Amine thiourea derivatives

One of the most commonly used class of derivatization agents for diasteromer formation are isothiocyanates and isocyanates. Enantiomers of /3-blockers, amphetamine, epinephrine, methamphetamine, and mexiletine have been resolved after derivatization with these agents. Isothiocyanates produce thiourea derivatives upon reaction with primary and secondary amines. Thiourea derivatives also provide a strong UV absorbance for the detection of enantiomers lacking a strong UV chromophore. Isocyanates produce ureas when reacted with amines. The physical properties of these ureas are similar to thiourea derivatives. Isocyanates will also react with alcohols to yield carbamates. 

The roles of the catalytic functions are not necessarily opposite or limited to Lewis acid/base pairs. For example, amine thiourea derivatives like Takemoto s catalyst 4 merge the hydrogen bond donor capability of the thiourea moiety with Bronsted base functionality of the amine function and revealed itself particularly efficient organocatalysts for Michael reactions of various 1,3-dicarbonyl compounds with nitroolefins (Scheme 3) [17-19]. 

Some bifunctional hydrogen-bond donor/Brpnsted base catalysts are shown in Figures 2.39 and 2.40. They comprise chiral amino alcohols and amino phenols, chiral amine-thiourea derivatives, and chiral guanidines, among others. In the absence of detailed experimental NMR or kinetic studies [179], most of our... 

Miao, Chen, and coworkers have reported an efficient enantioselective Biginelli reaction catalyzed by a chiral bifunctional primary amine-thiourea derivative 43 with a carbohydrate in the catalyst skeleton and using an external Brpnsted acid in a cooperative way, with t-BuNH TFA as additive (Scheme 9.15) [54]. This protocol renders a wide range of optically active DHPMs 44 in high yields and with good to excellent enantioselectivities (up to 99% ee). 

Scheme 1.17 Michael additions of malonates to a,P-unsaturated enones catalysed by a primary amine thiourea derived from epiquinine.

Chiral amines and diamines are readily available substrates for the synthesis of ligands for transition metal-catalysed reactions since they can easily be transformed into chiral ureas and thioureas. Therefore, several groups have prepared chiral symmetrical ureas and thioureas, dissymmetrical ureas and thioureas, amino-urea and thiourea derivatives. Finally polyureas and non-soluble polythioureas were also prepared and tested as ligands for asymmetric catalysis. 

Diamines can also react with only one equivalent of isothiocyanate to form bi-functionnal amine-thiourea ligands 59-68% yields obtained for several alkyl isothiocyanates. However, reaction of phenyhsocyanate with 1,2-diamines could also lead to the formation of the guanidine derivative by cyclisation and elimination of H2S (Scheme 4) [42,43]. 

Moreau and co-workers have also prepared (ll ,2K)-l,2-diaminocyclo-hexane amino-urea and thiourea derivatives [43]. Diphenylethylenediamine-substituted monothioureas are more stable than the cyclohexyldiamine counterpart, but they can also rearrange to guanidine derivatives, especially at high temperature or in the presence of metal [43]. Under the same conditions, thioureas also rearrange to guanidines in the presence of amines. Selective formation of substituted guanidines from thiourea derivatives of diaminocy-clohexane or diphenylethylenediamine were also reported in a recent paper from Ishikawa [44]. 

Reaction of isothiocyanate with amine gives the corresponding thioureas. Many reports are appeared.102 111 The thiourea derivatives have been prepared by reactions of isothiocyanates with arylamines (Scheme 39) and reacted with some substrates to afford heterocyclic compounds, such as 2-amino-4//-ben-zothiazine, 1,3-thiazine, 1,3-thiazinone and l,3-thiazolidin-4-one.112 115... 

Cyclic thiourea derivatives having three different types of cyclophane structure (ortho-meta, meta-meta and meta-para) and a lariat-type thiourea have been synthesized, using reaction of isothiocyanate with amine.230 Cyclic thioureas have been obtained from formaldehyde aminals and sulfur (Sg) (Scheme 77).231... 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

The Takemoto group synthesized a series ofdiaminocyclohexane-based thiourea derivatives (e.g., 12, 40, 57, and 58) for catalysis of the Michael addition [149-152] ofmalonates to trons-j3-nitrostyrenes (Figure 6.18) [129, 207]. In the model, Michael addition of diethyl malonate to trons-]3-nitrostyrene at room temperature and in toluene as the solvent tertiary amine-functionalized thiourea 12 (10mol% loading) was identified to be the most efficient catalyst in terms of catalytic activity (86%... 

Figure 6.18 Chiral amine 56 and thiourea derivatives (10mol% loading) screened in the asymmetric Michael addition of diethyl malonate to trcms-P-nitrostyrene in toluene.

Figure 6.30 Secondary amine- and primary amine-functionalized biflinctional thiourea derivatives (15mol% loading) screened in the model Michael addition of acetone to tram-P-nitrostyrene in toluene at rt.

The Jacobsen group independently focussed on the development of primary amine-functionalized thiourea derivatives and published, in 2006, the thioureas 100-103 incorporating the established tert-leucine (amide) motif (Figure 6.14) and the diaminocyclohexane or diphenylethylenediamine chiral backbone, respectively (Figure 6.31) [262]. The catalyst screening was carried out in the asymmetric Michael addition [149-152] of 2-phenylpropionaldehyde, an a,a-disubstituted aldehyde, to 1-nitrohex-l-ene (at 20mol% loading, DCM, rt, variable equiv. of H2O)... 

The same group reported primary amine-fimctionahzed diphenylethylene-thiourea derivatives 104 and 105 to catalyze the enantioselective and diastereose-... 

Figure 6.49 Binaphthyl-derived tertiary amine-functionalized bifunctional thiourea derivatives screened in the MBH reaction between 2-cyclohexen-l-one and 3-phenylpropionaldehyde at rt in dichloromethane.

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