Nucleophilic substitutions ether formation

Ring expansion of haloalkyloxiranes provides a simple two-step procedure for the preparation of azetidin-3-ols (Section 5.09.2.3.2(f)) which can be extended to include 3-substituted ethers and O-esters (79CRV331 p. 341). The availability of 3-hydroxyazetidines provides access to a variety of 3-substituted azetidines, including halogeno, amino and alkylthio derivatives, by further substitution reactions (Section 5.09.2.2.4). Photolysis of phenylacylamines has also found application in the formation of azetidin-3-ols (33). Not surprisingly, few 2-0-substituted azetidines are known. The 2-methoxyazetidine (57) has been produced by an internal displacement, where the internal amide ion is generated by nucleophilic addition to an imine. 

Even polyalkoxy-s-triazines are quite prone to nucleophilic substitution. For example, 2,4,6-trimethoxy-s-triazine (320) is rapidly hydrolyzed (20°, dilute aqueous alkali) to the anion of 4,6-dimethoxy-s-triazin-2(l )-one (331). This reaction is undoubtedly an /S jvr-4r2 reaction and not an aliphatic dealkylation. The latter type occurs with anilines at much higher temperatures (150-200°) and with chloride ion in the reaction of non-basified alcohols with cyanuric chloride at reflux temperatures. The reported dealkylation with methoxide has been shown to be hydrolysis by traces of water present. Several analogous dealkylations by alkoxide ion, reported without evidence for the formation of the dialkyl ether, are all associated with the high reactivity of the alkoxy compounds which ai e, in fact, hydrolyzed by usually tolerable traces of water. Brown ... 

Fig. 11 Plots of log EM vs number of bridge methylenes for the formation of catechol, resorcinol, and hydroquinone polymethylene ethers by intramolecular nucleophilic substitution in 99% Me2SO. (Reproduced with permission from Dalla Cort et al., 1980)...

Formation of ring-substituted arylamine thio ethers occurs also by proton-catalyzed thermal rearrangement of the corresponding sulfenamides73,82,83. This alternative pathway may not completely be excluded in thio ether formation from nitrosoarenes, but it seems unlikely since these thio ethers were produced at neutral pH and low temperatures68. The discovery of the fc -conjugate additionally favors the pathway of nucleophilic ring addition of thiolate to the sulfenamide cation. 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

Oxidation of 2-(trimethylsilyloxy)furan (301) with iodosobenzene in the presence of boron trifluoride etherate and alcohols or acids results in the formation of 5-substituted 2(5//)-furanones 303. The first step of this conversion gives intermediate 302, which on nucleophilic substitution by alcohols or acids affords the products (89TL3019) (Scheme 75). 

An alternative method for benzoxepine ring assembly uses the formation of cyclic ethers. Thus, benzoxepino[4,3-f>]indole 130 can be synthesized by the treatment of the keto-alcohol 129 with hot alcoholic base to produce the product in 90% yield as a result of intramolecular nucleophilic substitution (Equation (19) (1993AX(C)2126)). 

Pedersen used reactions of nucleophilic substitution to synthesize most of the crown ethers he has obtained. On the other hand, Lehn and his coworkers [17] (Fig. 7.1.4) carried out cyclization reactions involving amide formation under high dilution conditions in their quest for cryptands such as 54. Pedersen analysis of the selective inclusion of alkali metal cations into the crown ethers cavity... 

Electrochemical reduction of TNT led to the formation of TAT-3HC1 selective acidic hydrolysis of this compound led to the formation of 2,6-diamino-4-hydroxytoluene dihydrochloride, which was neutralised to 2,6-diamino-4-hydroxytoluene [38, 40, 46]. The interaction of the last product with perfluorotoluene using aromatic nucleophilic substitution reactions led to the formation of 3,5-diamino-4-methyl-2, 3, 5, 6 -tetrafluoro-4-trifluoromethyldiphenyl ether [38, 47] (Scheme 4.17). 

Rate and equilibrium constants have been reported for the reactions of butylamine, pyrrolidine, and piperidine with trinitrobenzene, ethyl 2,4,6-trinitrophenyl ether, and phenyl 2,4,6-trinitrophenyl ether in acetonitrile, hi these reactions, leading to cr-adduct formation and/or nucleophilic substitution, proton transfer may be rate limiting. Comparisons with data obtained in DMSO show that, while equilibrium constants for adduct formation are lower in acetonitrile, rate constants for proton transfer are higher. This probably reflects the stronger hydrogen bonding between DMSO and NH+ protons in ammonium ions and in zwitterions.113 Reaction of 1,3,5-trinitrobenzene with indole-3-carboxylate ions in methanol has been shown to yield the re-complex (26), which is the likely precursor of nitrogen- and carbon-bonded cr-adducts expected from the reaction.114 There is evidence for the intermediacy of adducts similar to (27) from the reaction of methyl 3,5-dinitrobenzoate with l,8-diazabicyclo[5.4.0]undec-8-ene (DBU) cyclization eventually yields 2-aminoindole derivatives.115... 

The oxidation of phenol ethers 26 by [bis(trifluoroacetoxy)iodo]benzene in the presence of external or internal nucleophiles affords products of nucleophilic substitution 28 via the intermediate formation of the cation radical intermediate 27 according to Scheme 12 [21,27 - 30]. 

Although chlorobenzene is rather inactive in usual reactions, its activity is enhanced by complex formation, and two products are formed by the reaction of stabilized carbanions on the complexed chlorobenzene 207, depending on the conditions [44], The anion of a-methy l propionitrile reacts at the meta position at —78 °C, and the mete-substituted product 208 is obtained by oxidation with I2. However, equilibration (rearrangement) of the carbanion occurs at 25 °C, because the attack of the carbanion is reversible, and the substitution product 209 of the chlorine is obtained. The fluorobenene 210, coordinated by Cr(CO)3, is very reactive. Reaction of y-butyrolactone to the o-lithiated fluorobenzene 211 gives rise to the alkoxide 212, which displaces the fluoride intramolecularly to give the cyclic ether 213 [52], In other words, the complex 211 can be regarded as the 1,2-dipolar synthon 214. However, Cr(CO)3-complexed aromatic bromide and iodide can not be used for the nucleophilic substitution. 

Treatment of 4-(2-bromoalkyl)azetidin-2-ones 205 with L1AIH4 in diethyl ether yielded 2-(l-alkoxy-2-hydroxyethyl)-azetidines 206 and small amounts (1-5%) of r-4-(2-bromoalkyl)azetidines 81 (Equation 56) <20060L1101 >. A 1,2-fission of the starting material followed by a nucleophilic substitution of bromide led toward the formation of these compounds. 1,4,4-Trisubstituted azetidin-2-ones 207 could be reduced to the corresponding azetidines 208 using lithium aluminium hydride in diethyl ether under reflux for 7-16h (Equation 57) <1996JOC6500>. 

Trimethylsilyl ethers of several steroidal ketones were a-fluorinated by 4-(difluoroiodo)toluene, in moderate yield because of concomitant elimination, accompanied by the formation of other by-products from nucleophilic substitution to a phenyliodonium intermediate. The analogous reaction with xenon difluoride resulted in much better yields but different stereochemistry [50],... 

Finally, it is worth noting that the formation of cyclic ethers by intramolecular nucleophilic substitutions is quite favorable if the resulting ring is three, five, or six mem-bered, as shown in the following reactions ... 

The array of dienophiles amenable to these hetero Diels-Alder reactions is not limited to enol ethers and enamines since allylsilanes and simple alkenes have also been successfully employed [370, 371]. More recently, it has been shown that methoxy allenes such as 4-41 undergo formation of 6H-l,2-oxazines 4-43 upon cycloaddition to nitrosoalkenes such as 4-34 and subsequent tauto-merisation of the intermediate exo-methylene compound 4-42 (Fig. 4-9) [372, 373]. In these studies, 4-43 proved to be a versatile synthetical intermediate allowing oxidative demethylation or reductive removal of the methoxy group as well as nucleophilic substitutions after the generation of an azapyrylium ion [372 - 374]. Furthermore, ring contraction reactions of these oxazines leading to pyrroles [373] and y-lactames [375] are known. 

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