Intramolecular reactions nucleophiles

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. 

An efficient carboannulation proceeds by the reaction of vinylcyclopropane (135) or vinylcyclobutane with aryl halides. The multi-step reaction is explained by insertion of alkene, ring opening, diene formation, formation of the TT-allylpalladium 136 by the readdition of H—Pd—I, and its intramolecular reaction with the nucleophile to give the cyclized product 137[I08]. 

The TT-allylpalladiLim complexes formed as intermediates in the reaction of 1,3-dienes are trapped by soft carbon nucleophiles such as malonate, cyanoacctate, and malononitrile[ 177-179). The reaction of (o-iodophenyl-methyl) malonate (261) with 1,4-cyclohexadiene is terminated by the capture of malonate via Pd migration to form 262. The intramolecular reaction of 263 generates Tr-allylpalladium, which is trapped by malononitrile to give 264. o-[odophenylmalonate (265) adds to 1,4-cyciohexadiene to form a Tr-allylpalladium intermediate via elimination of H—Pd—X and its readdition, which is trapped intramolecularly with malonate to form 266)176]. 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

As supporting evidence, rapid isomerization of the ds- and maui-Tr-allylpal-ladium complexes 27 and 28 is catalyzed by Pd(Ph3P)4 in THF even at -15 C to give a 45 55 equilibrium mixture from either 27 or 28[29-31].. Actually, in the intramolecular reaction of soft nucleophiles of 29 and 30, a trans-ds mi.xttire (31 and 32) (1 1) was obtained from /raiw-allylic acetate 29. On the... 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

The molecule below has four stereoisomeric forms exoO exoCH2Br, exoO endoCH2Br, and so on. Examine electrostatic potential maps of the four ions and identify the most nucleophilic (electron-rich) atom in each. Examine the electron-acceptor orbital (the lowest-unoccuped molecular orbital or LUMO) in each and identify electrophilic sites that are in close proximity to the nucleophilic. Which isomers can undergo an intramolecular E2 reaction Draw the expected 8 2 and E2 products. Which isomers should not readily undergo intramolecular reactions Why are these inert ... 

Finally, aromatic nucleophilic denitrocyclization reactions are reviewed for the first time by Stanislav Radi (Prague, Czech Republic). The nitro functionality is a good leaving group, especially for intramolecular reactions, and many such reactions lead to polycyclic heterocyclic ring systems. Frequently, these transformations are a method of choice for preparative purposes. 

Scheme 2.37 Intramolecular reaction of an oxygen nucleophile to give dihydrofurans.

Finally, an intramolecular reaction of an oxygen nucleophile to give 2,5-dihy-drofuran derivatives 146 is shown in Scheme 2.37. Since the vinylaziridines were generated in situ by treatment of imines 143 with ylide 144, this ylide is formally acting as an equivalent of the 2,5-dihydrofuran anion [57]. 

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. 

These side reactions may occur if the /V-acyliminium ion is not trapped quickly enough by a nucleophile. So problems may arise with relatively poor nucleophiles or if there is too much steric hindrance, while in the case of intramolecular reactions, unfavorable stereoelectronic factors or intended formation of medium- or large-sized rings may play a role. The reaction conditions, such as the nature of the (acidic) catalyst and the solvent, may also be of importance. 

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction71 Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones. The reaction shows a preference for formation of five- over six-membered72 rings and is a stereospecific anti addition when carried out under basic conditions. 

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. 

According to the stepwise electrophilic reaction mechanism, the differences in the stereochemistries of the products from the reactions of alkenes with cyclic 49 and acyclic 51 disulfonium dications can be explained by the larger rates of the intramolecular reactions. In the case of a cyclic dication, the carbocationic center in intermediate 94, which is formed as the result of initial attack by a S-S dication on a double C=C bond reacts with nucleophile intramolecularly, thus conserving the configuration of the substituents at the double bond. On the other hand, an acyclic dication undergoes transformation to two separate particles (95 and dimethylsulfide) with a consequent loss of stereoselectivity. Additional experiments with deuteretad alkenes confirm that reaction is not stereoselective, lending further support to the stepwise mechanism (Scheme 36).106... 

Fig. 23 Entropy effects on intramolecular reactions of polymethylene chains. Plot of 9AS (e.u.) against number of single bonds for (O) nucleophilic substitutions at saturated carbon ( ) electron-exchange reactions (A) quenching of benzophenone phosphorescence. The straight line has intercept +30 e.u. and slope —4.0 e.u. per rotor. The right-hand ordinate reports the purely entropic EM s calculated as exp(0AS /J )...

The intramolecular reaction between carbenoids and amides is clearly emerging as a powerful tool for the synthesis of saturated oxazolo[3,2-tf]pyridine derivatives as shown by the cyclization of simple to extremely functionalized substrates 379 <2003CC440> and 381 <20050L47> (Scheme 100) trapping the intermediate isomtinchnone 1,3-dipoles by external (MeOH) or internal (indole) nucleophiles results in new heterocyclic fused systems with especially high efficiency. 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

Calculation of EM. The reference intramolecular reaction is nucleophilic attack by the anion of a carboxylic acid of pK, 3.15 on 2-phenoxy-l,3,2-dioxaphosphorinan-2-oxide. The rate constant for this reaction can be calculated as 7.67 x 10-10 dm3 mol 1 s-1 at 39° using the formula derived by Khan and Kirby (1970), and allows the direct calculation of the EM for the corresponding intramolecular reaction (COO-—P3—6n of A.5.5). The EM is assumed to be the same for the corresponding endocyclic reaction of the diphenyl ester anion (A.5.6), and has been shown not to differ significantly for endocyclic and exocyclic displacements (Bromilow etal., 1972)... 

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

More /V-acylurea is generated if tertiary amine is present because the latter removes any protons that might prevent the rearrangement (see Section 2.12). The two intramolecular reactions also occur to a greater extent when interaction between the O-acylisourea and the /V-nucleophile is impeded by the side chain of the activated residue. This means that more 2-alkoxy-5(4//)-oxazolone and /V-acylurea are generated when the activated residues are hindered (see Section 1.4). A corollary of the above is that the best way to prepare an /V-acylurea, should it be needed, is to heat... 

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