Nucleophilic reactions thiophenols

Thiophenol is electrochemically oxidized to diphenyl disulfide near 1.7 V (vs. Ag/AgCl), because the thiophenolate radicals undergo coupling. Although diphenyl disulfide is further oxidized under the given potential of 1.7 V, the cationic species formed are rapidly inactivated by a nucleophilic reaction with... 

Among the best nucleophiles of all at doing conjugate addition are thiols, the sulfur analogues of alcohols. In this example, the nucleophile is thiophenol (phenol with the O replaced by S). Remarkably, no acid or base catalyst is needed (as it was with the alcohol additions), and the product is obtained in 94% yield under quite mild reaction conditions. 

Aryl radicals electrochemically generated from the cleavage of aryl halide radical anions have been observed to react with nucleophiles other than iodide (Pinson and Saveant, 1974, 1978 Saveant, 1980), a reaction known as the SrjjI reaction (Bunnett, 1978). The most commonly used nucleophiles are thiophenolate, mercaptides, and cyanide ion. The reactions observed are... 

Buten-2-one 4-cation equivalent. The reagent is available by an exchange reaction of 3-oxobutyraldehyde 1,1-dimethylacetal with benzotriazole and partial elimination with NaOH under phase transfer conditions. The reagent undergoes addition-elimination with various nucleophiles (piperidine, thiophenol, 2-nitropropane, malonic esters, etc.). 

Alkoxyisocyanates. Methanol and 4-5 drops of triethylamine added to a soln. of startg. carbodiimide in benzene, heated at 80" for 8-10 h, and worked up after removal of the corresponding amide (Y 86-92%) at 5-10° - product. Y 58%. F.e. and nucleophiles (phenols, thiophenols, imines), also reaction with water and /cr/-butyl-amine, s. M.V. Vovk et al., Zh. Org. Khim. 24, 727-32 (1988) 1,1-acoxyisocyanates s. ibid. 1237-40. 

The role of the quaternization of the azasubstituent in the nucleophilic substitution at 2-halogenothiazoles is in fact emphasized by the reactivity of 2-halogenothiazoles with undissociated thiophenol (35), which proceeds faster than the corresponding reaction of 2-halogenothiazoles with thiophenolate anion, through the pathways shown in Scheme 6. Moreover, the 4-halogenothiazoles do not react with undissociated thiophenols, while the 5-halogenothiazoles react well (48). 

The action of sulfur nucleophiles like sodium bisulfite and thiophenols causes even pteridines that are unreactive towards water or alcohols to undergo covalent addition reactions. Thus, pteridin-7-one smoothly adds the named S-nucleophiles in a 1 1 ratio to C-6 (65JCS6930). Similarly, pteridin-4-one (73) yields adducts (74) in a 2 1 ratio at C-6 and C-7 exclusively (equation 14), as do 4-aminopteridine and lumazine with sodium bisulfite. Xanthopterin forms a 7,8-adduct and 7,8-dihydropterin can easily be converted to sodium 5,6,7,8-tetrahydropterin-6-sulfonate (66JCS(C)285), which leads to pterin-6-sulfonic acid on oxidation (59HCA1854). 

The catalytic effect of protons has been noted on many occasions (cf. Section II,D,2,c) and autocatalysis frequently occurs when the nucleophile is not a strong base. Acid catalysis of reactions with water, alcohols, mercaptans, amines, or halide ions has been observed for halogeno derivatives of pyridine, pyrimidine (92), s-triazine (93), quinoline, and phthalazine as well as for many other ring systems and leaving groups. An interesting displacement is that of a 4-oxo group in the reaction of quinolines with thiophenols, which is made possible by the acid catalysis. 

The reaction of 1,2,4-triazine 4-oxides 55 with thiophenols proceeds in the same manner, resulting in the corresponding 5-arylmercapto-1,2,4-triazines 80 in high yields. Thiophenols in this case react as S-nucleophiles, in spite of the relative phenols—the C-nucleophiles (01RCB1068). 

However, heterocycles containing thiophenols have not been reported. It has been observed that the thiophe-nolate ion undergoes nucleophilic attack by the halo/ nitro compounds more easily than the phenolate ion in displacement reactions [37-39]. The experimental result shows that the reactivity of 3-nitro-N-phenyl-phthali-mide with 4-methyl-thiophenolate (reaction 1) is 100 times faster than that of 4-methyl phenolate [40] (reaction 2) ... 

No addition products with S-nucleophiles have yet been reported except for the reaction of 2-methylthio-4,6-diphenylthiopyrylium iodide with sodium thiophenolate involving a 2//-thiopyran intermediate (86S916). 

With OH and SH, the nucleophilic substitution of Cl has been reported. Thus, with NaOH, there is a report of successful nucleophilic substitution in 50% aq. acetone at room temperature to give the phenol complex in 36% yield. The latter is then spontaneously deprotonated to give the cyclohexadienyl complex (Eq. (24)). An identical reaction was carried out using NaSH in MeCN (50% yield) to give the thiophenol complex which was deprotonated [72] Eq. (25). These reactions would be especially valuable because direct synthesis of the phenol or thiophenol complexes from ferrocene is not possible due to the strong interaction between the heteroatom and A1C13 [11, 19]. Recent improvement and use of this reaction were achieved [88],... 

A-Protected amines were assembled on solid-phase via sulfonamide-based handle 58 (Scheme 27) [67]. Tertiary sulfonamides were generated upon reaction with allylic, benzylic and primary alcohols under Mitsu-nobu conditions. Secondary amines were released from the support using mild nucleophilic conditions such as treatment with thiophenol and potassium carbonate. 

The base-catalyzed joint reaction of nitroalkenes with thiophenol in the presence of aldehydes gives y-phenylthio-P-nitro alcohols in one pot (Eq. 4.5).8 The joint reaction of nitroalkenes with thiols and a,p-unsaturated nitriles (or esters) has also been achieved. (Eq. 4.6).9 P-Nitro sulfides thus prepared show unique reactivity toward nucleophiles or tin radicals. The nitro... 

General. Toluene, chlorobenzene, and o-dichlorobenzene were distilled from calcium hydride prior to use. 4-Dimethylaminopyridine (Aldrich Chemical Co) was recrystalled (EtOAc), and the other 4-dialkylaminopyridines were distilled prior to use. PEG S, PEGM s, PVP s, and crown ethers were obtained from Aldrich Chemical Co., and were used without purification. BuJ r and BU. PBr were recrystallized (toluene). A Varian 3700 VrC interfaced with a Spectraphysics SP-4000 data system was used for VPC analyses. A Dupont Instruments Model 850 HPLC (also interfaced with the SP-4000) was used for LC analyses. All products of nucleophilic aromatic substitution were identified by comparison to authentic material prepared from reaction in DMF or DMAc. Alkali phenolates or thiol ates were pre-formed via reaction of aqueous NaOH or KOH and the requisite phenol or thiophenol in water under nitrogen, followed by azeotropic removal of water with toluene. The salts were transferred to jars under nitrogen, and were dried at 120 under vacuum for 20 hr, and were stored and handled in a nitrogen dry box. 

The Marshall Unker [23] has been widely used to synthesize compounds that can be cleaved by primary and secondary amines to afford the corresponding amides. Marshall linker was used in the synthesis of three or more diversity-site hbraries because it allowed the addition of one more diversity element at the cleavage step. While the original reported linker [23] involved the oxidation of the Unker before cleavage, the efficient release of the resin-bound compounds using nucleophiles from the unoxidized linker has been reported [16, 24]. Similarly to the acid-labile linkers, the kinetics of the cleavage reaction and time required for this reaction directly affect the synthesis efficiency, purity and yield of the final products. A cleavage study was carried out on seven resin-bound thiophenol esters (34—40) on Marshall Unker with 3 amines (41-43) (Scheme 12.11 and Tab. 12.4). 

Swartz and Stenzel (1984) proposed an approach to widen the applicability of the cathode initiation of the nucleophilic substitution, by using a catalyst to facilitate one-electron transfer. Thus, in the presence of PhCN, the cathode-initiated reaction between PhBr and Bu4NSPh leads to diphe-nydisulfide in such a manner that the yield increases from 10 to 70%. Benzonitrile captures an electron and diffuses into the pool where it meets bromobenzene. The latter is converted into the anion-radical. The next reaction consists of the generation of the phenyl radical, with the elimination of the bromide ion. Since generation of the phenyl radical takes place far from the electrode, this radical is attacked with the anion of thiophenol faster than it is reduced to the phenyl anion. As a result, instead of debromination, substitution develops in its chain variant. In other words, the problem is to choose a catalyst such that it would be reduced more easily than a substrate. Of course, the catalyst anion-radical should not decay spontaneously in a solution. 

Scheme 6.2 represents Sj j l substitution that takes place when sodium thiophenolate attacks e,4-tert-butyl-c,2-methyl-fl,4-nitro-e,4-(4-nitrophenyl) cyclohexane. Light irradiation stimulates the reaction. It is carried out under nitrogen in HMPA. The ion-radical type of the process has been established by means of inhibitors. It was found that the stereochemical outcome of the reaction depends on the concentration of the PhSNa nucleophile. At a low concentration of PhSNa, the reaction leads to a mixture of phenylthiyl derivatives the content of a,SPh-substituted product is higher than that of c,SPh product by 20%. At a high concentration of PhSNa, the reaction produces practically a single stereoisomer bearing the a-PhS group. 

The authors have also studied the deprotection by less basic nucleophiles such as thiophenolate and iodide. Deprotection by the latter anion may lead to a side-reaction when condensation of the allyl iodide formed with the de-protected phosphorothioate leads to the corresponding S-allyl phosphoroth-ioate. To suppress this side reaction thiourea was used to trap the allyl iodide. 

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