Amine thiourea reaction

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]. 

With ketone donors, both syn and anti selective reactions are possible. Typically, a,p-unsaturated nitro compounds are used as acceptors. The majority of these reactions are syn selective (Scheme 28) [94, 269, 271, 278, 279, 288-309]. This is a result of favored formation of the (fj-configured enamine and favorable electrostatic interactions between the nitro group and the enamine (Scheme 29) [290, 291, 310]. Of the known anti selective reactions, primary amine-thiourea catalysts such as 158 appear to perform best (Scheme 28) [271, 299, 301]. 

Apart from the increased catalytic efficiency, this structure design produced two positive side effects. In contrast to monofunctional (thio)ureas, which exhibit low solubility in nonpolar solvents due to intermolecular hydrogen-bonding association, tertiary amine thioureas of type 12 revealed intramolecular hydrogen bonding between the amine group and the amide protons making these (thio)ureas soluble in nonpolar reaction media such as toluene. The analysis of the X-ray crystal-... 

Scheme 6.154 Proposed catalytic cycle for the binaphthyl amine thiourea-promoted MBH reaction of aldehydes with 2-cyclohexen-l-one revealing the bifunctional mode of action of catalyst 148, 149, and 150.

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

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. 

Cyclohexanediamine-derived amine thiourea 70, which provided high enantio-selectivities for the Michael addition [77] and aza-Henry reactions [78], showed poor activity in the MBH reaction. This fact is not surprising when one considers that a chiral urea catalyst functions by fundamentally different stereoinduction mechanisms in the MBH reaction, and in the activation of related imine substrates in Mannich or Streclcer reactions [80]. In contrast, the binaph-thylamine thiourea 71 mediated the addition of dihydrocinnamaldehyde 74 to cyclohexenone 75 in high yield (83%) and enantioselectivity (71% ee) (Table 5.6, entry 2) [79]. The more bulky diethyl analogue 72 displayed similar enantioselectivity (73% ee) while affording a lower yield (56%, entry 3). Catalyst 73 showed only low catalytic activity in the MBH reaction (18%, entry 4). 

Table 5.6 The chiral tertiary amine/thiourea-catalyzed MBH reaction of dihydrocinnamaldehyde with cyclohexenone.

Table 5.7 Bifunctional tertiary amine/thiourea catalyst in MBH reaction of cyclohexenone and selected aldehydes.

Figure 10 Schematic representation of the most common reactions for labeling an amine (a) reaction with isothiocyanate to give a thiourea (b) reaction with a Succinimidil ester to give an amide (c) reaction with a sulfonyl chloride to give a sulfonamide (d) reaction with an aldehyde to give an imine (Schiff s base) and (e) reaction with a carbodiimide-activated carboxylic acid to give an amide.

Japanese workers have developed a new synthesis of ureas and thioureas through the reaction of carbon dioxide or carbon disulphide with diphenyl phosphite and primary amines. The reaction is thought to take place via an intermediate (85), followed by elimination to give isocyanate or direct displacement by amine. The principles of this new synthesis have also been applied to the preparation of peptides and amino-acid esters. 

It appears also that, for the synthesis of large libraries, there are few reactions that fulfil these prerequisites. Among the reactions that proved to have wide applicability, amide bond formations and peptide-like protecting group strategies can be found. In a general way all amine functionalization reactions are usually effective and lead to stable structures (i.e. sulfonamide, carbamate, urea, thiourea formation, reductive amination and nucleophilic substitution). Moreover, for any of these reactions the suitable linker can be easily selected from various literature sources. 

Mannose can interact specifically with macrophages and dendritic cells via surface mannose receptors involved in endocytosis and phagocytosis [61]. A mannose moiety can be introduced onto chitosan or chitosan-g-polyethyleneimine (PEI) molecules by a thiourea reaction between the isothiocyanate group and the amine groups (Eig. 6) [62, 63]. The mannose-bearing polymers show enhanced macrophage-specific bioactivity both as a vaccine and as a gene delivery system. 

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. 

Scheme 2.9 Enantioselective Michael reactions of ketones with nitrost5renes catalyzed by primary amine-thiourea catalysts.

On the other hand, several primary amines have also been successfully employed as catalysts in the reaction using aldehydes as Michael donors. Important representative examples are shown in Figure 2.7, like bifunctional sulfamide 36 and primary amine-thioureas 37a and 23b,the latter being developed by Jacobsen and very similar to that used by the same group in the reaction with ketones as donors (see Scheme 2.7) and which performs exceptionally well in the Michael reaction of a,a-disubstituted aldehydes to both aromatic and aliphatic nitroolefins. 

There is an interesting variant of this reaction which involves the use of tert-butyldimethylsilyloxyacetaldehyde as Michael donors and chiral primary amine thiourea bifunctional catalyst 37b (Scheme 2.13). In this case, the diastereoselectivity of the reaction changed from the usually observed syn relative stereochemistry at the final Michael adduct to the formation of the anti diastereoisomer as the major product. This change in diastereoselectivity was explained in terms of the generation of a Z-enamine intermediate assisted by the formation of an intramolecular hydrogen bond between the secondary... 

Another example of organocatalytic AFC alkylation reaction with p,y-unsaturated a-keto esters was reported by Wang and co-workers in 2012. In the presence of 10 mol% rosin-derived tertiary amine-thiourea 96, a variety of p,y-unsaturated a-keto esters reacted with 1-naphthol smoothly to afford the modified chromanes 97 in good yields (79-86%) with up to 96% ee (Scheme 6.39). Again, the hydrogen bonding between substrates and catalyst was proposed to be a key element for the enantioselective control. 

Scheme 6.39 Rosin-derived tertiary amine-thiourea 96 catalyzed AFC reaction of P,y-unsaturated a-keto esters with 1-naphthol reported hy Wang.

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]. 

A highly enantioselective conjugate addition of nitromethane and nitroethane to acyclic enones has been recently achieved using chiral cyclohexanediamine-derived primary amine thiourea 48 (Scheme 2.57) [168], With respect to the electrophile, the reaction shows a broad substrate scope and not only 1-aryl- but also 1-alkyl enones afford the corresponding chiral y-nitroketones with good yields and excellent enantioselectivities (92-99% ee). 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

Recently, the formation of Mannich products via reaction of lactones with a variety of Al-Boc-aldimines, catalyzed by the bifunctional rosin-derived amine thiourea eatalyst 66, was reported by the Wang group (Scheme 5.32) [43]. The formation of... 

Tsogoeva et al. described the use of the primary amine thiourea-based organocatalyst 73 in an asymmetric Mannich-type reaction of unmodified aldehydes and ketones 7 with readily available and stable a-hydrazonoesters 74 (Scheme 5.35) [46]. Moderate to good yields and excellent enantioselectivities (90-99% ee) were reported. However, the anti-diastereoselectivity appeared generally poor (8-72% de). 

In the domino Michael/alkylation reaction applied to the synthesis of 3-(2H)-furanones, the ethyl 4-bromoacetoacetate 203 and nitrostyrene 204 were first trialed with a range of catalysts. In this instance, the so-called modified Feist Binary reaction was completed with an I-threonine bifunctional tertiary amine/thiourea catalyst 205 to produce the furanone 206 in excellent yield and high enantioselec-tivity (Scheme 7.42) [107]. In another report, the furan ring as part of other bicyclic or tricyclic systems was also prepared through an enantioselective Michael addi-tion/nucleophilic substitution reaction (Scheme 7.43) [108]. When diketones and ( )-P,P-bromonitrostyrenes 207 were stirred, again with a bifunctional thiourea... 

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