Ureas cyclocondensation

Aminoquinoline and ethyl /3-aminocrotonate at 180-190°C for 6 h yielded N,N -di(2-quinolyl)urea. Cyclocondensation of 2-chloroquinoline... 

Substantial MW rate enhancements have been reported in the Biginelli synthesis of dihydropyrimidines [50, 51] under homogeneous conditions. The synthesis involves a one-pot cyclocondensation of a /i-ketoester with an aryl aldehyde and urea or thiourea in the presence of a catalytic amount of HC1 in ethanol solution. An example of this synthesis is shown in Scheme 4.17. 

The Biginelli reaction is a cyclocondensation between ethylacetoacetate, an arylal-dehyde and urea derivatives to obtain dihydropyrimidines. Transfer this reaction to the solid-phase chemistry, allow the preparation of libraries of this kind of products (Scheme 3.18) [288]. 

Starting 5,5-trimethyloxazolidine-2,4-dione (9.8.1) is in turn synthesized by the cyclocondensation of the ester of 2-hydroxyisobntyric acid with urea [26-28]. 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

Appropriately substituted hydroxy amides and ureas can be used instead of diamines. Thus, acid-catalyzed cyclocondensation of iV-carbamoyl prolinols 137 (R1 = H, (CH2)3) (Scheme 27) with aldehydes RCHO (R = Ph, 2-MeOC6H4, 2-naphthyl, etc.) stereoselectively afforded a series of pyrroldine-fused oxadiazepinones 46 (Scheme 5) <1990CPB2627, 1990H(30)287, 1996LA927>. Similar heterocyclization of 4-(2-hydroxyethylthio)-2-azetidinone with acetone dimethyl acetal was used in the synthesis of azetidinone-fused oxathiazepanes of type 33 (X = S) (Figure 4) <1980JA2039>. 

In 1893, the Italian chemist Pietro Biginelli (University of Florence) for the first time reported on the acid-catalyzed cyclocondensation reaction of ethyl acetoacetate 1, benzaldehyde 2, and urea 3 [1], The reaction was carried out by simply heating a mixture of the three components dissolved in ethanol with a catalytic amount of HC1 at reflux temperature. The product of this novel one-pot, three-component synthesis that precipitated on cooling the reaction mixture was identified as 3,4-dihydropyrimidin-2(lH)-one 4 (Scheme 4.1) [2]. This reaction is nowadays referred to as the Biginelli reaction , Biginelli condensation or as the Biginelli dihydropyrimidine synthesis . 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

Cyclocondensation of alkyl(aryl)isothiocyanates with 4-aryl-3-arylimino-5-imino-l,2,4-thiadiazolidines (Hector s bases) 126 in the presence of strong bases leads to the formation of the corresponding (l,2,4-thiadiazolidinyl)thio-ureas 127 and heteropentalene stmctures 41 (Scheme 35), for which an isomerization equilibrium with the open form 42 was proposed (see Section 6.03.4.2) <1997IJB399>. 

The reaction of A,iV -bis(trimethylsilyl)ureas with phenylsulfenyl chlorides furnished iV-arylthioureas. The treatment of the latter with various organodichlorophosphines led to the formation of l,3,2-diazaphosphetidin-4-one derivatives (Table 4) <1995ZFA2001>. A similar [3+1] cyclocondensation reaction of iV-arylselenourea with dichloromethyl-and dichlorophenylphosphines has been carried out <1996ZFA1250>. The reaction of chloromethyldichlorophos-phine with A,iV -dimethyl-iV,iV -bis(trimethylsilyl)urea led to the spirocyclic P(lll)-P(v) diphosphorus compound 59 (Scheme 37) <1997ZFA1325>. 

An alternative solution to the workup issue relied on the attachment of CH-acidic compounds 64 to a soluble polymer support (PEG-4000). The approach improved the yields of the dihydropyrimidinones 66 by the use of a 2-fold excess of other components—urea and aldehyde in the microwave-assisted solvent-free cyclocondensation [118]. Another single-step approach towards 4,5-disubstituted pyrimidines was based on cyclocondensation of a variety of aromatic, heterocyclic and aliphatic ketones, formamide and HMDS as the ammonium source [119]. The high temperature (215 °C) required to effect the formation of pyrimidines was secured by microwave dielectric heating in sealed vessels (Scheme 45). 

Bismuth(m) nitrate catalyzes Michael addition of a,/Yunsaturated ketones with amines, thiols, and carbamates, although the promoting role of Bi(N03)3 is not fully understood (Equation (91)).100 The Biginelli cyclocondensation of a mixture of (3-keto esters, aldehydes, and urea is mediated by BiCl3, affording 3,4-dihydropyrimidin-2(lH)-ones (Equation (92)).149 Bi(OCOCF3)3 is an efficient catalyst for the regio- and chemoselective synthesis of /3-enaminones in water.150... 

Formal substitution of the carbonyl group of enaminones by an imino group leads to enamino imines. In the reaction with isocyanates or isothiocyanates they result in urea or thiourea derivatives, which can be transformed to pyrimidines or pyrimidones depending on substitution340 (equation 258). Treatment of similar enaminoimines with hydroxylamine gives regiospecifically isoxazoles by thermal cyclocondensation of the isolated oximes341 (equation 259). 

Trialky I hcxahydro-1,3,6-triazocin-2-ones were prepared by the cyclocondensation of iV,iV, iV -trialkyldiethyl-enetriamines with urea, phosgene, or carbon dioxide. Thus, trimethyldiethylenetriamine was reacted with urea, producing l,3,6-trimethylhexahydro-l,3,6-triazocin-2-one 115 in 80% yield (Equation 16 <1995EPP670316>). 

The classic Biginelli reaction features the cyclocondensation of an aldehyde, a urea and an active methylene compound to form dihydropyrimidinones (Fig. 4). The reaction has been extensively utilized and reviewed [20] and its applications to drug discovery have also been highlighted [21]. This chapter will focus on some of the most recent developments and applications of Biginelli reactions to the discovery of biologically active molecules. 

One route to these compounds is the reaction of 3-amino-1,2,4-triazoles (312) with dicyanodiamide (485) to yield (49USP2473797 53JOC1610) 5,1-diamino-l,2,4-triazolo[4,3-a]l,3,5-triazines (486). The 1,3,5-triazine ring of 7-methoxy-3-phenyl-l,2,4-triazolo[4,3-a] 1,3,5-triazine (489) was formed (70T3357) by the direct cyclocondensation of 0-methyl-N-(5-phenyl-l,2,4-triazol-3-yl)urea (488) with methyl diethoxyacetate (487) or triethyl orthoformate. 3,5,7-Triamino-1,2,4-triazolo[4,3-a] 1,3,5-triazine (490) was prepared (53JOC1610 63ZOB1355) in one step by the reaction of two equivalents of dicyanodiamide (485) with one equivalent of hydrazine dihydrochloride. 

S-methylisothiourea (which is more correctly termed a substituted amidine) has already been mentioned above and elsewhere <8uoci30l>. Pyruvaldehyde reacts with ureas to form 4,5-dihydroxyimidazolin-2-ones which dehydrate to hydantoins <86JHCii25>, while benzil gives 4,5-diphenyl-4-imidazolin-2-ones ((241) R R = Ph) when heated with thioureas in acidic solution (Scheme 173) <9UCS(P2)1501>. Direct cyclocondensation of an a-bromoketone with urea forms around 50% of 2-imidazolinone when refluxed in ethylene glycol in the presence of an excess of... 

The ot-halogen acids are often used in reactions with primary amines and urea,27,28 as well as in cyclocondensations of chloroacetates and ureas. Some 3-(benzothiazol-2-yl)-2-thiohydantoins derivatives have been obtained by this fashion.29... 

The use of /l-alkyl-/l-methoxyvinyltrifluoromethylketones aifords various heterocycles with a CF3 group (95JHC739). Thus, cyclocondensation has been performed with hydroxylamine, semicarbazide, thiosemicarbazide, phenylhydrazine, and urea. 

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