introduced into reaction with 700 is similar to that for fluorinated p-dicarbonyl compounds discussed in the previous section and includes amidines (Table 35, Entries 1, 2), (thio)urea and its derivatives (Entries 3-5), guanidines (Entry 6), semicarbazide derivatives (Entry 7), and electron-rich amino heterocycles (Entries 8-12). 

Enaminones 701 demonstrated similar behavior in the reactions with NCN binucleophiles compared with p-alkoxy-substituted enones 700 (Table 36). It should be noted, however, that rather unusual substituents were introduced into the molecules of the target pyrimidines using reagents 701 (Entries 3-9). hi particular, the enaminone fragment of 701 can be a part of aminouracil moiety (Entry 9), although in this case, CCCN-fCN mechanism for the pyrimidine ring formation is possible. 

Two enones of general formula 702 were introduced into reaction with NCN binucleophiles, namely, 768 [453] and 769 [475] (Scheme 152). In case of 768, one of the ethoxy groups can be retained in the final strucmre. Reactions with 769 were accompanied with the dithiane ring opening to give thiols 771. 

Chromone derivatives and their analogues 704 and 705 were used for synthesis of 4-fluoroalkylpyrimidines. In both cases, reaction with NCN binucleophiles was accompanied with recyclization of the y-(thia)pyrone ring to give (2-(thio) hydroxyphenyl)-substituted pyrimidines or their analogues (Table 37). 

Aromatic (786) and xylose-derived (787,788) fluorinated enones were successfully introduced into reaction with amidines or analogous NCN binucleophiles to give pyrimidines 789 in 58-80 % yields (Scheme 156) [485],... 

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