Thiourea-proline

The Tsogoeva group, in 2006, reported the introduction of newly designed bifunctional secondary amine-functionalized proline-based thioureas (95 and 96) and the primary amine-functionalized thioureas (97-99) for catalysis of the asymmetric addition of ketones to trans-P-nitrostyrenes (Figure 6.30) [260, 261]. Using... 

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% ... 

Octahydroquinazolinones and their mercapto derivatives 290 (X = O and S, respectively) have been synthesized by a three-component condensation of dimedone 289, urea/thiourea and an aldehyde in aqueous H2SO4 (06BMC4479) or under microwave irradiation without solvent (Scheme 113) (05MI6). Similar L-proline/TEA catalyzed reaction of 291 gave 292 (X = O, S) (Scheme 113) (09T9350). 

Scheme 3.21 Enantioselective Michael addition of nitroalkanes to acyclic enones catalyzed by imidazolidines 53a and 53c, proline tetrazole 2a and amine-thiourea ent-37b.

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

The use of chiral diols as co-catalyst in aldol reaction led to an improvanent of the achieved results [41]. Thus, when acetone (3a, 8.18 equiv.) was reacted with benzaldehyde (2 h) in DMSO at 0°C catalyzed by (5)-proline (30 mol%) the expected product 4 was obtained in 72% ee, while a 96% ee was achieved in the presence of (R)-BINOL (0.5 mol%). A hypothetical explanation from the authors for this effect is the possible template effect of the chiral diol which may activate and ordered the aldehyde and enamine nucleophile. The same reason was claimed for the beneficial effect achieved by addition of a 10 mol% of (3,5-bistrifluoromethylphenyl)thiourea in the aldol reaction between cyclohexanone (3b) and several aromatic aldehydes catalyzed by proline (1,10 mol%) in hexane a 25°C [42], In this case, reaction times, yields as well as diastereo- and enantioselectivities were improved (75-98%, 76-88% de, 98-99% ee), with these results being also attributed to the enhancement of the proline solubility by the formation of a host-guest proline-thiourea complex. 

Pyrrolidine thiourea derivative 136 (50 mol%) afforded the best results (49% yield, 33% de, 85% ee), among several proline derivatives, in aldol reaction of a-ketoester and 4-pentenal, which was a key step in the total synthesis of (H-)-trachyspic acid [224]. 

Proline derivatives possess a prominent position among the aminocatalysts utilised for carbonyl activation. In combination with the readily tunable properties of the (thio)urea functionality for electrophile activation, the development of bifunctional chiral pyrrolidine-based (thio)ureas was a rational extension. In 2006, Tang and coworkers reported thiourea 55 that can catalyse the conjugate addition reaction between cyclohexanone and nitroalkenes (Scheme 19.63). In the presence of 20 mol% of chiral thiourea 55 and butyric acid as the cocatalyst, the q -products were delivered in high yields (up to 98%) and in excellent diastereo- (up to >99 1 dr) and enan-tioselectivities (up to 98% enantiomeric excess). In addition to aromatic nitroalkenes, aliphatic nitroalkenes were also tolerated, but required a long reaction time (6 days). 

It seems appropriate to remember that there are also other classes of molecules that are catalytically active thanks to one of the mentioned mechanisms (ureas, thioureas, phosphoric acids, etc.) as well as molecules with two or more different functional sites (bifunctional organocatalysts) one of which is often an alcoholic/phenolic/carbojqrlic group (amino-alcohols, aminoacids, proline derivatives, aminophenols, etc.) they will be not discussed in this chapter because they have already been examined in previous chapters or because they contain nonsustainable elements. 

Aldol additions of acetone (1) as a nucleophile to ketones without a-acidic protons are feasible. The proline-catalyzed aldol reaction between acetone (1) and 1-aryl-2,2,2-trifluoroethanone (128) led to tertiary alcohol 129 in good yield but with low stereoselectivity [146]. A proline-derived sulfonamide 130 performs much better (Table 3.10, entry 2). Kokotos prepared a prolinamide-thiourea catalyst 131, which under optimum conditions can be used in 2 mol%, even at 0°C (entry 3) [ 147], With proline, the reaction was completed within hours, while more stereoselective catalysts 130 and 131 required 2 days. So far, these are the catalysts of choice for this tran ormation [146-148]. 

A different approximation was reported by Tang, Li, and co-workers [56] by using Seebach s nitroallylic acetate reagent 85, cyclohexanones, and proline-thiourea derivative XXVI as a catalyst. Nitroallylic acetate reacts with cyclohexanones via a double Michael addition, affording the final fused bicyclic ketones 86 in excellent yields and stereoselectivities (Scheme 10.24). 

More recently, it has been reported that primary amines derived from cinchona alkaloids [75] as well as proline derivatives [76], combined with achiral Brpnsted or Lewis acids, may also efficiently catalyze the enantioselective Biginelli reaction. Alternatively, a carbohydrate-based bifnnctional primary amine-thiourea catalyst was developed for this transformation, with similar enantiocontrol [77]. 

Chiral organocatalysts were to the fore in Michael transformations prolines, thioureas, NHCs, BINAPs, and diamines, or combinations thereof. 

Lactol (134, 2-hydroxy-THF) can a-alkylate pentan-2-one under mild conditions, using a proline derivative and an unsymmetrical (but achiral) thiourea as co-catalysts, to give THF derivatives (135), with some enantioselectivity. However, kinetic studies show that the ee is time-dependent, and typically decreasing. While racemization of (135) explains some of the effect, it also appears that there are two competing mechanisms with opposing enantioselectivities operating." ... 

Aminothiourea-prolinal dithioacetal (234), in the presence of PhC02H, can catalyse Michael addition of ketones R CH2COR and aldehydes to nitroalkenes at 3 mol% loading to afford the 3yn-configured products with <99 1 dr and <99% ee under solvent-free conditions at room temperature. The related carbohydrate-derived thiourea is believed to activate both 8-diketones and nitroalkenes via coordination (235) the Michael adducts were obtained in <89% ee " Another variant of the thiourea motif with a cinchona alkaloid scaffold exhibited higher stereocontrol in the same reaction (<98% ee), carried out in MeCN at —40°C ... 

A number of derivatives of L-azetidine-2-carboxylic acid, a naturally occurring antimetabolite of proline, have been prepared. Its reaction with phenyl isothiocyanate gave the thiourea (187), which on treatment with dicyclohexylcarbodi-imide (DCC) formed 2-phenylimino-5-thiazolidinone (188). The thiazolidinone, which acylates morpholine at room temperature,... 

A. S. Demir, S. Basceken, Tetrahedron Asymmetry 2013, 24, 515-525. Study of asymmetric aldol and Mannich reactions catalyzed by proline-thiourea host-guest complexes in nonpolar solvents. 

A number of other-than-proline-derived organocatalysts have been involved to induce chirality in Michael additions of various C-nucleophiles onto a range of Michael acceptors. Among them, bifunctional organocatalysts possessing a thiourea moiety and a tertiary amino group were designed by Takemoto et al. 

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