Organocatalysts thiourea

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

Figure 6.3 Stereoselective, chiral thiourea derivatives of achiral benchmark thiourea organocatalyst N,N -bis [3,5-(trifluoromethyl)phenyl]thiourea 9 stereoselective hydrogen-bonding thiourea organocatalysts incorporating the privileged 3,5-bis(trifluoromethylphenyl)thiourea moiety. The (thio)urea catalyst structure is the leitmotif for the chapter organization.

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

Scheme 6.55 Design principle of amine-functionalized bifunctional thiourea organocatalysts derived from privileged monofunctional thiourea 9 cooperating with an amine base additive (A) and basic bifunctional mode of action of chiral amine...

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

The proline-derived thiourea organocatalyst (154) (20 mol%) in conjunction with n-butyric acid (10 mol%) exhibited high stereoselectivity (<99 1 syn. anti and <98% ... 

In 2008, Jorgensen and coworkers reported that oxazolones 140 could also smoothly undergo addition to nitroalkenes 124 in the presence of bifunctional cinchona-based thiourea organocatalysts such as 81a and 81a. The reaction with 4-phenyloxazolones (140, R1 = ph) took place at C4 affording the adducts 141 with moderate to good ee values (up to 83% ee). On the other hand, 4-alkyloxazolones (R = Me, i-Bu) were added to the C2-position of 140, furnishing 142 with a moderate to high enantioselectivity (up to 92% ee) (Scheme 9.48). The adducts 141 can be used... 

Herrera, R.P., Sgarzani, V, Bemardi, L. and Ricci, A. (2005) Catalytic enantioselectiveFriedel-Crafts alkylation of indoles with nitroalkenes by using a simple thiourea organocatalyst. Angewandte Chemie - International Edition, 44, 6576-6579. 

Tang and coworkers" used bifunctional urea and thiourea-derived orga-nocatalysts (4a,b) for the Michael addition of cyclohexanone to nitro-olefins (Scheme 9.29). Using pyrrolidine-thiourea 4b afforded the desired y-nitroalkanes with high diastereo- and enantioselectivity under solvent-free conditions (up to 99 1 dr, 88-98% ee). Subsequently, Xiao and coworkers screened various bifunctional pyrrolidine-thiourea organocatalysts and identified 4c to be efficient at catalysing the Michael addition of various ketones to nitrostyrenes. Comparable results were observed (up to 99 1 dr and 99% ee) when the reactions were performed in both aqueous media and organic solvents. 

Scheme 9.31 Pyrrolidine-thiourea organocatalyst (4i) for Michael additions.

In 2005, Sons and coworkers introduced a novel bifunctional thiourea organocatalyst based on a Cinchona alkaloid for the asymmetric conjugate addition of nitromethane to tra s-chalcones. Using 10 mol% of thiourea 17, various electron-rich and electron-poor chalcones were well tolerated providing the desired adducts in high yields (80-94%) and very high enan-tioselectivities (95-96%) (Scheme 19.24). It has to be highlighted that... 

Fluorous thiourea organocatalyst (103) promotes Michael reaction of aldehydes with maleimides in high yield, and ee sometimes >99%. Catalyst (103), easily prepared 0 in one step from readily available materials, can be recovered by filtration and is reusable. 

An unprecedented enantio-selective Michael/hemiketalization/retro-Henry cascade sequence catalysed by a simple bifunctional indane amine-thiourea organocatalyst (7)... 

In another one-pot reaction, chiral isoxazoline-fused benzazepines 31 were formed from the reaction of P-nitrostyrene derivatives 30 and 1,3-dicarbonyl species such as dimethyl malonate. The first step is a nitro-Michael addition reaction between the nitro olefin and dimethyl malonate catalyzed by a chiral thiourea organocatalyst, followed by addition of DMAP and Boc anhydride with heating to promote nitrile... 

In this pivotal example, the authors have demonstrated the ability of bifunctional thiourea organocatalyst 28 to provide the sufficient activation of organoboronic acids in the Petasis reaction using quinolones 26, as a powerful method for the enantio- and regioselective synthesis of 1,2-adducts 29 against the possibility of generation of 1,4-adducts (Table 4.1) [28],... 

Another big family of organocatalysts that has been successfully used in hydrogen transfer, although less explored, is the chiral thiourea organocatalysts (for pivotal reviews concerning chiral thioureas, see [141-154] and for the pioneering use of... 

An extension of this work was reported by the same research group using P-nitroacrylates 71 and the same thiourea organocatalyst 69 with the main aim of... 

Brpnsted bases have been explored in cooperative catalysis to deprotonate substrates that subsequently add to metal-activated electrophiles. Regarding the use of these organocatalysts in cooperative catalysis, the combination of quinine and quinine-derived thiourea organocatalysts with Cu(II)-PhBox and Cu(OTf) has been employed in aza-Henry [23] and... 

Another member of the ep -cinchona-based thiourea organocatalyst family, depicted in Scheme 1.19, was applied by Vakulya et al. to the asymmetric Michael addition of nitroalkanes to chalcones, giving excellent yields and enantioselectivities of up to 98% ee. The extension of this methodology was further explored to encompass a,p-unsaturated A-acylpyrroles, as a chalcone mimic. The corresponding Michael products were obtained in high yields and enantioselectivities of up to 94% ee, as shown in Scheme 1.19. This simple novel approach allowed a concise stereoselective synthesis of (i )-rolipram to be accomplished. 

In 2009, Feng et al. reported the asymmetric hydrophosphonylation of a-keto esters catalysed for the first time by cinchona-derived thiourea organocatalysts. Thus, a series of aromatic and heteroaromatic a-keto esters reacted with dimethyl phosphite to afford the corresponding a-hydroxy phosphonates in high yields and enantioselectivities of up to 91% ee (Scheme 2.53). 

A chiral primary amine-thiourea organocatalyst was successfully applied for the first time by Tsogoeva et al. to the asymmetric Mannich reaction of ketones with readily available and stable a-hydrazonoesters, which proceeded with good yields and high enantioselectivities of up to 99% ee (Scheme 3.17). Interestingly, whereas acyclic ketones gave a tf-Mannich products, an excess of syn diastereomers was observed with the cyclic ketones. In both cases, only low... 

---