Cinchona Mannich reaction

PTCs Derived from Cinchona Mannich Reactions 427... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

Direct Mannich reactions of cyclic 1,3-dicarbonyls with acyl imines, R1-CH=N-CO2R2, gives o -quaternary-carbon-bearing products (9 X = CH2, O Y = Me, OMe, OEt) with yieldIdelee up to 98/90/99%, using cinchona alkaloid catalysts 25 ... 

A highly enantioselective direct Mannich reaction of simple /V-Boc-aryl and alkyl- imines with malonates and /1-kclo esters has been reported.27 Catalysed by cinchona alkaloids with a pendant urea moiety, bifunctional catalysis is achieved, with the urea providing cooperative hydrogen bonding, and the alkaloid giving chiral induction. With yields and ees up to 99% in dichloromethane (DCM) solvent, the mild air- and moisture-tolerant method opens up a convenient route to jV-Boc-amino acids. 

The use of bifunctional thiourea-substituted cinchona alkaloid derivatives has continued to gamer interest, with the Deng laboratory reporting the use of a 6 -thiourea-substituted cinchona derivative for both the Mannich reactions of malo-nates with imines [136] and the Friedel-Crafts reactions of imines with indoles [137]. In both reports, a catalyst loading of 10-20 mol% provided the desired products in almost uniformly high yields and high enantioselectivities. Thiourea-substituted cinchona derivatives have also been used for the enantioselective aza-Henry reactions of aldimines [138] and the enantioselective Henry reactions of nitromethane with aromatic aldehydes [139]. 

Catalytic enantioselective Mannich reactions provide one of the most versatile approaches for the synthesis of optically active chiral amines. Recently, several organocatalytic protocols have been developed using the parent cinchona alkaloids or their derivatives. 

In 2005, Schaus and coworkers found that the natural cinchona alkaloids such as cinchonine (CN) or cinchonidine (CD) themselves can serve as highly enantioselective catalysts (10mol%) for the Mannich reaction of P-keto esters 57 with the various carbamate-protected aryl imines 58 [25]. Using either CN or CD, both enantiomers of the resulting secondary amine products 59 were obtained in excellent yields (up to 99%) and ee values (up to 96% ee) (Scheme 8.19). The extension of this protocol to encompass the use of the 2-substituted-l,3-dicarbonyl nucleophiles 60... 

Soon after, the groups of Ricci [35] and Schaus [36] also employed a-amidosulfones as stable imine precursors in cinchona-catalyzed Mannich reactions. Ricci and coworkers reported [35] that, under PTC conditions (toluene/aqueous K2C03) using 75 as a catalyst (1 mol%), both the aliphatic and aromatic a-amido p-tolylsulfones 76 reacted with the malonates to afford the Mannich adducts 77 with high levels of enantioselectivity (85-99% ee) (Scheme 8.25). The subsequent decarboxylation/ transesterification of 77 gave the corresponding [3-amino acid derivatives without any alternation of the optical purities. The chiral dihydropyrimidones 80 were also successfully synthesized by Schaus and coworkers via the cinchonine catalyzed... 

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Beside the cross aldol reaction, the Mannich reaction, too, has been the object of successful efforts using organocatalysis. The use of small organic molecules such as proline, cyclohexane diamine and Cinchona alkaloid-derived catalysts has proven extraordinarily useful for the development of asymmetric Mannich reactions in traditional polar solvents such as DMSO, DMP, DMF, etc. However, very few studies have been conducted so far in non-conventional solvents. 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

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

In the previons section, secondary chiral amines were employed that give rise to enamine formation npon reaction with ketones or aldehydes. Chiral tertiary amines, unable to form enamines, are nevertheless capable of inducing enantioselectivity in case substrates are used that contain sufficiently acidic protons such as aldehydes, ketones or active methylene compounds [33]. The cinchona alkaloids, by far the most versatile source of Brpnsted base catalysts, have played a prominent role in various types of asymmetric organocatalytic reactions [34], which is also true for the Mannich reaction. 

Schans and co-workers envisioned the apphcation of cinchona alkaloids 47a-d as chiral Brpnsted base catalysts in the asymmetric Mannich reaction of acetoacetates 45 with iV-acylimines 23a, 46a-c (Schane 5.25) [35]. Promising results were reported when the chiral base cinchonine (47a) was employed, while the cinchona alkaloid quinine (47b) gave considerably lower selectivities. Opposite selectivities were observed when the pseudo-ematiamers cinchoitidine (47c) and qniitidine (47d) were used. 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

Mannich Reactions with Cinchona-derived PTC Catalysts... 

Nucleophilic addition to the C=N bond of imine derivatives is quite important in organic chemistry for the synthesis of functionalised amines and related nitrogen-containing compounds. This section introduces an enan-tioselective Mannich reaction, including an aza-Henry reaction that uses nitroalkanes as a nucleophile, via PTC catalysis in the presence of Cinchona-derived quaternary ammonium salts. 

More recently, Pihko introduced bifunctional tertiary amine-thioureas 26 and 27 for the Mannich reaction of Boc-imines with malonates. ° Dimethylamino-tertiary amine thiourea 26 proved ideal for aliphatic imines, while the Cinchona derivative 27 provided the best results for aromatic substrates. Catalyst loadings as low as 1 mol% could be employed providing the products in high yields and excellent enantioselec-tivities (Scheme 19.34). Notably, both catalysts presented cooperative assistance via intermolecular hydrogen bonding, as first shown by Smith in 2009. ... 

The enantioselective vinylogous Mannich reaction of siloxyfurans with ketimines catalyzed by a cinchona alkaloid amide/Cu(OAc)2 combination afforded furan-2(5fJ)-one containing contiguous tetra- and trisubstituted stereocenters with high selectivity (13AGE5557). 

On the other hand, Zhao s group achieved remarkable results with bifunctional cinchona alkaloid and thiourea catalysts [35], which, over the years, have been broadly employed as catalysts in Mannich reaction. Indeed, as Brpnsted bases, the preferred bifunctional catalyst 46 can lead to the Mannich three-component product 47 with extranely high diastereo- and... 

A second method to achieve the synthesis of the enantioenriched dihy-dropyrimidone core of SNAP-7941 was based on the cinchona alkaloid-catalysed Mannich reaction of p-keto esters with acylimines. Therefore, the reaction of a p-keto ester with an a-amido sulfone performed in the presence of cinchonine produced the Mannich product as a mixture of two diastereomers in an excellent yield (Scheme 3.20). This diastereomeric mixture was transformed in high yield into a key intermediate of the synthesis of SNAP-7941, showing a good enantioselectivity. This compound was finally converted into desired SNAP-7941, which is an inhibitor of MCHl-R in a G protein-coupled receptor. 

Another cinchona alkaloid-catalysed Mannich reaction was reported by Barbas et al, occurring between a thioester and an a-amido sulfone, leading in the presence of KOH to the unti-Mannich product in 79% yield, with both moderate diastereo- and enantioselectivity of 64% de and 45% ee, respectively. Finally, Akiyama et al. have developed a new method for the enantioselec-tive synthesis of y-butenolide derivatives, which involved the vinylogous Mannich-type reaction catalysed by a novel chiral phosphoric acid bearing iodine groups at the 6,6 -positions. Aliphatic as well as aromatic aldimines... 

Later, an enantioselective one-pot tandem Mannich-hydroamination reaction was reported by Liu and co-workers on the basis of a sequential organo- and gold catalysis.The proeess involved propargylated malonitrile and oxindole imine derivatives as substrates and employed a chiral cinchona alkaloid, such as a quinidine phenol derivative, to induce the enantioselective Mannich reaction and a gold catalyst, such as XPhosAuNTfa... 

SCHEME 11.20 Cinchona alkaloids as catalysts in the asymmetric Mannich reaction. 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

SCHEME 11.21 Bifunctional cinchona aUcaloid/thiourea-catalyzed asymmetric Mannich reaction. 

Cinchona alkaloids with a thiourea group have also been applied for the asymmetric preparation of amino acid derivatives. Recent examples include an asymmetric Mannich reaction leading to P-amino ester derivatives with a benzoxazole moiety [77] and the formation of P-amino esters with a benzothiazole group [78]. The latter reaction was catalyzed efficiently by a C9 thiourea derivative (26) with a 2,6-dichloro-4-(trifluoromethyl)phenyl group connected to the thiourea group as shown in Scheme 6.34. 

Very recently. Song, Yang, and coworkers described a domino Mannich reaction catalyzed by a chiral thiourea derivative of a cinchona alkaloid (111 in Figure 42.5). They showed how amino-benzoxazoles 128 are viable amine components for the imine formation with aldehydes 127 in three-component Mannich reactions (Scheme 42.28) [70]. 

Mannich Reaction Carbamate-protected alkyl imines are important building blocks in the synthesis of chiral alkyl amines. However, they are usually unstable, and most of them cannot be prepared in pure form. As the optimal substitutes, a-amido sulfones 142 were first used in the PTC-catalyzed enantioselective aza-Henry reaction in 2005 [57]. Subsequently, Song et al. reported a chiral Cinchona alkaloid thiourea (130b)-catalyzed Mannich reaction with in situ generation of... 

Zhang HL, Syed S, Barbas CFI. Highly enantio- and diaster-eoselective Mannich reactions of glycine Schiff bases with in situ generated A-Boc-imines catalyzed by a cinchona alkaloid thiourea. Org. Lett. 2010 12(4) 708-711. 

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