Thiourea-mediated reactions

Scheme 4.2 Some pioneering examples of urea- and thiourea-mediated reactions.

There does not seem to be a clear consensus as to the mechanism of PbS formation in these and similar studies. It is often stated that the formation of PbS occurs via decomposition of a Pb-thiourea complex species [4,21,22]. This was often based on the absence of any measurable concentration of sulphide on alkaline hydrolysis of thiourea. However, as discussed in Section 3.3.3.1, this is not a valid criterion for the absence of a sulphide-mediated reaction. Even today, it cannot be stated categorically which mechanism is operative or even dominant. 

Scheme 19.71 Secondary amine-thiourea mediated Mannich addition reactions of ketones and aldehydes to preformed or in situ generated imines.

Heck Reactions. The Heck reaction is a Pd-catalyzed olefi-nation usually performed between an aryl halide or triflate and an acrylate ester. While phosphines are traditionally used as ancillary ligands, new Pd(dba)2-mediated reactions have been performed with a variety of other ligand types. These include chelating Wheterocyclic carbene/phosphine ligands, benzimidazoles, and quinolinyl oxazolines. Air stable catalysts have been prepared from Pd(dba)2 and sterically hindered thiourea ligands (eq 24). An effective immobilized catalyst has been prepared from Pd(dba)2 and a dendritic phosphine-containing polymer. ... 

The formation of N-acyUminium ions by a thiourea-mediated catalytic reaction was investigated with P-indolyl ethyl hydroxylactams. The generation of the N-acyltmrriinium in the presence of an indole can be successfully used in a Pictet-Spengler-type cycUzation of such compounds, affording highly enantioenriched indoUzidinones and quinoUzidinones (Scheme 26.14) [88]. 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

Sodium alkoxide-mediated reaction of 2,2-disubstituted [2- C]malonates with urea and thiourea produces (Figure 6.121), respectively, 5,5-disubstituted (lH,3H,5H)-[5- C]pyri-midine-2,4,6-triones 406 (or 5,5-disubstituted [5- " C]barbiturates) and the corresponding 2-thioxo-(l//,5fl)-[5- " C]pyrimidine-4,6-diones 407. some of which have been widely... 

A general and efficient solid-phase synthesis of A-9-substituted 2,8-diamino purines 62 has been described. The key synthetic transformation uses a carbodiimide-mediated cyclization of a thiourea 60. The reaction was performed using microwave reaction conditions on solid phase <06TL8897>. 

In Ught of the recent developments in thiourea, diol, and phosphoric-acid-mediated catalysis, far fewer studies have focused on the use of chiral carboxyhc acids as suitable hydrogen bond donors. To this end, Mamoka synthesized binaphthyl-derived dicarboxylic acid 49 which catalyzes the asymmetric Mannich reaction of N-Boc aryl imines and tert-diazoacetate (Scheme 5.65) [120]. The authors postulate that catalytic achvity is enhanced by the presence of an addihonal car-boxyhc acid moiety given that use of 2-napthoic acid as catalyst provided only trace amounts of product... 

Continuing the theme of small molecules as catalysts for organic reactions, Eric Jacobsen of Harvard has reported (J. Am. Chem. Soc. 2004,126, 10558) the design of a peptide thiourea that mediates enantioselective Pictet-Spengler cyclization, e.g. of 1 to 2. 

Chloro-l-methylpyridinium iodide (683) functions as an important mediator in a variety of different reactions. Esters are formed in high yield from acids and alcohols when reacted with one equivalent of (683) in the presence of two equivalents of triethylamine (Scheme 158) (75CL1045). cv-Hydroxy acids are lactonized under similar conditions (76CL49). The pyridinium salt (683) will also convert thioureas into carbodiimides (77CL575) and pyridine-2-thiones to pyridyl sulfides (75CL1159). 

A series of A - / - n i trobe nzenesul fony 1 imincs have been reported to undergo asymmetric aza-Morita-Baylis-Hillman reactions with methyl acrylate mediated by DABCO in the presence of chiral thiourea organocatalysts with unprecedented levels of enantioselectivity (87-99% ee), albeit only in modest yields (25 19%). Isolation of a DABCO-acrylate-imine adduct as a key intermediate, kinetic investigation, and isotopic labelling, have been employed to determine the mechanism.177... 

Alkynes continue to be used as a reactive functionality in quinoline synthesis. The readily available thiocarba-mates, thioamides, and thioureas allow intramolecular cyclization of pendant alkynes to give modest to good yields of the quinolines (Equation 118) <20030L1765>. An intermolecular reaction involving a zinc-mediated alkynylation-cyclization provides an efficient route to 4-trifluoromethyl-substituted quinolines (Equation 119) <2002JOC9449>. 

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 5.8 Chiral bis-thiourea and DMAP-mediated MBH reaction of cyclohexenone and aldehydes.

Table 5.15 Chiral thioureas 114 and DABCO-mediated aza-MBH reaction.

Acetylcholineesterase and choline oxidase Au foil was treated with cystamine to produce a base layer of ami-nothiolate units, was derivatized by reaction of the amino group and disodium-4,4 -diisothiocyanato-trans-stilbene-2,2 -disulfonate. Enzymes were immobilized at the isothiocyanate group via thiourea link. The bifunctional sensor for ACh was prepared by stepwise immobilization of four layers of the enzyme ChO and three layers of AChE. Choline generated was detected amperometircally with the use of 2,6-dichloro-phenolindophenol as a mediator in solution. Electrical communication between the enzyme and the electrode is achieved either by the use of ferrocenecar-boxylic acid as mediator in the assay buffer or by immobilization of [(ferrocenyl methyl)amino] hexa-noic acid on the enzyme layer. [92]... 

A new microwave-assisted protocol for the generation of diversely substituted 3,4-dihydropyrimidine-5-carboxylic acid esters 40 has been developed by Kappe and co-workers [88, 89] using trimethylsilyl chloride (TMSCl) as a mediator for the Biginelli MCR. This involved the reaction of S-ethyl acetothioacetate or ethyl acetoacetate, an aromatic aldehyde and (monosubstituted) urea or thiourea as building blocks. Also sterically hindered aromatic and heterocyclic aldehydes... 

Thioamides and thioureas also undergo the silyl-mediated cascade reaction. For example, compound 503 gave 504 in 67% yield, while structural variants generally afforded related cyclized products in 50-87% yield. Thiourea 505 provided 506 in 64% yield, although a related substrate whose alkyne tether was conformationally more flexible failed to produce any cyclized product. 

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