Ureas condensation with ketone

Enamination. Ketone condensation with secondary amines using BSA [or bis(trimethylsilyl)urea] as dehydrating agent is quite advantageous. lodomethane is also present. 

Condensation of cyclic ketones 273 with urea/thiourea and an aromatic aldehyde furnished bicyclic derivatives 274-276, depending upon... 

Aldehydes and ketones may frequently be identified by their semicarbazones, obtained by direct condensation with semicarbazide (or amino-urea), NH,NHCONH a compound which is a monacidic base and usually available as its monohydrochloride, NHjCONHNH, HCl. Semicarbazones are particularly useful for identification of con jounds (such as acetophenone) of which the oxime is too soluble to be readily isolated and the phenylhydrazone is unstable moreover, the high nitrogen content of semicarbazones enables very small quantities to be accurately analysed and so identified. The general conditions for the formation of semicarbazones are very similar to those for oximes and phenylhydrazones (pp. 93, 229) the free base must of course be liberated from its salts by the addition of sodium acetate. 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

The 5-methyl-5-ethyloxazolidine-2,4-dione may be prepared by reacting methyl ethyl ketone with sodium cyanide and with ammonium thiocyanate followed by desulfurization. This intermediate may also be prepared by condensing a-hydroxy-a-methylbutyramide with ethyl chlorocarbonate or by condensing ethyl a-hydroxy-a-methylbutyrate with urea. Another method described (Traube and Aschar, Ber., 46, 2077-1913) consists in the condensation of ethyl a-hydroxy-a-methylbutyrate with guanidine followed by hydrolysis. 

There are a series of communications about the formation of dihydroazines by direct reaction of urea-like compounds with synthetic precursors of unsaturated carbonyls—ketones, containing an activated methyl or methylene group. The reaction products formed in this case are usually identical to the heterocycles obtained in reactions of the same binuclephiles with a,(3-unsatu-rated ketones. For example, interaction of 2 equiv of acetophenone 103 with urea under acidic catalysis yielded 6-methyl-4,6-diphenyl-2-oxi- 1,6-dihydro-pyrimidine 106 and two products of the self-condensation of acetophenone— dipnone 104 and 1,3,5-triphenylbenzene 105 [100] (Scheme 3.32). When urea was absent from the reaction mixture or substituted with 1,3-dimethylurea, the only isolated product was dipnon 104. In addition, ketone 104 and urea in a multicomponent reaction form the same pyrimidine derivative 106. All these facts suggest mechanism for the heterocyclization shown in Scheme 3.32. 

The first step in the mechanism is believed to be the condensation between the aldehyde and urea, with some similarities to the Mannich Condensation. The iminium intermediate generated acts as an electrophile for the nucleophilic addition of the ketoester enol, and the ketone carbonyl of the resulting adduct undergoes condensation with the urea NH2 to give the cyclized product. 

Where R4 is a hydrogen or carbon atom, 10.15 is simply an amidine. However, urea 10.16, thiourea 10.17, or guanidine 10.18 and their derivatives may be used. These nucleophiles may be condensed with ester and nitrile functionalities as well as with aldehydes and ketones. Such condensations to afford pyridimidine derivatives are usually facilitated by acid or base catalysis, although certain combinations of reactive electrophilic and nucleophilic compounds require no catalyst at all. Some examples are shown below. 

Similarly, urea TV, 0-acetal 64 undergoes condensation reaction with weak carbon acids to afford acyclic 1,1-enediamines with the elimination of alcohol and amine42,95. A number of active methyl compounds such as an aliphatic ketone, acetophenone, imino ester and thioacetoamide has been successfully converted to 1,1-enediamines. Lactones, lactams and thiolactams condense with 64 to give enediamines 65 in moderate yields (equation 24). Very weakly activated methyl groups are also reactive towards urea A, 0-acetal 64, and 1,1-enediamines 66-71 are prepared from the corresponding reactants42,95. 

When urea (or thiourea) reacts with a-hydroxy ketones or a-diketones the products are imidazolin-2-ones (or -thiones) (70AHC(12)103,66RCR122). The reaction is limited to the preparation of 4,5-alkyl(or aryl)- or l,4,5-trialkyl(or triaryl)-imidazoles since an oxygen or sulfur function appears at C-2. Benzoin condenses with iV-phenylthiourea in hexanol in the presence of catalytic quantities of HCl to give l,4,5-triphenylimidazoline-2-thione (131) in 50-60% yield (Scheme 69). While 1-methylurea can also take part in the reaction. 

Coumarins. - There is interest in the synthesis of 3-substituted coumarins cyclization of substituted salicylaldehydes with cyanoacetamide, followed by treatment with phosphoryl chloride in DMF, has given coumarin-3-carbonitriles. High yields of 3-phenylcoumarins were obtained when ortho-hydroxy-aldehydes or -ketones were treated with phenylacetyl chloride-potassium carbonate.When cyclohexane-1,3-diones (187) were condensed with triethyl orthoformate and either urea and thiourea and the initial product (188) was allowed to condense with nitriles, the 3-carboxamide (189) was obtained in good yield.The antibacterial activity of some sulphones has prompted the synthesis of 3-arylsulphonyl-coumarins by oxidation of sulphides. ... 

Route 2 Synthesis of Compound 241 Employing Vinyl Ketone 264 Compound 270 of Scheme 30.51 was treated with cuprous cyanide in DMF at reflux to furnish a cyano compound (275) in 65% yield (Scheme 30.52). Following established methods, 275 was converted to the corresponding vinyl ketone (264), which was condensed with aldehyde (262) under Stetter conditions to provide a diketone (276). A regular sequence has been employed to convert 276 to the final urea (229). 

Hosseini-Sarvaria (2011b) reported the synthesis of quinoline derivatives (60) by the condensation of 2-aminoaryl ketones (58) with methylene carbonyl compounds (59) catalyzed by nanoflake ZnO as a reusable heterogeneous catalyst under solvent-free conditions involving Friedlander heteroannulation (Scheme 9.14). The employed catalyst was synthesized from zinc acetate dihydrate and urea. It constitutes a simple, environmentally benign, and cost-effective method for the synthesis of quinolines. Tamaddon and Moradi (2013) reported the application of nano-ZnO as a reusable heterogeneous catalyst for the synthesis of Biginelli dihydropyrimidines... 

Condensation of ketones with ureas and thioureas Synthesis of 1-ureido-l,3-dienes... 

Whereas condensation of a-hydroxy ketones such as benzoin and acetoin on heating with formamide [240] or ureas in acetic acid [239, 242] to form imidazoles such as 769 or 770 is a well known reaction, only two publications have yet discussed the amination of silylated enediols, prepared by Riihlmann-acyloin condensation of diesters [241], by sodium, in toluene, in the presence of TCS 14 [241, 242]. Thus the silylated acyloins 771 and higher homologues, derived from Riihl-... 

There are many important [5 + 1] two-bond formation heterocyclic syntheses and in certain instances this approach constitutes the method of choice for the preparation of particular classes of heterocycle. Where a carbon atom constitutes the one-atom fragment it is almost invariably present in the form of an electrophilic species such as an aldehyde, carboxylic acid, ketone, ester, acid chloride, urea, etc., and fundamentally condensation consists of reaction of this electrophilic species with a 1,5-dinucleophilic reagent. Where the one-atom fragment is either nitrogen, oxygen or sulfur then the heteroatom may function either as a nucleophile or, in the case of nitrogen and sulfur, also as an electrophile. Almost... 

The synthetic utility of these derivatives towards the preparation of condensed heterocycles has been demonstrated. Thus, treatment of 252 with cyclohexanone under acidic conditions (66JOC3852) (Friedlander reaction) and molten urea affords the naphthyridine 253 and pyridopy-rimidinone 251, respectively (Scheme 76) (89JHC105). Application of these reactions on the isomeric iV-pivaloylamino pyridine ketones affords analogue heterocycles 254-257. 

The reactions of thiourea and guanidine with cycloalkanones are carried out in the same manner [101]. But it is worthwhile noting that muticomponent reactions of urea-like compounds with ketones, containing an activated methyl or methyle-negroup, often do not stop after the formation of a pyrimidine ring. In fact numerous derived condensation processes can lead to more complicated polycyclic compounds, which are especially typical for the reaction of cycloalkanones [101]. 

N—C—O + C—C. The construction of the oxazole ring by the condensation of a-halogeno ketones with primary amides (equation 122) is the Bliimlein-Lewy synthesis (1884/1888). The method succeeds best when the resulting oxazole contains one or more aryl substituents. The use of formamide leads to oxazoles with a free 2-position and in this case it is possible that the reaction proceeds as in equation (113). 2-Aminooxazoles are produced by the action of a-halogeno ketones on urea and its derivatives (equation 123) or on cyanamide (80ZOR2185). The mercury(II) sulfate-catalyzed condensation of alkynic alcohols or their esters with primary amides leads to trisubstituted oxazoles (equation 124). 

The reaction of urea (and thiourea) derivatives with a-hydroxy-ketones yields imidazoles. Thus, condensation of benzoin with N-pheny 1 thiou rea in hexanol in the presence of catalytic quantities of HC1 (or dry HC1) gives l,4,5-triphenylimidazole-2-thione (21) in 50-60% yield.100... 

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