Organocatalysts bifunctional amine-thiourea organocatalyst

A number of BINOL-based bifunctional organocatalysts, for example (7.171-7.173), containing both Bronsted acidic and Lewis basic sites have been used to good effect in the asymmetric MBH reaction. The amine-thiourea (7.171) promotes the MBH reaction of aliphatic aldehydes with 2-cyclohexenone with ees ranging from 80 to 94% while both the (pyridinylaminomethyl)BINOL (7.172) and phosphine (7.173) catalyse the aza-Bayhs-Hilhnan reaction of simple a,p-carbonyls such as MVK and phenyl acrylate with N-tosyl arylaldmines with similar levels of enantioselectivity. 

In 2005, Wang and coworkers reported a new bifunctional binaphthyl-derived amine thiourea 16 as an efficient organocatalyst for the Morita-Baylis-Hillman reaction of cyclohexenone with aliphatic, aromatic and sterically hindered aldehydes. The design of the catalyst follows Takemoto s design of a bifunctional motif. This catalytic protocol provided access to useful chiral allylic alcohol building blocks in high yields and high enan-tioselectivities (Scheme 19.21). 

The first primary amine-thioureas as effective bifunctional organocatalysts were reported in 2006. Tsogoeva and Wei synthesised a thiourea based on (l5,25)-diphenylethylene-l,2-diamine and a chiral arylethyl moiety, for the Michael reaction between aliphatic ketones and aromatic nitro-olefins (Scheme 19.36). Utilising catalyst 29 (15 mol%) and acetone as the Michael donor, the Michael products were obtained in high yields (84-99%) and enantioselectivities (90-91% enantiomeric excess). When cyclohexanone 31 was employed, product 33 was obtained in high yields (82 and 89%, respectively), good diastereoselectivity (up to 83 17 symanti) and excellent enantioselectivity (96 and 98% enantiomeric excess, respectively). 

For a recent NMR study on the active conformation and the aggregation state of an amine-thiourea bifunctional organocatalyst, see G. Tarkanyi, P. Kiraly, T. Soos, S. Varga, Chem. Eur. J. 2012, 18, 1918. 

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

In addition, various chiral amine-thioureas have been successfully applied to promote asymmetric Mannich reactions. As an example, Takemoto and Miyabe have employed a chiral bifunctional organocatalyst possessing a thiourea moiety and a tertiary amino group as catalyst of the Mannich reaction between ethyl malonate and A-Boc arylimines, which provided the corresponding products in excellent yields and enantioselectivities (93-98% ee), as shown in Scheme S.lb. The degree of enantioselectivity was shown to be dependent on the reaction temperature, with the best results obtained at low temperature. 

Takemoto et al. were the first to report that bifunctional organocatalysts of the thiourea-tert-amine type efficiently promote certain Michael reactions, for example, the addition of 5-dicarbonyl compounds to nitro olefins [29-31]. 

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...

Fig. 3.10 Thiourea-based organocatalysts. a-c Chemical structure of the bifunctional thiourea-tertiary amine catalyst, bis(3,5-trifluoromethyl)phenyl cyclohexylthiourea (thiourea), and N,N-dimethylcyclohexylamine (Moditied from Dove et til. [42]). d Proposed dual activation pathway of lactide ROP [41] (Adapted with permission from Pratt et al. [41]. Copyright 2013 American Chemictil Society)...

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

Thioureas (and less often ureas) as organocatalysts were introduced into synthetic practice by Jacobsen and Schreiner. Further development included the design of bifunctional catalysts combining two thiourea subunits or a thiourea group and chiral amines. ... 

Nitrocyclopropanation of a,p-unsaturated ketones 16usingbromonitromethaneas an ambiphilic substrate in the presence of organocatalysts E-I allows the preparation of several interesting trisubstituted cyclopropanes 17 in high levels of both diastereo and enantioselectivities. A general scheme compiling selected recent achievements on this purpose is depicted in Scheme 5.7. Chiral primary [25] and secondary [26, 27] amines as well as thiourea [28] and squaramide [29] derivatives E-I (all of them as bifunctional catalysts) were capable of catalyzing the transformation. 

The majority of the organocatalysts that are commonly employed are chiral Lewis or Brpnsted bases, and the catalytic potential of base functionalities has been referred to in previous chapters to some extent already. As discussed before, the use of chiral primary or secondary amines for enamine or iminium activation belongs to the most important applications of asymmetric organocatalysts nowadays. In addition, also the interplay between an acidic (thio)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such bifunctional thiourea-containing acid-base catalysts, chiral catalysts containing a (Lewis or... 

Like the reactions discussed in Section 28.5.1.2, a highly enantioselective aza-nitroaldol reaction of imines (173) with nitroalkanes (157) is achieved by use of guanidinium-thiourea bifunctional organocatalyst 204 in the presence of external base such as CSCO3 under phase-transfer conditions. Both catalytic activity and enantioselectivity depend upon the substituents on the guanidinium group. The mono-substituted catalyst 190 gives poor results (yield 89%, 9% ee), whereas cyclic amine-substituted catalyst 204 provides excellent enantiomeric excess (Scheme 28.25) [104]. 

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