Sulfoxides nucleophiles

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). 

A AlI lation. 1-Substitution is favored when the indole ring is deprotonated and the reaction medium promotes the nucleophilicity of the resulting indole anion. Conditions which typically result in A/-alkylation are generation of the sodium salt by sodium amide in Hquid ammonia, use of sodium hydride or a similar strong base in /V, /V- dim ethyl form am i de or dimethyl sulfoxide, or the use of phase-transfer conditions. 

I itro-DisplacementPolymerization. The facile nucleophilic displacement of a nitro group on a phthalimide by an oxyanion has been used to prepare polyetherimides by heating bisphenoxides with bisnitrophthalimides (91). For example with 4,4 -dinitro monomers, a polymer with the Ultem backbone is prepared as follows (92). Because of the high reactivity of the nitro phthalimides, the polymerkation can be carried out at temperatures below 75°C. Relative reactivities are nitro compounds over halogens, Ai-aryl imides over A/-alkyl imides, and 3-substituents over 4-substituents. Solvents are usually dipolar aprotic Hquids such as dimethyl sulfoxide, and sometimes an aromatic Hquid is used, in addition. 

Nucleophilic Substitution Route. Commercial synthesis of poly(arylethersulfone)s is accompHshed almost exclusively via the nucleophilic substitution polycondensation route. This synthesis route, discovered at Union Carbide in the early 1960s (3,4), involves reaction of the bisphenol of choice with 4,4 -dichlorodiphenylsulfone in a dipolar aprotic solvent in the presence of an alkaUbase. Examples of dipolar aprotic solvents include A/-methyl-2-pyrrohdinone (NMP), dimethyl acetamide (DMAc), sulfolane, and dimethyl sulfoxide (DMSO). Examples of suitable bases are sodium hydroxide, potassium hydroxide, and potassium carbonate. In the case of polysulfone (PSE) synthesis, the reaction is a two-step process in which the dialkah metal salt of bisphenol A (1) is first formed in situ from bisphenol A [80-05-7] by reaction with the base (eg, two molar equivalents of NaOH),... 

Solvent for Displacement Reactions. As the most polar of the common aprotic solvents, DMSO is a favored solvent for displacement reactions because of its high dielectric constant and because anions are less solvated in it (87). Rates for these reactions are sometimes a thousand times faster in DMSO than in alcohols. Suitable nucleophiles include acetyUde ion, alkoxide ion, hydroxide ion, azide ion, carbanions, carboxylate ions, cyanide ion, hahde ions, mercaptide ions, phenoxide ions, nitrite ions, and thiocyanate ions (31). Rates of displacement by amides or amines are also greater in DMSO than in alcohol or aqueous solutions. Dimethyl sulfoxide is used as the reaction solvent in the manufacture of high performance, polyaryl ether polymers by reaction of bis(4,4 -chlorophenyl) sulfone with the disodium salts of dihydroxyphenols, eg, bisphenol A or 4,4 -sulfonylbisphenol (88). These and related reactions are made more economical by efficient recycling of DMSO (89). Nucleophilic displacement of activated aromatic nitro groups with aryloxy anion in DMSO is a versatile and useful reaction for the synthesis of aromatic ethers and polyethers (90). 

Many other examples are known of non-selective reactions of halo groups in pyridopyridazines with amines, alkoxides, sulfur nucleophiles such as hydrosulfide and thiolate ions, or thiourea, hydrazine(s), cyanide ion and dimethyl sulfoxide, or on catalytic reduction. 

The alkylthio group is replaceable by nucleophiles. The positions 7 and 4 react under mild conditions in that order the 2-alkylthio functions require more drastic treatment. Conversion of l-methyl-4-methylthiopteridin-2-one (157) into the 4-methylamino derivative (158) can be achieved by stirring with methylamine at room temperature (equation 48). The reactivity of an alkylthio group can often be further enhanced by oxidation to the corresponding sulfoxide and sulfone. Thus, reaction of l,3-dimethyl-7-methylthiolumazine (160) with m-chloroperbenzoic acid yields 7-methylsulfinyl- (161) and 7-methylsulfonyl-l,3-dimethyllumazine (162 equation 49) (82UP21601). 4-Amino-2-methylthio-7-... 

Hydroxy and mercapto substituents at the 3- and 5-positions can also exist in tautomeric forms (see Section 4.01.5.2) and can be alkylated at either the substituent or the ring nitrogen atom. 3-Methoxy groups are not replaced by nucleophiles, but both 3- and 5-alkylthio groups react readily, as does 3-methoxy-l,2-benzisothiazole. Alkylthio compounds can be oxidized to sulfoxides and sulfones, and the latter readily undergo nucleophilic replacement. All the hydroxy compounds react with phosphorus pentachloride to give the chloro derivatives. 

Scheme 6 depicts a typical penicillin sulfoxide rearrangement (69JA1401). The mechanism probably involves an initial thermal formation of a sulfenic acid which is trapped by the acetic anhydride as the mixed sulfenic-acetic anhydride. Nucleophilic attack by the double bond on the sulfur leads to an episulfonium ion which, depending on the site of acetate attack, can afford either the penam (19) or the cepham (20). Product ratios are dependent on reaction conditions. For example, in another related study acetic anhydride gave predominantly the penam product, while chloroacetic anhydride gave the cepham product (7lJCS(O3540). The rearrangement can also be effected by acid in this case the principal products are the cepham (21) and the cephem (22 Scheme 7). Since these early studies a wide variety of reagents have been found to catalyze the conversion of a penicillin sulfoxide to the cepham/cephem ring system (e.g. 77JOC2887).

In the presence of suitable a,/5-unsaturated carbonyl compounds (3) the nucleophilic methylide (2) undergoes conjugate addition followed by expulsion of dimethyl sulfoxide to give cyclopropanes (5). 

Recently developed trifluoromethylatmg agents capable of transferring the trifluoromethyl group as a cation to strongly nucleophilic compounds such as carbanions and sulfur and phosphorus nucleophiles are prepared from o-biphenyl trifluoromethyl sulfoxide [164] and are shown in equation 141... 

On treatment with a strong base such as sodium hydride or sodium amide, dimethyl sulfoxide yields a proton to form the methylsulfinyl carbanion (dimsyl ion), a strongly basic reagent. Reaction of dimsyl ion with triphenylalkylphosphonium halides provides a convenient route to ylides (see Chapter 11, Section III), and with triphenylmethane the reagent affords a high concentration of triphenylmethyl carbanion. Of immediate interest, however, is the nucleophilic reaction of dimsyl ion with aldehydes, ketones, and particularly esters (//). The reaction of dimsyl ion with nonenolizable ketones and... 

Nitro ilkenes are gener illy prepared by the subsdnidon reacdon of fi-nirro sulfides and sulfoxides with a variety of carbon nucleophiles via an addidon-eliminadon sequence. This method is partiadarly usefiil for the preparadon of cyclic nitroalkenes fEq. 4.100. ... 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

A conceptually new direct oxidative glycosylation with glycal donors, employing a reagent combination of triflic anhydride and diphenyl sulfoxide, has recently been reported by Gin [83], This new 3-glycosylation method works very well with hindered hydroxy nucleophiles, including sterically shielded carbohydrate hydroxy systems, and can be run on large scales. 

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