Catalyst thio ureas

Meanwhile, chiral (thio)urea catalysts have been employed for a variety of imine addition reactions consisting of Mannich, aza-Henry, Pictet-Spengler, and hydrophosphonylation reactions. ... 

Schreiner[1,114,125] guidelines for (thio)urea catalyst structure design, DA reactions and 1,3-dipolar cycloadditions ("catalytic amount" 1 mol% 12)... 

In the following book chapter [118] the last 10 years of research on (thio)urea organocatalysts are summarized considering catalyst design concepts, experimental details such as structure optimization studies, screening conditions, reaction conditions, the typical substrate and product spectrum of each procedure as well as proposed mechanistic scenarios for each published methodology (-150 articles). 

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.

Figure 6.10 Active sites of lipase (1), triflinctional (thio)urea derivatives (38 39) mimicking the acive site of serine hydrolases (2), and acetyl-catalyst intermediate of the biomimetic transesterification between vinyl trifluoroacetate methanol and 2-propanol, respectively (3).

Figure 6.12 Polystyrene-bound Schiff base (thio)urea catalysts HTS-optimized in the asymmetric Strecker reaction between N-allyl-protected benzaldimine and TBSCN key results obtained from the different libraries.

On the basis of the observed stereoinduction trend, the addition of HCN took place over the diaminocyclohexane portion of the catalyst away from the amino acid and amide unit. The last hypothesis led to the prediction that a more sterically demanding amino acid or amide unit (Figure 6.14) could additionally favor the cyanide attack compared to the less bulky diaminocyclohexane unit and thus making the Schiff base catalyst more enantioselective in Strecker reactions of aldimines and ketimines. To evaluate this perspechve, the authors performed a model-(mechanism-) driven systematic structure optimizations by stepwise modification of the amide, the amino acid, and the (thio)urea unit of catalyst 42 and examined these derivatives of 42 (lmol% loading ) in the model Strecker reaction (toluene ... 

In contrast to monofunctional (thio)urea organocatalysts, bifunctional catalyst structures enable simultaneous coordination, activation, and suitable relative orientation of both reaction components (the electrophile and the nucleophile) resulting in high... 

Berkessel and co-workers synthesized a library of structurally diverse tertiary amine-functionalized catalyst candidates incorporating a chiral 1,2- or 1,4-diamine chiral backbone [231, 232, 246]. Structure-efficiency studies through sequential modification of the diamine backbone, the tertiary amine functionality, the (thio) urea N-substituents as well as of the amide substituent pattern, exemplarily illustrated a Jacobsen-type 1,2-diamine-based structure (figure 6.24), identified... 

Scheme 6.89 Proposed mechanistic picture for the asymmetric alcoholytic DKR of racemic aziactones promoted by bifunctional (thio)urea catalysts 64, 77, and 78 (A) hydrogen-bonded azlactone-64 complex supported by NMR methods (B).

Figure 6.40 (Thio)urea catalysts derived from dihydroquinine and dihydroquinidine screening results obtained from the asymmetric Michael addition of dimethyl malonate to frans-p-nitrostyrene.

C9-epi-122 98% conv. (99% ee) after 30h, respectively (Figure 6.40). This structure-efficiency relationship supported the results already published by the Soos group for quinine- and quinidine-derived thioureas (Figure 6.39) [278]. C9-epimeric catalysts were found to be remarkably more efficient in terms of rate acceleration and stereoinduction than the analogs of natural cinchona alkaloid stereochemistry. This trend was also observed for the corresponding (thio)ureas derived from DHQD as shown by the experimental results in Figure 6.40 [279]. 

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

Thio)urea Catalysts Derived from Chiral Amino Alcohols... 

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

Connon and co-workers synthesized a small library of novel axially chiral binaphthyl-derived bis(thio)ureas 152-165 and elucidated the influence of the steric and electronic characteristics of both the chiral backbone and the achiral N-aryl(alkyl) substituents on catalyst efficiency and stereodifferentiation in the FC type additions of indole and N-methylindole to nitroalkenes (Figure 6.50) [315]. 

A screening of (R)-bis-N-tosyl-BlNAM 151 and axially chiral (thio)urea derivatives 152-162 (10mol% loading 0.36 M catalyst concentration incorporating the N-aryl(alkyl) structural motif was performed at various reaction temperatures in di-chloroform using the asymmetric FC addition of N-methylindole to trans-Ji-nitrostyrene as model reachon (product 1 Scheme 6.158). The structure of bis(3,5-bistrifluoromethyl) phenyl functionalized binaphthyl bisthiourea 158 was identified... 

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

Figure 6.51 Biflinctional (thio)urea-phoshine catalysts 166-168 prepared from (R)-2 -diphenylphosphanyl- [1,1 ]binaphthalenyl-2-ylamine and the corresponding iso(thio) cyanate the yield of the catalysts is given in parentheses. Catalyst screening results ofthe...

The catalyst screening experiments were performed in the asymmetric Henry addition of nitromethane (10 equiv.) to 4-nitrobenzaldehyde in the presence of DABCO (20mol %) as the base and (thio)ureas 157, 158, 163, and 170-175 (each 10mol% loading). After 12h in reaction time at room temperature and in THF as the solvent, the corresponding Henry adduct was obtained in excellent yields (99%) but with very low ee values (7-17%) nearly independently of the sterical hindrance of the axiaUy chiral backbone skeleton (e.g., 172 and 174 each 99% yield 11% ee). Thioureas appeared slightly more enantioselective (e.g., 163 83% yield, 33% ee 171 99% yield, 15% ee) than their urea counterparts probably due... 

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