Open-chain ureas

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

In the currently accepted mechanistic pathway outlined in Scheme 7, the key step in the Biginelli sequence involves the acid-catalyzed formation of an Wacyliminium ion intermediate of type 719 from the aldehyde and urea precursors <1997JOC7201, 2000ACR879, 20040R1>. Interception of the iminium ion 719 by the CH-acidic carbonyl component 715, presumably through its enol tautomer, produces an open-chain ureide 720, which subsequently cyclizes to hexahydropyrimidine 721. Acid-catalyzed elimination of water from 721 ultimately leads to the... 

Z-Pyrans are transformed to the corresponding 7t-isoelectronic 1,4-dihy-dropyridine derivatives by ammonia,2,37,68,69 ammonium acetate,76,440,841 primary amines,37,62,68,442 hydroxylamine,37 arylhydrazines,3,3,3 urea,440 and thiourea.440 The open-chain intermediates are rarely isolated.62... 

Open chain esters, amides and alkyl-ureas may also be bitter (Table XIX). The c- bi-values depend on the hydrophobicity of the side chains. Primary, secondary and tertiary amines are bitter (Table XX). The c-tbi-values of compounds with equal side chains decrease in the same order. But with the i-butyl-residue, c j reaches a minimum with the secondary amine. Possibly there are problems with three somewhat bulky residues at the receptor site, ctbi increases with hydrophilic substituents in the side chain, as is shown with the ethyl and hydroxy-ethyl compounds. 

The first step in the mechanism of the Biginelli reaction is the acid-catalyzed condensation of the urea with the aldehyde affording an aminal, which dehydrates to an A/-acyliminium ion intermediate. Subsequently, the end form of the 3-keto ester attacks the A/-acyliminium ion to generate an open chain ureide, which readily cyclizes to a hexahydropyrimidine derivative. 

Hexobarbital is prepared by reacting together methyl urea and methyl-a-methyl-a-cyclo-hexen-1-yl-a-cyano acetate when an open-chain ureide is formed as an intermediate with the elimination of a molecule of methanol. This upon hydrolysis affords spontaneous closure of the ring thereby resulting into the formation of hexobarbital. 

It is prepared by the interaction of urea with methyl-2-ethyl-a-cyclo-hexene-l-yl-a-cyano acetate in the presence of sodium ethoxide when a molecule of methanol is eliminated with the formation of an open-chain ureido which upon hydrolysis results into spontaneous ring closure and gives rise to cyclobarbital. 

Dimethyl urea is prepared by the interaetion of urea and methylamine, whieh upon treatment with eyanoaeetie aeid yields an open-chain nitrite with the elimination of a molecule of water. This resulting compoimd undergoes cyclization in the presence of alkali. The cyclized compound on treatment with nitrous acid, followed by reduction, reaction with formic acid and subsequently with alkali gives rise to the formation of theophylline, which upon methylation finally yields caffeine. 

Unlike the classical Biginelli reaction, which only tolerates open-chain jS-keto esters, cyclic j5-diketones can also participate in a related MGR [66], This procedure requires Meldrum s acid 29a (X = O and Z = CMc2) or barbituric acid derivatives 29b (X = NH or NMe and Z = GO), urea, and aldehydes (Scheme 17.21). The mixture was irradiated in a domestic MW oven for 4 min under solvent-free conditions. The reaction requires a Bronstedt acid as catalyst to give, selectively, a family of novel heterobicyclic compounds 30 in good yields (70-83%). 

Other components of the design [138—142] include the choice of the crown size or even the use of open-chain metalloclefts, not necessarily polyether armed. The issue of special importance for extraction and transport applications is the selection of substituents ensuring a necessary lipo-philicity-solubility balance. For example, use of a cyclohexano moiety as shown above, instead of the more common o-phenylene bridge between nitrogens, enhances solubility in the membrane phase. The modification of the polyether chain with binaphthyl or calixarene substituents provides high membrane transport rates due to increased ionophore lipophilicity [138,142]. Some representative examples (initial fluxes, in 10 mol cm h , through o-nitrophenyloctyl ether-impregnated Accurel membrane 1 M source urea [138]) are as follows. 

The modified Gabriel reagent (168) has been shown to have considerable potential for the synthesis of iV-Boc-a-amino-acids, by condensation with a-bromo-esters followed by hydrolysis and decarboxylation (Scheme 38) yields are high throughout.A new route to a-amino-acids is by aminoalkylation of olefins by open-chain adducts of glyoxylic acid and amides, carbamates, and ureas. ... 

Synthesis.—Very few examples of the synthesis of thioureas by thionation of the corresponding ureas using phosphorus pentasulphide, especially in the case of open-chain thioureas, were known prior to the period covered by this review. Voss found it expedient to subject this reaction to a... 

This mechanism now appears to receive little support since most subsequent investigations indicate that open-chain structures and not cyclic structures are present in the early stages of the urea-formaldehyde reaction. 

In the mechanism of the Biginelli synthesis [265], the rate-determining step is the acid-catalyzed formation of an acylimine 35 from aldehyde and urea. By N-protonation (or metal-N-coordination), the imine 35 is activated (as an iminium ion) and intercepted by the P-ketoester (as enol or metal enolate) to give rise to an open-chain ureide 36, which subsequently cyclizes (via the cyclic ureide 37 and its dehydration) to afford the dihydropyrimidinone 33. Biginelli compounds of type 33 have been synthesized independently in multistep sequences [266]. 

Discovery by Bengen (7) that urea forms addition compounds with the aliphatic straight-chain hydrocarbons has opened new possibilities for the removal and separation from petroleum of such materials as waxes which are preponderantly nonbranched. Urea-wax addition compounds are apparently formed readily at ordinary room temperatures, and as these compounds have very definitely defined crystal structure (75), their separation should be easily accomplished. 

Figure 16-25 The active site of urease showing the two Ni+ ions held by histidine side chains and bridged by a carbamylated lysine (K217 ). Abound urea molecule is shown in green. It has been placed in an open coordination position on one nickel and is shown being attacked for hydrolytic cleavage by a hydroxyl group bound to the other nickel. Based on a structure by Jabri et al.i36 and drawing by Lippard.437...

Marine lipids with their diversity of unsaturated and branched chain acid moieties are a difficult class of materials to analyze. Ruminants (sheep, goats, cows, etc.) have a bacterial "factory" in the rumen which is able to produce branched-chain partially-hydrogenated lipids from ingested plant lipids. These lipids are incorporated into the milk and meat of the animals and eventually into animals which feed upon the ruminants. As a rule animal lipids are highly complex in comparison to plant materials. Although the branched chain materials are usually present in low concentration when compared to the common fatty acid moieties, complete description of these fats requires more sophisticated GC and thus long open tubular columns in tandem with mass spectrometry and computer analysis of the data has become an important approach. Even with a 100-m column, subcutaneous lipids of barley-fed lambs were so complex that prior fractionation with urea adducts was necessary (17). 

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