Substitution intramolecular

We have seen that primary and secondary halogenoalkanes when attacked by a hydroxide anion normally undergo inversion at the carbon centre at which substitution occurs, because they proceed via an SN2 pathway. In the case of l-chloro-2-hydroxyalkanes, it is observed that when treated with a hydroxide 

In this case, the hard hydroxide anion has removed the hard proton on the hydroxyl group to form an alkoxide ion in a simple Bronsted-Lowry acid/base reaction. Suggest what is the next step in this reaction, remembering that overall there is retention of the stereochemistry at the carbon bonded to the chlorine atom. 

The alkoxide anion performs an internal attack upon the C-Cl bond. This proceeds in a similar manner to a normal SN2 reaction. Thus, there is an attack from the opposite side to the C-Cl bond, with the required inversion of configuration at that carbon, to produce the epoxide. Suggest what may follow in order to produce the 1,2-diol with overall retention at the carbon centre. 

There is now an attack upon the epoxide by a hydroxide anion, which inverts the carbon centre for the second time, and this produces the monoanion of the diol, which is then protonated from the solvent to form the 1,2-diol. Notice how the two sequential inversions lead to overall retention of configuration. 

This is an example of the neighbouring group effect, in which a nearby group that has an available lone pair, performs an internal SN2 reaction on the centre to be substituted. The neighbouring group is said to be lending anchimeric assistance in the reaction. In so doing, it forms a cyclic compound, which is then 

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The use of free-radical reactions for this mode of ring formation has received rather more attention. The preparation of benzo[Z)]thiophenes by pyrolysis of styryl sulfoxides or styryl sulfides undoubtedly proceeds via formation of styrylthiyl radicals and their subsequent intramolecular substitution (Scheme 18a) (75CC704). An analogous example involving an amino radical is provided by the conversion of iV-chloro-iV-methylphenylethylamine to iV-methylindoline on treatment with iron(II) sulfate in concentrated sulfuric acid (Scheme 18b)(66TL2531). 

Substitution, addition, and group transfer reactions can occur intramolecularly. Intramolecular substitution reactions that involve hydrogen abstraction have some important synthetic applications, since they permit functionalization of carbon atoms relatively remote from the initial reaction site. ° The preference for a six-membered cyclic transition state in the hydrogen abstraction step imparts position selectivity to the process ... 

In the initial step " the a-halo ketone 1 is deprotonated by the base at the a -carbon to give the carbanion 4, which then undergoes a ring-closure reaction by an intramolecular substitution to give the cyclopropanone derivative 2. The halogen substituent functions as the leaving group ... 

Peroxyacetals 58106 and peresters such as 61107 are also effective transfer agents, however, at typical polymerization temperatures ( 60 CC) they are thermally unstable and also act as initiators. Compounds such as 62 which may give addition and 1,5-intramolecular substitution with fragmentation have also been examined for their potential as chain transfer agents (l,5-SHi mechanism).108... 

Recently, a simple and general synthetic method for the preparation of N-alkylisothioazolidines involving [2,3]-sigmatropic rearrangement of appropriately substituted allylic sulfoxides to corresponding sulfenates, followed by intramolecular substitution of the latter, has been described (equation 28)126. 

The 8-methyl-8,14-cycloberbine 364, derived from the protoberberine 324 via the betaine 363, was reduced with sodium borohydride or lithium aluminum tri-tert-butoxyhydride to give a diastereoisomeric mixture of cis-and trans-alcohols (7.8 1 or 1 7.8, respectively) (Scheme 64).t)n exposure to formaldehyde the mixture underwent N-hydroxymethylation and subsequent intramolecular substitution on the aziridine ring to give the oxazolidine 365. Removal of the hydroxyl group in 365 was accomplished by chlorination followed by hydrogenolysis with tributyltin hydride. Reductive opening of the oxazolidine 366 with sodium cyanoborohydride afforded ( )-raddeanamine (360), which has already been converted to ochotensimine (282) by dehydration. 

Reaction of the same neutral borabenzene-ligand adduct, C5H5B-PMe3, with a transition, rather than an alkali, metal alkyl or amide can furnish r 6-boratabenzene complexes in a single step (Scheme 8).17 This efficient transformation presumably proceeds through initial ir-coordination of CsHsB-PMes to the transition metal, followedby an intramolecular substitution reaction. In contrast to other approaches to the synthesis of T 6-boratabenzene complexes, this synthetic route does not have a parallel in if-cyclopentadienyl chemistry. 

It can be assumed that the substrate 2-549 undergoes two elimination steps after lithiation to give 2-552 via 2-550 and 2-551. The last step is an intramolecular substitution affording 2-553, which was further transformed into the desired bioactive compound CMi-977 (also named LDP-977) (2-554). 

Another pyrrole synthesis based on intramolecular substitution of the nitro group by amino function is presented in Eq. 10.7, in which the Michael addition of enamines to nitroalkenes is used.9... 

For very electrophilic carbene ligands bound to a metal center which also has coordinated an aromatic phosphine ligand,there is the possibility of the following intramolecular substitution reaction leading to a metallacycle ... 

While nitrogen sources such as chloramine-T and PhI=NTs have been used for aziridination reactions, TsNC12 has not been explored until now. The reaction of TsNCL, with Pd(OAc)2 and K2C03 provides the expected N-tosyl aziridines in good yields <06TL7225>. This reaction presumably proceeds through an initial amidohalogenation reaction catalyzed by palladium. The chloroamide is then converted to the aziridine via an intramolecular substitution reaction. 

Chiral acetamido selenides 147, obtained from alkenes with camphorselenenyl sulfate, underwent intramolecular substitution in the presence of PhSeOTf or SO2CI2 to afford enantiomerically pure oxazolines 148 <00EJO3451>. 

The electron-transfer-induced cyclization of homochrysanthemol proceeds via a flve-membered transition state, from intramolecular substitution at the quaternary cyclopropane carbon, to generate the flve-membered cyclic ethers (69) and (70). In contrast, the intramolecular photo-induced cyclization of chrysanthemol goes via a six-membered transition state involving attack at the terminal vinyl carbon. 

Several unique synthetic strategies for bidentate(amino)(oxy)- and (amino)(aryl) carbenes have been described (Scheme 10). For the former, the reaction of the amino(phosphino)carbene with an ort/io-quinone leads to the transient formation of a zwitterionic species featuring both a phosphonio nucleofuge and an aryloxide nucleophile that allow for a subsequent intramolecular substitution process. The... 

The strained ring in aziridines makes them reactive, with ring opening under attack from any nucleophile to create a new nucleophUe-carbon bond. Aziridine rings can be formed from intramolecular substitution of a halogen atom by the nitrogen in nitrogen mustards. 

Meyers and Ford (76JOCI735), and Hirai et al. (72CPB206) have used 2-(alkylthio)-2-oxazolines or thiazolines to prepare the corresponding thi-iranes upon treatment with bases and subsequently with carbonyl compounds. The reactions of 2-pyridyl sulfides are expected to proceed similarly as shown in Scheme 22, since the oxazoline ring is a good leaving group in the intramolecular substitution reaction. When optically active oxazolines are used, asymmetric induction takes place to afford the optically active thiiranes in 19-32% enantiomeric excess (ee). The process is shown in Scheme 23. 

Beak and coworkers accomplished the asymmetric deprotonation of several Ai-Boc-iV-(3-chloropropyl)arylmethylamines (240) with enantiomeric excesses up to 98 2 (equation 56). The intermediate lithium compound 241 cyclizes to form pyrrolidines 242 in good yields and enantioselectivities. The rapid intramolecular substitution step conserves the originally achieved high kinetic differentiation in the deprotonation step. 

N-Alkyl isoindolo[2,l-fc][2,4]benzodiazepines 190 (R = alkyl. Scheme 38, Section 3.1.1.2) are synthesized by an intramolecular N-acyliminium ion-amide reaction (1997TL2985, 1998T1497). Isothiocyanates 23 undergo under basic conditions in DMF ring closure by an intramolecular substitution between N1 of the pyrrole ring and isothiocyanate group to afford benzo[/]pyrrolo[l,2-c] [l,3]diazepine-5-thiones 25 (Scheme 2, Section 2.1.1.1 (2005BMCL3220)). 

Among dichloro bis-electrophiles, malonyl chloride with enamine 183b affords pyridone 189, probably resulting from C-alkylation and cyclocondensation followed by aromatization (02T2821). Finally, o-chloro-benzoylchloride leads to C-benzoylation and subsequent intramolecular substitution of the isolable intermediate to yield quinoline 190 (03ARK (is.2)146). 

By monitoring the reaction of 13 with base by CNMR spectroscopy, the 4,5-epoxy carboxylate C was observed after 5 min together with a small amount of the the final product D. The reaction was complete within about 4 h. Opening of the epoxide C to give D was most likely preceded by an intramolecular substitution by the carboxylate at C-4. This resulted in an inversion at C-4 and formation of a lactone, which was immediately opened in the basic medium. The intramolecular exo-opening rather than an endo-opening... 

An intramolecular substitution of trimethylamine fix>m 17 gave a bicyclic oxetane 18 in a diastereoselective process <98MI2185>. A [2+2]cycloaddition of 2,2,4,5-tetrasubstituted 2,3-dihydrofuran to aryl aldehydes gave the bicyclic oxetane 19 <98JCS(P1)3261>. 2,2-Disubstituted-3-bromooxetane was obtained by a 4-endo-tcig cyclization process of 3,3 -disubstituted allyl alcohol in the presence of bis(collidine)bromine hexafluorophosphate <99JOC81>. 

Thieno[2,3- ]pyridines are produced in good yields (50-90%) from pyridine derivatives substituted in the 2-position with an a-fluorosulfide side chain, 119, via an intramolecular substitution reaction. The cyclization reaction requires treatment with base <1995JOC7654>. 

In this process coordinated water or hydroxy is eliminated by the free donor group of quinque-dentate-acting (p), (EDTA) or (PDTA) or bidentate-acting (ptn). Thus an intramolecular substitution completes the chelation. 

In another example, the formation89 of racemic 1,4-anhydroribitol by the action of dilute hydrochloric acid for 20 hours at 100° on D-ribitol 1-phosphate has likewise been assumed to take place by protonation of the oxygen atom of the ester function, followed by an intramolecular substitution by the hydroxyl group on C-4. Formation of this protonated phosphoric ester likewise explains the ra-cemization observed, caused by partial migration of the ester group at C-l to C-5. 

The ready deprotonation of the vinyl aminosulfoxonium salts 46 with a strong base at the a-position prompted a study of their reactions with weaker bases. It was speculated that in this case a vinyl-allyl isomerization of 46 might occur, followed by an intramolecular substitution of the allyl aminosulfoxonium salt... 

Scheme 1.3.20 Asymmetric synthesis of unsaturated bicyclic tetrahydrofurans via intramolecular substitution of allyl aminosulfoxonium salts.

The acyclic sulfonimidoyl-substituted amino acids 24 were selected as starting material for the synthesis of the unsaturated prolines of type 63. Because of the facile synthesis of the unsaturated bicyclic tetrahydrofurans 53 from the vinyl aminosulfoxonium salts 46 (cf. Scheme 1.3.20), it was speculated that upon treatment with a base the vinyl aminosulfoxonium salts 67 would experience a similar isomerization with formation of the allyl aminosulfoxonium salts 69, which in turn could suffer an intramolecular substitution of the allylic aminosulfoxonium group (Scheme 1.3.24). The methylation of sulfoximines 24 with Me30Bp4 gave... 

The following equations depict the intramolecular substitution of an allylic oxy group by a -hybridized carbon nucleophile [63]. A silyl group effectively directs its adjacent carbon to neutralize the allyl cation. 

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