Bronsted thiourea catalysts

The small-molecule catalysts are covered in Chapters 5 and 6. In Chapter 5, Joshua Payette and Hisashi Yamamoto discuss the importance of polar Bronsted-acid-type catalysts as well as cooperative effects in hydrogen bonding catalysis. Chapter 6 by Mike Kotke and Peter Schreiner is then devoted to the single most popular small-molecule catalyst types, the thiourea catalysts. Chapter 6, the longest of all chapters, also provides an excellent overview of the history and development of the field of small-molecule hydrogen bond catalysis. 

A number of Bronsted acidic organocatalysts have been applied to the asymmetric hydrophosphonylation of aldimines. Thiourea catalysts related to (6.130) catalyse the asymmetric hydrophosphonylation of a range of aliphatic and aromatic aldimines with high ee and BINOL-derived phosphoric acid derivatives similar in structure to (6.131) are effective catalysts in the asymmetric phosphonylation of cinnamaldehyde-derived aldimines. Asymmetric hydrophosphonylation of aromatic aldimines can also be achieved with high ee using cheap, commercially... 

Organocatalytic asymmetric hydrophosphonylation/Mannich reactions using thiourea, cinchona and Bronsted acid catalysts 12SL1108. Organocatalytic asymmetric transformations of modified Morita—Bayhs— HiUman adducts 12CSR4101. 

The greater scope of this reaction was attributed to the dual cyclic Bronsted acid/H-Bond donar cocatalysis mechanism. The catalytic cycle initially involves imine protonation by the chiral thiourea catalyst 170 associated via H-bonding to the conjugate base (X ) of a weak Bronsted acid (H-X, benzoic acid in this case) additive. Intramolecular cyclization of the protonated iminium ion 146, followed by rearomatization regenerates the Bronsted acid cocatlayst (benzoic acid). Note for brevity, the plausible rearrangement (RR) step of the inital CCij-spiroalkylated adduct to the final tetrahydrohydroisoquinoline scaffold 147 is not shown. 

I n this chapter, we wish to discuss the recent advancements in chiral Bronsted acid catalysis. We will focus chiefly on (i) thiourea catalysts [55], (ii) guanidium salts (protonated amine catalysts), (iii) diol catalysts, and (iv) phosphoric acids [56]. The first three catalysts are classified as neutral or weak Bronsted acids, which may be called hydrogen bond catalysts [57]. In contrast, phosphoric acids, being stronger acids, are Bronsted acid catalysts in a narrow sense (Figure 2.9). 

Br0nsted Base-Derived Thiourea Catalysts 353 Chiral Bifunctional Bronsted Base Thiourea Catalyst... 

Figure 13,6 Basic scaffold of chiral Bronsted base derived thiourea catalysts.

The synthetic utility of the bifunctional catalysts in various organic transformations with chiral cyclohexane-diamine derived thioureas was established through the works of Jacobsen, Takemoto, Johnston, Li, Wang, and Tsogoeva. In the last decade, asymmetric conjugate-type reactions have become popular with cinchona alkaloid derived thioureas. The next section presents non-traditional asymmetric reactions of nitroolefins, enones, imines, and cycloadditions to highlight the role of chiral Bronsted base derived thiourea catalysts. 

The low reaction rates usually associated with the MBH reaction can be increased either by pressure [15a, 22, 34], by the use of ultrasound [35] and micro-wave radiation [14a], or by the addition of co-catalysts. Various intra- or inter-molecular Lewis acid co-catalysts have been tested [26, 36, 37] in particular, mild Bronsted acids such as methanol [36, 57d], formamide [38], diarylureas and thioureas [39] and water [27a, 40] were examined and found to provide an additional acceleration of the MBH reaction rate (Table 5.1). 

There is also a modified version of Takemoto s catalyst, which incorporates a benzimidazole heterocycle as the H-bonding donor site in place of the thiourea moiety." This catalyst 82 has been tested with success in several Michael-type reactions of 1,3-dicarbonyl compounds to nitroalkenes, in particular focused on the use of malonates as donors (Scheme 4.20), providing the corresponding adducts in excellent yields and enantioselectivities. p-Ketoesters have also been tested, although in this case the performance of the catalyst was found to be highly dependent on the structure of the p-ketoester employed. It has also to be pointed out that the reaction required the incorporation of a Bronsted acid cocatalyst such as TFA for achieving the best enantioselectivity, although the presence of this co-catalyst did not have any influence in the catalytic activity. 

Despite this, bifunctional thiourea-tertiary amine catalysts have also emerged as useful and very convenient compounds for the activation of enones in Michael reactions. The mentioned problems associated to the single position available for H-bonding interactions and to the lower Bronsted basicity of the carbonyl moiety are circumvented by the formation of a double H-bonding network in which both lone pairs at the oxygen atom participate with two... 

In the absence of a catalytic amount of Lewis acids such as Mg(OTf)2, weak Bronsted acids, such as thioureas, BINOL, and BINOL-derived phosphoric acids, could not promote this reaction alone. The reaction could not proceed with phosphoric acid salts, suggesting that the use of free acid is essential for effective catalysis. The combination of chiral phosphoric acid 13e and Lewis acid Mgp2 (4 1 ratio) was identified to be the optimal catalyst for the AFC alkylation reactions of phenols with p,y-unsaturated a-keto esters, affording the alkylation product in good yields with up to 99% ee. Not only free phenols but also indoles could be successfully applied in AFC reactions with P,y-unsaturated a-keto esters under the binary-acid catalysis (82-94% ee). 

The roles of the catalytic functions are not necessarily opposite or limited to Lewis acid/base pairs. For example, amine thiourea derivatives like Takemoto s catalyst 4 merge the hydrogen bond donor capability of the thiourea moiety with Bronsted base functionality of the amine function and revealed itself particularly efficient organocatalysts for Michael reactions of various 1,3-dicarbonyl compounds with nitroolefins (Scheme 3) [17-19]. 

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