Binucleophiles

Thus, reaction of a 1,2-binucleophile with a 1,3-bielectrophile would lead to a five-membered heterocycle, as would the reaction of a 1,4-binucleophile with a 1,1-bielectrophile. Considering the reactions in this manner has several advantages and provides a convenient framework for considering synthetic approaches to target heterocycles. 

One of the practically important synthetic pathways to aryl-containing pyrazole derivatives is a reaction of oufi-unsaturatcd ketones with dipolar molecules or 1,2-binucleophiles. There are dozens of stereotypical publications on this topic and in this chapter we will not cite all existing references related to the synthesis and properties of pyrazole derivatives based on unsaturated carbonyl compounds but will cover the most general and some specific examples as well as mechanisms. 

The most usable and well-known pathway for the synthesis of five-membered nitrogen-containing heterocycles is condensation involving a,P-usaturated carbonyls and 1,2-binucleophilic compounds, e.g., derivatives of hydrazine and hydroxylamine (Scheme 2.8). The procedure based on these reactions was successfully applied for a long period [45, 46, 47, 48, 49, 50, 51, 52, 53]. 

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]. 

Binucleophiles provide access to five- and seven-membered heterocycles such as oxazolidine... 

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. 

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]. 

Reactions considered in this section have, as their guiding principle, bond formation occurring via reaction of a binucleophilic component with an electron-deficient bielec-trophilic counterpart. As the number of available binucleophiles containing two heteroatoms is comparatively small, the principal emphasis is placed on the bielectrophilic component of the reaction. Reagents under consideration may be arbitrarily classified into three general groups ... 

Table 1 Some Examples of Commonly Encountered Binucleophiles...

Table 1 lists some of the common binucleophiles utilized in heterocyclic synthesis, the numerical prefixes referring to the relative positions of the nucleophilic centers to each other. Higher order binucleophiles, e.g. 1,5-systems, come readily to mind and the above illustrative examples rapidly increase in scope when the incorporation of these structural elements into heterocyclic systems is considered. This last group offers many opportunities for ring annulations. 

Numerous examples of the ring closure of a binucleophilic system with a 1,1 -bielectrophile leading to five-membered heterocycles with three or more heteroatoms have been described, the popularity of this route no doubt reflecting the comparative ease with which the penultimate product may be obtained. 

As the bielectrophile contains two atoms of the five-membered ring, reactions to be considered under this category require a 1,3-binucleophile (see Table 1). An appreciable number of applications have been reported in the literature and illustrative examples are described below. One should also consider reactions discussed in Section 4.03.2.2 above as extensions of this concept. 

Binucleophiles give regiospecific addition to trifluoromethylacetylene with and without subsequent cyclization. Initial attack by the softer nucleophile occurs preferentially at the carbon p to the trifluoromethyl group [6] (equation 7). 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

Another type of cyclization leading to acetylenylpyrazoles is the interaction between a-acetylenic and -diacetylenic ketones and nitrogen-containing binucleophiles. 

Since in an aqueous medium the cyclization-completing stage involves the reaction of a cationoid intermediate with a binucleophile Y such as YNH2 (81UK1252), the end product structure is largely determined by the relative activity of C-1 and C-3 electrophilic centers in this intermediate. 

The effect of the nature of the substituent at the acetylene bond is not so noticeable. Substitution reduces the C-3 activity due to polarization effects and steric factors. As aresult, in the cyclization with hydrazines and hydroxylamines an increase in the content of 5-substituted pyrazoles and isoxazoles is observed (81UK1252). As mentioned above, nonsymmetiic nitrogen-containing binucleophiles H2N—YH (Y = O, NMe, NPh) react with l-heteroalk-l-en-3-ynes in two alternative pathways by functions H2N and YH. 

A decrease in the basic properties of the reagent in going from 1,2-diaminoethane to 1,2-diaminobenzene leads, in the case of ynaminoketones (X = Me), to the 1,3-orientation of binucleophile and the formation of the benzodiazepines 356, suggesting that the carbonyl group is also involved in the heterocyclization. 

These observations indicated that an intermolecular double condensation to give a bis N-(methylene-4-oxocoumarinyl)-l,4 aromatic diamine had occurred. Data from the elemental analysis indicated that the calculated and observed values were within the acceptable limits ( 0.4%) and in conformity with the assigned structure. In the addition of molar equivalents of 1,4-aromatic binucleophilic compounds to compound 72 we did not observe any heterocyclic compounds resulting from the further intermolecular nucleophilic attack on the single condensation product. Since the condensation of 3-(dimethylaminomethylene)-chromane-2,4-dione with aromatic binucleophilic compounds is the only route to the new coumarinic compounds, this represents a useful synthetic method. 

AHyl Anions Derived from Five and Six Membered Heterocycles (1,3-Binucleophilic Components)... 

The above examples represent Jl-heteroaromatic annulation involving the reaction of allyl anions whose double bond is a part of the heterocyclic ring system (Scheme 1). The corresponding a-oxoketene dithioacetals (1,3-electrophilic component) were generally derived from nonheterocyclic carbonyl precursors. Alternatively the Jl-heteroaromatic annulation can also be employed to a-oxoketene dithioacetals derived from heterocyclic ketones (1,3-bielectrophile) and hetero/nonheteroallyl anions (1,3-binucleophile). These reactions are described below. 

In our review we present general and specific examples of all these three types of MCRs, which involve aminoazoles as 1,3-binucleophile reagents. In the following sub-chapters, the most part of published original articles and selected patents in this topic will be observed and discussed. 

This procedure can be used for the MCRs based on other 1,3-binucleophiles. For example, the same authors applied it to form pyrido[2,3-d]pyrimidine-6-carboxamide derivatives from 6-aminouracile [40]. 

In some cases, the question of positional and regioselectivity arises for MCR based on aminoazole. Regioselectivity problem concerning the presence of nonequivalent reaction centers in 1,3-binucleophile molecule is more specific for... 

Among binucleophiles used in this reaction 3-amino-l,2,4-triazole and 2-aminothiazole were also selected. However, in the reaction of the latter with phenyl isonitrile and formaldehyde, only the moderate yields of the target product 101 were observed by the LC-MS analysis of the crude reaction mixture. In case of aminotriazole, any product of the reaction was failed to be detected (Scheme 47). 

As it has been already mentioned in the Introduction, aminoazoles besides the role of 1,3-binucleophiles can take part in the MCRs as 1,1-binucleophiles with participation of exclusively exocyclic NH2-group. Usual products of such multi-component interaction are five-membered heterocycles having azole ring as a substituent. 

Spirocyclopropane-annelated 1,4-benzoxathiane 176 has been obtained through Michael addition of binucleophilic o-hydroxythiophenol onto methyl 2-chloro-2-cyclopropylideneacetate 177, followed by ring closure through nucleophilic substitution of the chlorine atom <2003EJ0985>. 

Reactions of this type can occur either between a binucleophile and a bielectrophile, or between two molecules each containing both a nucleophilic and an electrophilic center, e.g. HSCH2C02H. 

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