Heterocycles as nucleophiles

Heminal-activated haloolefins with heterocyclic fragments in reactions with N-heterocycles as nucleophiles 98UK317. 

Heterocycles as nucleophiles in nucleophilic substitution reactions by electron transfer 03CRV899. 

Scheme 3.35 Enantioselective aza-Michael reactions using nitrogen heterocycles as nucleophiles.

TABLE 3.5. Heterocycles as Nucleophiles in the Direct Aldol Reaction... 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

The first representatives of this group of compounds, 1,5-benzotelluroazepinones 57, have been prepared in 17% yield by the reaction between 2-iodopropyolanilides and NaHTe (98H631). The reaction proceeds, most probably, as nucleophilic substitution of the iodine, resulting in telluroles 58 and the subsequent nucleophilic addition of a hydrotelluride group to the triple bond. An alternative mechanism involving initial addition of NaTeH to the triple bond followed by the nucleophilic substitution of the iodine atom was mled out because the anilides PhNHCOC=CR do not react with NaTeH under the conditions at which the heterocycles 57 were obtained. Neither of the adducts PhNHCOCH=C(R)TeH or [PhNHCOCH=C(R)Te]2 was isolated. 

The foregoing examples show that the nucleophilic attack to nitroarenes at theorr/io-posidcn followed by cyclizadon is a generid method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion dedved from ethyl isocyanoacetate as the reacdve anion for the preparadon of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyriirddines depending on the stnicture of nitroarenes fEqs. 9.56 and9.57. The synthesis of pyrroles is discussed in detail in Chapter 10. 

When the hydride ion of lithium alanate is used as nucleophile, cyclohexa-2,4-dien-l-ol is obtained as a labile addition product which eliminates water on standing to give benzene.12 The reaction of an oxepin derivative that possesses a hexamethylene bridge across C3-C6 with sodium methoxide gives an addition product 5 in which the seven-membered heterocyclic system is retained.213 214... 

As shown by Heindel and Corley (1979), ring closure also takes place if the nucleophilic nitrogen is part of a heterocycle, as in the diazotization of 5-amino-3-methyl-2-H-l,2,4-benzothiadiazine-l, 1-dioxide (6.50). In the tricyclic compound 6.51 formed initially, the thiadiazinedioxide ring is opened rapidly in water, forming 1-acetyl-7-aminosulfonyl-l-i/-benzo-l,2,3-triazole (6.52). 

In an earlier study the authors proposed a [3.2.0] bicyclic sulfonium salt 8 as the reactive intermediate in the trimethylsilyl iodide mediated ring contraction of 4-methoxythiephane <1996T5989>. Enantiomerically pure thio-lane derivatives were synthesized via a ring contraction of a seven-membered sulfur heterocycle by nucleophilic transannular substitution <2000TA1389>. The thiepane derivative 15, derived from d-sorbitol, was converted into the dimesyl derivative 16 following deprotection under acidic conditions. Treatment of 16 with sodium azide in DMSO at 120°C yielded the corresponding thiolane as a mixture of two diastereoisomers, 17a and 17b, in a 5 1 ratio (see Scheme 1). 

N-Heteroaromatic compounds like pyridine, pyridazine, pyrazine, isoquinoline, and their derivatives42,250 react with diphenyl cyclopropenone in a formal (3+2) cycloaddition mode to the C=N bond of the heterocycle. As expected from the results discussed earlier (p. 67), the reaction is initiated by attack of nitrogen at the cyclopropenone C3 position and followed by stabilization of the intermediate betaine 390 through nucleophilic interaction of the Cl/C3 bond with the activated a-site of the heterocycle, giving rise to derivatives of 2-hydroxy pyrrocoline 391—394). In some cases, e.g. diphenyl cyclopropenone and pyridine42, further interaction with a second cyclopropenone molecule is possible under the basic conditions leading to esters of type 392. 

In this approach, the SENA skeleton is assembled from nitroalkene (42) and nucleophile 56.With the exception of two examples (entries 1 and 2 in Table 3.2), the reaction does not stop at SENA 51, which either undergoes intramolecular cyclization through [3 + 2]-cycloaddition to give fused heterocycles (as a rule after elimination of trimethylsilanol) (198-200) or is involved in [3+ 2]-cycloaddition with specially added methyl vinyl ketone or methyl acrylate to form (after elimination of silanol) substituted isoxazolines in rather high yields (201). 

Two transformations should be discussed in more detail (1) presence of the amino group in 275 was utilized for the synthesis of the fused isoquinolinium salt 276 bearing the bicyclic heterocycle as an A-substituent <2003JHC1041> (2) selective nucleophilic substitution of 277 with pyrrolidine was reported <2001ZOR604> to yield only substitution on the phenyl substituent without formation of an amide from the ester group 278. 

Catalysed alkylation of tosylmethylisocyanate (TOSMIC) [63, 64] has extended its versatility in the preparation of l, 4-dicarbonyl compounds and as a l, 3-dipolar precursor for the synthesis of heterocyclic compounds. The alkylation reactions should not be conducted in carbon disulphide, as nucleophilic attack by the methylene group on the carbon disulphide leads, after ring closure and S-alkylation, to a 4-alkylthio-1,3-thiazole system [65]. 

The cyclic form of glucose is termed glucopyra-nose, since the new ring system is a reduced form of the oxygen heterocycle pyran. Nucleophilic attack onto the planar carbonyl may occur from either of its two faces, generating two different stereochemistries at this new chiral centre, designated as a or p. This new chiral centre is termed the anomeric centre. Since there are other chiral centres in the molecule, the mixture of a- and -anomeric forms is not a racemate, but a mixture of diastereoisomers (see Section 3.4.4). The mixture does not contain 50% of each anomer (see below). Although both forms are produced, the form with the equatorial hydroxyl is thermodynamically favoured (see Section 3.3.2). 

Alkylation of pyrrohdine and piperidine heterocycles was investigated extensively by Gawley and coworkers. The initial evaluation of 2-lithio-A-methylpiperidine and 2-lithio-A-methylpyrrolidine as nucleophiles was conducted on racemic material, but... 

Alkylation. Saturated 5(47/)-oxazolones are readily available compounds that can be easily obtained from a wide variety of natural amino acid derivatives. These heterocyclic compounds can be considered as nucleophilic synthons of a-amino acids and their most exploited reactivity, apart from oxazolone ring opening, is the reaction at C-4 with a variety of electrophiles. 

Heterocyclic amines also react as nucleophiles and, in this context, indole reacts with 404 to yield the unsaturated oxazolone 406, an intermediate in the synthesis of tryptophan (Scheme 7.13It is noteworthy that 406 is the product of carbon-carbon bond formation. Imidazole also reacts with 404 but in this case the product is 396, identical with that obtained from the 4-(chloromethylene) derivative 395. ... 

The effects of substituent groups in the reactions of the cationic heterocycles with nucleophiles are entirely as expected. Appropriately situated substituent groups which can function as leaving groups can be displaced (e.g. equation 41), and ANRORC reactions are very common (e.g. equations 42 and 43). The latter type of reaction is of particular... 

Simple considerations such as these account adequately for many of the familiar reactions of substituted 7r-deficient heterocycles, such as nucleophilic displacement, tautomerism in hydroxy, mercapto and amino heterocycles, facile deprotonation of alkyl substituents, decarboxylation of carboxymethyl groups and electrophilic substitution of benzo-fused and aryl-substituted heterocycles. These individual effects are discussed separately in the following subsections. 

In the 1,4-dinucleophile - 1,2-dielectrophile approach the most common situation is where heteroatoms function as nucleophiles and 1,2-dicarbonyl compounds, 1,2-dihalides or sulfonate esters, a-halocarbonyl compounds, etc., as the dielectrophile component. Representative examples are given in equations (76)-(79). Condensation of hydrazine and its derivatives with 1,4-dicarbonyl compounds is the common situation in the 1,2-dinucleophile- 1,4-dielectrophile approach, and the vast majority of pyridazine derivatives are prepared in this way (e.g equations 80 and 81). Sulfur 1,4-dielectrophiles have been used in related processes, but the method is not readily adaptable to the synthesis of oxygen heterocycles. 

Studies on the Chemistry of Thienoannulated 0,N- and S,N-Containing Heterocycles. 1. Nucleophilic Substitution Reactions on Chlorinated Thiophene Derivatives as a Basis for the Synthesis of Thienoannulated 0,N- and S,N-Heterocycles, Puschmann, I. Erker, T. Heterocycles 1993,36,1323. See also Studies on the Chemistry of Thienoanellated 0,N- and S,N-Containing Heterocycles. II. Synthesis on Thieno-Dilthiazem Analogs, Puschmann, 1. Erker, T. Heterocycles 1995, 41, 709. 

Dihydro-1,3-oxazines have served both as nucleophilic and electrophilic agents in the preparation of carbonyl compounds. The multiple uses of this heterocycle are nicely revealed in the synthesis of methyl jasmonate (739) (73JOC175). 

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