Nitrogen nucleophiles intramolecular reactions

Additions to l,3-dienes6 (12, 367-368 14, 249-250 15, 245). This reaction can be used to effect intramolecular cyclization of cyclic 1,3-dienes substituted by a suitable nitrogen nucleophile. Thus reaction of the amido diene 1 with lithium acetate catalyzed by Pd(OAc)2 (with benzoquinone as reoxidant) provides the ds-fused heterocycle cis-2, in which the acetoxy group is cis to the ring fusion, formed by an overall trans-1,4-oxyamidation of the diene system. Addition of a trace of LiCl improves the yield and results in an overall cis- 1,4-oxyamidation (equation I). Acetamides and carbamates can also be used in place of amides. 1,4-Chloroamidation can also be effected by use of 2 equiv. of LiCl. 

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. 

For reactions of A-acyliminium ions with alkenes and alkynes one has to distinguish between A-acyliminium ions locked in an s-trans conformation and those which (can) adopt an s-cis conformation. The former type reacts as a (nitrogen stabilized) carbocation with a C —C multiple bond. Although there are some exceptions, the intramolecular reaction of this type is regarded as an anti addition to the 7t-nucleophile, with (nearly) synchronous bond formation, the conformation of the transition state determining the product configuration. 

An intramolecular Michael type reaction of a nitrogen nucleophile to nitroalkene, as shown in Eq. 4.31, provides a useful method for the preparation of 2,2-dimethyl-l-carbapenam.37... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

The second stage of the reaction is of particular interest. It is essentially an intramolecular reaction between the anion and the cation. The phosphorus atom of the anion is able to react nucleophilically at the ring carbon atom with amines similar to reactions of 1,3,2,5-dioxaborataphosphori-nanes with amines or 1,3,5-diazaphosphorinanes. The cation is the 1,3,5-diazaphosphorinane derivative. Thus, the reaction between the anion and the cation is a series of nucleophilic attacks of nitrogen atoms, belonging to the cation, at carbon atoms of the anion. 

A Cu(OAc)2-catalyzed intramolecular diamination of alkenes using sulfamide substrates such as compound 214 provides a route to fused thiadiazolidines 215 (Equation 48) <2005JA11250>. In this reaction, the transition metal activates the alkene toward nucleophilic attack by the first nitrogen, then becomes displaced by the second nitrogen nucleophile (a net M +z to M reduction). 

The use of a nitrogen nucleophile in the side chain (as an amide) also leads to an intramolecular 1,4-addition under the standard conditions for the palladium-catalyzed 1,4-oxidation reactions52. Nitrogen nucleophiles employed for this reaction comprise tosy-lamides, carboxamides, carbamates and ureas. The reactions are run in acetone-acetic acid with p-benzoquinone (BQ) as the oxidant. In most cases highly stereo- and regioselective reactions were obtained and some examples are given in Table 3. 

Part of the great efficiency of the intramolecular reactions of [26] and [27] is undoubtedly due to the correct alignment of the rigidly held nucleophile and carbonyl group. Molecular models show that in one of the conformations of [27] in which steric interactions are minimized, the phenoxide ion is immediately adjacent to the carbonyl group and in an excellent position for perpendicular attack (Bender, 1960) but other factors must also be important. Correct orientation would not explain why anionic nucleophiles are superior to neutral nucleophiles. Extensive studies have not been carried out with nitrogen nucleophiles in carbamate ester hydrolysis, but Hegarty and Frost (1972) found that carbamate [29] underwent elimination to an isocyanate. This can be contrasted with the... 

As described in detail in CHEC-II(1996) <1996CHEC-II(6)1 > N-acylation of 1,2-diazines is often used to make the nucleus more susceptible for nucleophilic attack (see Section 8.01.5.4.4). Intramolecular reactions on nitrogen... 

When a-substituted JV,iV-dimethylacetamidines are used as the bidentate nucleophiles, the reaction proceeds according to Scheme 6. The primary attack occurs at an a position by the nucleophilic nitrogen to yield the zwitterionic adduct 77 (Amax = 506 nm) and is followed by intramolecular ring closure at the y position leading to a bicyclic adduct (78). In contrast, with the N-oxide of 3,5-dinitropyridine the points of attachment of the reagent are both a to the aza group. 

Nitrogen nucleophiles such as amines (and in intramolecular cases, amides and tosamides) readily add to alkenes complexed to palladium(ll) and iron(ll) with reactivity and regiochemical features parallel to those observed for oxygen nucleophiles. However, these metal-assisted animation reactions are subject... 

The conversion of an amide in this way is termed the Hofmann reaction or the Hofmann rearrangement. The mechanism of the reaction involves an intramolecular 1,2-carbon-to-nitrogen nucleophilic shift of the alkyl (or aryl) group... 

Nitrogen nucleophiles also react smoothly. The reaction of optically active propargyl mesylate 198 with aniline without a catalyst gives 200 with inversion. However, the Pd-catalysed reaction affords 199 with retention of stereochemistry [44], The 4-ethenylidene-2-oxazolidinone 202 is obtained by intramolecular reaction of the biscarbamate of the 2-butyn-l,4-diol 201 [45],... 

Thioamides exhibit a pronounced nucleophilic character due to their nitrogen atom. Alkyl halides often react at room temperature to give thioimi-doester salts which may be subsequently used. This reaction was applied [134] to the preparation of an enaminoketone, the cyclohexenone ring being formed by base treatment of a ketone and intramolecular reaction with the iminium salt. A similar sequence [135] was mentioned in Scheme 28. 

Intramolecular reactions are Taster and cleaner than interraolecular reactions. hen e want to make a C-N bond in a ring, therefore, we no longer have to take any special precautions and we can use a nitrogen nucleophile and any carbon electrophile. Two useful disconnections are ... 

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