Amides cyclization reactions, nitrogen nucleophiles

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. 

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. 

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. 

C.ii.b. Intramolecular Attack by Nitrogen Nucleophiles. The nitrogen nncleophiles, which are compatible with the reaction conditions (HOAc and 1,4-benzoquinone), consist of electron-deficient ones such as amides, carbamates, ureas, and sulfonamides. Because of the low nucleophilicity of these, no intermolecular 1,4-additions involving C—bond formation is known. However, if the nitrogen is tethered to the diene, a cyclization takes place in good yields. 

The above results closely define the fates of individual atoms and the stereochemistry of reactions involved in penicillin/cephalosporin biosynthesis as well as indicating the pathway followed. What remains unknown are the mechanisms of the two ring-closure reactions from 7.118). There are, however, several attractive possibilities, for )8-lactam formation at least. One suggestion is that cyclization occurs by a variation of the ene reaction see 7.119). This is an alternative to the simpler idea of nucleophilic attack of amide nitrogen on the sp carbon of a thioaldehyde or its sp receptor equivalent. A quite different possibility is that cyclization is associated with oxidation of the amide nitrogen nucleophilic displacement at this centre by an anion generated at the )5-carbon of the cysteine fragment follows see... 

Path C Aziridine formation. P-Tosyl derivatives of serine and threonine compounds protected on nitrogen by trityl or tosyl groups, can cyclize to aziridines in strongly basic media (272, 288, 289, 387). In the case of serine derivatives, this reaction is observed only when either the Ca-H acidity is reduced (amides) or the nitrogen atom retains high nucleophilicity (N-trityl derivatives). The tendency of threonine derivatives to form aziridines is much stronger, and less dependent on these factors. Thus, treatment of N,0-ditosylthreonine ester with bases yields primarily the aziridine (272). ... 

Non-deprotonated amides are weak nucleophiles and are only alkylated by trialkyl -oxonium salts or dimethyl sulfate at oxygen or by some carbocations at nitrogen [16, 83]. Alkylation with primary or secondary alkyl halides under basic reaction conditions is usually rather difficult, because of the low nucleophilicity and high basicity of deprotonated amides. Non-cyclic amides are extremely difficult to N-alkylate, and few examples of such reactions (mainly methylations, benzylations, or allyla-tions) have been reported (Scheme 6.21). 4-Halobutyramides, on the other hand, can often be cyclized to pyrrolidinones in high yield by treatment with bases (see Scheme 1.8) [84—86]. 

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

Transannular cyclization of unsaturated lactams was induced by mercury(ll) acetate, the weakly nucleophilic amidic nitrogen is the reaction center. The driving force for this cyclization is the strain of the bicyclic product, only one isomer was recovered regardless of the alkyl substituent. By reductive cleavage the bicyclic lactam, e.g., 6, was obtained in moderate to good yield125. 

The ease of cyclization of the 3-butenyl ureas (1, R2 = H, n = 2) was dependent mainly on the steric and electronic effects of the nitrogen substituents R1 and R2 when R1 is methyl, the best results were obtained when R2 is isopropyl, cf 6 when R1 is hydrogen no cyclization occurred and methanol (solvent) acted as the nucleophile. Generally, long reaction times were necessary, and the cyclizations were often incomplete. Furthermore, cyclization fails for /V-(5-heptenyl)-amides and (3-butenyl) carbamates. 

The initial step in this reaction is probably nucleophilic attack of the amidinc nitrogen at position C 2 of the 1,3-benzoxazinone, which in most cases results in opening of the heterocyclic system. The open-chain intermediate is not isolated, but forms the 1,3,5-triazine by cyclization to the amide carbonyl group.95... 

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