Nitrogen nucleophiles cyclization

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

A ring opening reaction of (1-lactams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles <06CC2616>. In the event, treatment of (3-lactam 3 with MeONa led to pyrrole-2-acetic ester 4 after cleavage of the amide bond, 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required. 

The advantage of the nitro group as radical precursor is best seen in the context of intramolecular nucleophilic trapping of alkene radical cations by nitrogen nucleophiles, when no cyclization was observed prior to treatment... 

An alternative substrate design, in which the alkene radical cation is substituted only at the internal position, forces the nucleophilic cyclization into the endocyclic mode, leading overall to bicyclic systems with a bridgehead nitrogen (Scheme 31) [139,140]. 

Intramolecular cyclizations. Intramolecular cyclizations of electron-rich chloroacetyl indoles leads to indolo[l,2-d][l,4]benzodiazepin-6-one 20 as a result of a side nucleophilic cyclization at the indole nitrogen (Equation (4), Section 2.1.1.1 (2005T5489)). 

In most of these reactions, it is nitrogen of a urea, thiourea, isothiourea, or an amidine which is the nucleophile for the addition to an appropriately situated electrophilic carbon. Conditions which enhance the electrophilic character of the carbon, or the nucleophilicity of the nitrogen, promote cyclization. Most commonly, this cyclization is affected by nitrogen addition to the electrophilic / -carbon of a Michael acceptor, and can be performed under acid or basic conditions. 

In general, the reaction of unsaturated 5(4//)-oxazolones 497 with nitrogen nucleophiles effects ring opening to give the corresponding unsaturated acylamino amides 498 (Scheme 7.158). Depending on the nucleophile, for example, amines, hydrazines, oximes, and so on, the products obtained can be cyclized and this process allows the synthesis of a wide variety of new heterocyclic compounds. 

Amino acids " " and aminobenzoic acids " " react as nitrogen nucleophiles to effect ring opening of unsaturated 5(4//)-oxazolones. Cyclization of the intermediate acylamino amide has opened the way for the synthesis of new series of imidazolones that now incorporate a carboxylic acid moiety into the N-1 substituent. These compounds are readily further elaborated into derivatives with diverse biological activity. 

Other nitrogen nucleophiles such as hydrazines, hydrazides, and Schiff bases have affected ring opening of oxazolones. Most often, hydrazine or substituted hydrazines are used. For example, hydrazinolysis of 525 affords the corresponding hydrazides 526 that, depending upon the substituents and the reaction conditions, can cyclize in the reaction medium to the aminoimidazolone 527 (Scheme 7.167 ... 

Fused ring heterocycles, prepared by cyclization of substrates with a tethered nitrogen nucleophile, have been used in the synthesis of amino sugars and aminocyclitols. The examples shown in Table 28 make use of imidate-type functionality (equation 101) to insure nucleophilic attack by nitrogen. The bro-mocyclization of N,W-dialkylaminomethyl ethers of 2-cyclohexen-l-ol to form bicyclic oxazolidine derivatives has been reported also.228b... 

Another aspect of regioselectivity with many nitrogen nucleophiles is the ambident nature of the nucleophile, which can lead to products of the same ring size through either N-cyclization or O-cyclization (see Scheme 12 for an example). As shown by entries 1 and 2 in Table 25, preferential N-cyclization to 3-lactams has been effected by use of sulfonyl or acyloxy substitution on nitrogen. However, these sub-... 

Cyclizations of systems in which nitrogen nucleophiles have been tethered to the oxygen atoms of unsaturated alcohols have been used for stereo- and regio-selective syntheses of 1,2- and 1,3-amino alcohols. A variety of nitrogen nucleophiles have been examined. 

Cyclizations with nitrogen nucleophiles involving alkynes and allenes have received little attention until recently. The cyclizations of several a-aminoallenes to 3-pyrrolines with silver tetrafluoroborate was reported by Claesson and coworkers (equation 133).264 A similar cyclization to form A -carba-penems has been reported (equation 134).265 Diastereomeric allenes (R1 R2) were shown to cyclize with complete stereocontrol. Cyclization with palladium chloride in the presence of allyl bromide or electrophilic alkenes allowed for the intermediate vinylpalladium species to be trapped by the electrophile.2651 A related product was obtained by cyclization of an alkynic substrate (equation 13S).265 Other examples of 5-endo cyclization of p-aminoalkynes50 include the formation of indoles by cyclization of 2-alkynylanilines with mercury salts200 or palladium chloride,266a,266b,266c formation of 1-pyrrolines with catalytic palladium chloride (equation 136)198 and formation of pyrroles by cyclization of hydroxy-substituted p-aminoalkynes.198,2666... 

Scheme 8E.34. Intramolecular cyclization using nitrogen nucleophiles.

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