Intramolecular nucleophilic displacement

By Nucleophilic Displacement — Intramolecular cyclization of urethane 12 followed by hydrolysis provided l,6 anhydro-2-amino-2-deoxy-4-0 methyl-P-D-mannopyranose 13 (Scheme 3). 

Preparative routes to aziridines and 1-azirines are derived from cycloelimination processes in which one, and sometimes two, bonds are formed directly to the nitrogen atom (Scheme 1). For aziridines these include the two intramolecular cyclization pathways involving either nucleophilic displacement by the amine nitrogen (or nitrenium anion) on the /3-carbon (route a) or nucleophilic displacement by a /3-carbanionic centre on the amine nitrogen... 

Intramolecular Nucleophilic Displacement of Fluorine Hudlicky, M Isr J Chem 17, 80-91 68... 

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

Intramolecular nucleophilic displacement of the bromo group by an azine-nitrogen occurs in the cyclization of A-2-quinaldyl-2-bromo-pyridinium bromide (248) to give the naphthoimidazopyridinium ring system. The reaction of 2-bromopyridine and pyridine 1-oxide yields l-(2-pyridoxy)pyridinium bromide (249) which readily undergoes an intramolecular nucleophilic substitution in which departure of hydrogen as a proton presumably facilitates the formation of 250 by loss of the JV-oxypyridyl moiety. 

The smooth intramolecular nucleophilic displacement of biphenyl carboxylic acids leading to benzocoumarins (See Section II.A.) inspired also investigation of the behavior of similar diphenyl ether, diphenyl sulfide and A-methyldiphenyl amine derivatives 458 under similar conditions. However, all these attempts to achieve cyclization to tricyclic compounds 459 were unsuccessful, probably due to the unfavorable stereochemistry for the formation of the required seven-mem-bered transition states and also to the presence of the deactivating bridge groups X (Eq. 42) [68JCS(C)1030]. 

Intramolecular nucleophilic displacement reactions of aromatic nitro group by various nucleophiles include cydization reactions, which provide practical methods for the synthesis of a variety of heterocycles. 1 hope that the text of this review suggests a wide range of potential of this reaction in organic synthesis of various heterocycles. However, it is necessary to stress that some structural types described in this review could be prepared with similar, or even better yields by other methods. In spite of this, there are many heterocyclic systems for the synthesis of which the denitrocyclization strategy is a method of choice. 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

The novel synthesis of chromanocoumarans illustrated in Scheme 159 constitutes a modification of the Heck arylation process (cf. Eq. 14 in Section IV,B,1) in which arylation of a 2H-chroman is followed by intramolecular nucleophilic displacement of the palladium moiety.235... 

Stereospecific contraction of the seven-membered nucleus was observed on treatment of the dimesylated thiepanetetrol derivatives 67 (obtained in turn from d-sorbitol) with sodium azide to give a 5 1 mixture of the bis(azido)tetrahydrothiophenes 68 and 69. Intramolecular nucleophilic displacement of either mesylate group initiates this ring contraction <00TA1389>. 

Treatment of the chlorobutyl derivative 109 with iodide in acetone afforded the new 1H, 2H, 3H, AH, 5//-[l,3]diazepino[2,l-i>][l,3]benzoxazol-6-ium ring system 110 via intramolecular nucleophilic displacement <00T8567>. 

Figure 27 shows plots of all the available EM s for closures of small- and common-sized saturated carbocycles and heterocycles by intramolecular nucleophilic displacement. Clearly, a-values as small as 0.1 would be required in order to calculate extrathermodynamically from (67) EM-values comparable to those actually observed for ring-sizes 3 and 4, and an even smaller value would be necessary for ring-size 5. This would lead to the conclusion that the effect of ring strain on cyclisation rates is insignificant. The same conclusion was recently drawn by Benedetti and Stirling (1983), based on rates and activation parameters for the cyclisation of bis-sulphonyl-stabilised carbanions to 3-, 4-, and 5-membered bis-sulphonylcyloalkanes. 

Intramolecular nucleophilic displacement of the imine or enamine moiety by Ser-130 to form a cross-linked vinyl ether F as the inactivated species... 

Katritzky et al. <1997JOC4148> described the cyclization of pyrrole derivatives 133 via lithiation at the benzotriazol-1-ylmethyl group and subsequent intramolecular nucleophilic displacement of tosylate to give in good yields dihydropyrrolizines 65, which lead to 3/7-dihydropyrrolizines 68 under treatment with malonate anion (see Section 11.01.5.3). 

The pyrrolidine derivative 314, a skeletal analog of the antitumor antibiotic anisomycin, was synthesized from the acetal derivative 16b. The 5-OH group of 16b was tosylated and then substituted with sodium azide. Reduction (sodium borohydride) of the lactone group afforded an open-chain derivative, which was selectively protected to give 313. Hydrogenation of the azide function, followed by p-toluenesulfonylation, led to 314 by an intramolecular nucleophilic displacement (284). 

For neutral nucleophiles (e.g. amines, alcohols, water) there is much evidence that the addition-elimination mechanism depicted in equation 1 fits very well most of the intermolecular and intramolecular nucleophilic displacements involving nitro-activated aromatic substrates1. 

A free-radical mechanism has been suggested for the nitrosation of 1,2-phenylenediamine (22) by peroxynitrite PN/CO2. 1,2,3-Benzotriazole (26) was formed as a result of an intramolecular nucleophilic displacement on the diazo hydroxide (25) by the neighbouring amine group. The authors suggest that the mechanism involves an initial H-atom abstraction or one-electron oxidation from (22) by CO3 , followed by the reaction of the product (23) with NO. The inhibitory effects of azide support a free-radical mechanism of the reaction. 

Studies of gas-phase S"n2 reactions at sp carbon have been made by Fourier transform ion cyclotron resonance mass spectrometry (FTlCRMS) and complemented by both semiempirical and ab initio MO calculations. The particular processes of interest involved intramolecular reactions in which neutral nucleophiles displace neutral leaving groups within cationic substrates, e.g. A-(2-piperidinoethyl)-2,4,6-triphenylpyridinium cation (59), in which the piperidino moiety is the nucleophile and 2,4,6-triphenylpyridine (60) is the leaving group. No evidence has been obtained for any intermolecular gas-phase 5) 2 reaction involving a pyridine moiety as a leaving group. The quantum mechanical treatments account for the intramolecular preference. 

Fig. 4 Synthesis of heterocycles through intramolecular nucleophilic displacement of the isocyanide derived group...

Convertible isocyanide reagent 66 allows a mild and chemoselective in situ post-Ugi activation of the isonitrile bom amide with simultaneous deprotection of the nucleophilic amine, that is, liberation and activation of two Ugi-reactive groups, if desired also under subsequent lactam formation [33]. Another recently introduced convertible isocyanide, l-isocyano-2-(2,2-dimethoxyethyl)-benzene 73, was shown effective by Rhoden et al. In the course of this short sequence, a hydrolytically labile W-acylindole 78 is formed, which is displaced intramolecularly by the amine portion of the former Boc-protected amino acid 75 (Scheme 13). 

Pyrrolo[2,l-c][l,4]benzothiazepine 297 (R=Ph) has been prepared by an intramolecular nucleophilic displacement of acetyl derivative 296 (Scheme 64 (1992H51)). The same compound and its aryl (R = Ar (1992H51)) and carboethoxy or cyano (R = C(30Et or CN (1990H1291)) analogs can also be obtained by a Pummerer rearrangement-cyclization of sulfinyl precursor 298. 

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