Nucleophilic substitution reactions alcohol synthesis

Sulfonate esters are especially useful reactants in nucleophilic substitution reactions in synthesis. They have a high level of reactivity and can be prepared from alcohols by reactions that do not directly involve the carbon atom at which substi-mtion is to be effected. The latter feature is particularly important in cases where the stereochemical and structural integrity of the reactant must be maintained. Trifluo-romethanesulfonate (triflate) ion is an exceptionally reactive leaving group and can... 

Alternatively, the Sn2 nucleophilic substitution reaction between alcohols (phenols) and organic halides under basic conditions is the classical Williamson ether synthesis. Recently, it was found that water-soluble calix[n]arenes (n = 4, 6, 8) containing trimethylammonium groups on the upper rim (e.g., calix[4]arene 5.2) were inverse phase-transfer catalysts for alkylation of alcohols and phenols with alkyl halides in aqueous NaOH solution to give the corresponding alkylated products in good-to-high yields.56... 

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]. 

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

Palladium-catalyzed nucleophilic substitution reactions of allylic substrates have become useful in organic synthesis. As allylic substrates, allyl alcohols, halides, carboxylates, phosphates or vinyl epoxides can be utilized. 

Nucleophilic substitution reactions have been effectively exploited in the synthesis of several classes of polymers. However, only scanty reports are available on the application of such reactions to the displacement of chlorine in bisdichloromaleimides, although several examples of displacement of chloride by nucleophiles in N-substituted dichloromaleimides exist in literature. Amines (5), phenols (6), and alcohols and thiols (7) have been used as nucleophiles in such reactions. 

Arenesulfonyl derivatives are frequently employed in organic synthesis to activate hydroxyl groups in nucleophilic substitution reactions or to protect primary and secondary amines. The interest in arenesulfonyl substituents as protective groups for unactivated aliphatic alcohols and amines has been recognized and their removal by photolysis has been described. ... 

This route is especially convenient because no over-alkylation of the anion of acetonitrile occurs. Over-alkylation can be a problem in attempts to methylate the anion of diethyl cyano-methylphosphonate (4) directly a mixture of unalkylated, monoalkylated and dialkylated products in a ratio of 1 2 1 is formed. The same problem arises with the alkylation of triethyl phosphonoacetate (11). For the preparation of a Ca-ester synthon, an alternative method to the propionitrile route is used (Scheme 7). This method has been used in the synthesis of labelled Cio-central units, described in the next Section. The starting material is acetic acid (9) which is converted into ethyl bromoacetate (10) as described above (Scheme 3). The ethyl bromoacetate (10) is reacted with triphenyl phosphine in a nucleophilic substitution reaction the phosphonium salt is formed (yield 97%). The phosphonium salt is deprotonated in a two-layer system of dichloromethane and an aqueous solution of NaOH. After isolation, the phosphorane 22 is reacted at room temperature with one equivalent of methyl iodide (19) the product consists mainly of the monomethylated phosphonium salt (>90%) which is deprotonated with NaOH, to give the phosphorane 23 in quantitative yield relative to phosphorane 22, and 23 is reacted with the aldehyde in dichloromethane. The ester product 12 can subsequently be reduced to the corresponding alcohol and reoxidized to the aldehyde 8. An alternative two-step sequence for this has also been used. First, the ester 12 is converted into the A -methyl-iV-methoxyamide (16) quantitatively by allowing it to react with the anion of A, 0-dimethylhydroxylamine as described above (Scheme 5). This amide 16 is converted, in one step, into the aldehyde 8 by reacting it with DIB AH in THF at -40°C [46]. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Esters can also be synthesized by an acid-catalyzed nucleophilic acyl substitution reaction of a carboxylic acid with an alcohol, a process called the Fischer esterification reaction. Unfortunately, the need to use an excess of a liquid alcohol as solvent effectively limits the method to the synthesis of methyl, ethyl, propyl, and butyl esters. 

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