Michael reactions thiolate anions

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

The attack by the thiolate anion on the N-oxide oxygen of 62 produces the intermediate sulfenic acid derivative 65, which, in the presence of thiols, further reacts with the thiolate anion, to give the oxime 66, which has been isolated among the reaction products. By contrast, spontaneous loss of the halide anion from 65 affords the ni-troso intermediate 67 that, by losing NO and the thiyl radical directly, or through 68, produces the a-nitrosoolefm 69. By a Michael type reaction with water this last product immediately yields the final oxime 70, which has been isolated among the reaction products. 

Greaney and coworkers have introduced the conjugate addition of thiols to Michael acceptors as an effective adaptive DCL strategy [46,47]. The reaction is well suited for biological DCL synthesis, taking place in water with no requirement for external reagents. As with disulfide bond formation, the reaction is subject to simple and effective pH control. Under mildly basic conditions, the thiolate anion adds rapidly to Michael acceptors under equilibrium conditions. Acidification effectively switches the reaction... 

The addition of a nucleophilic carbon species to an zr,/3-unsaturated ketone, aldehyde, ester or nitrile is called Michael reaction. Other nucleophiles such as amines, alkoxides or thiolates react similarly. In this case sodium hydride generates the anion of tert-butanethiol which undergoes an 1,4-addition at the conjugated ester. Regeneration of the double bond by elimination of bromine leads to the thermodynamically more stable E-ester 20. 

Thiolate anion and its analogues are known as good nucleophiles that quantitatively give Michael adducts. The reaction begins with the nucleophilic attack of thiolate ion... 

As electron-rich olefins are more reactive, vinyl-sulfones are the most reactive species and are capable of reacting with thiols, amines, and even with small nucleophilic alcohol groups. Less reactive are acrylamides and acrylates, which are reactive towards amines and thiols. Maleimides are the least reactive of the mentioned species and allow selective addition of thiols in the presence of amines in the pH range 6.5-7.5. However, hydrolysis of the imide, especially at elevated pH values [35], may be a concern for certain applications. The mentioned Michael addition reactions do not require organic solvents and can be carried out at physiological temperature and pH [36], In acidic conditions, the reaction is either very slow or does not proceed because protonation removes the nucleophilic form in the case of amines, and the thiolate anion is usually the active species in Michael additions involving thiols [25],... 

The thiol Michael addition reaction rate increases with pH, connected to the increase of thiolate anion concentration (Rizzi and Hubbell, 2005). The reaction on the polymeric system is shown in Fig. 14.9. 

Thiols and thiolate anions are very good nucleophiles. Various click reactions have been developed based on the nucleophilic attack of thiols on to the electrophilic substrates such as epoxides, isocyanates, halides, and Michael acceptors. The reactions are generally initiated by bases, which are added in catalytic amounts or are produced in catalytic amounts by photolatent bases that act as photoinitiators for these reactions [48]. The rates of these reactions are dependent on the substrates... 

Scheme 1.15). The final abstraction of proton is thermodynamically controlled and is a fast step. However, the attack of thiolate anion on the Michael acceptor is kinetically controlled. The overall rate and yield of these reactions can be altered by changing various factors such as solvent polarity, pH, strength of the base (catalyst), and nature ofEWGs on the C=C bond [53-55]. 

Apart from base catalysis, Michael addition of thiols can also be performed using nucleophUic catalysis. Primary and secondary amines and certain phosphines are the most commonly used catalysts. Nucleophile mediated thiol-Michael addition reactions have extensively been studied. The nucleophiles attack the Michael acceptors to generate a carbanion, which abstracts protons from thiols to generate thiolate anions, which in turn propagate the reaction (Scheme 1.16) [56]. NucleophUicity of the catalyst plays a crucial role in the kinetics of the nucleophile-based thiol-Michael addition reactions, as stronger the nucleophile, more easily the thiolate anion will be generated. 

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