Thioureas condensation with ketone

This preparation illustrates the ready formation of the thiazole ring by the condensation of an ot-halogeno-ketone and a thioamide. Thus chloroacetone, which may conveniently be represented in the enol form (I), condenses with thiourea (II) to give 2-amino-4-methylthiazolc (III). 

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]. 

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. 

As shown in Scheme 8, a common ketone precursor led to the pyrazolo[4,3- ]- and thiazolo[5,4- ]-fused 1,4-benzoxazines (96) and (97) <87JMC580>. For the synthesis of compound (96) the ketone was condensed with HC02Et and subsequently cyclized with hydrazine. For the synthesis of the thiazole (97) a-bromination of the ketone was followed by condensation with thiourea. The linear tricyclic structures (96) and (97) were supported by H and 13C NMR spectroscopic analyses. 

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... 

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. ... 

As an example, we present a solution-phase multigeneration strategy towards highly substituted thiazoles based on the Hantzsch condensation of thioureas 33 with 2-bromomethyl ketones 34 to give 2-aminothiazoles 35 in high yields, as shown in Scheme 3.4.4, using liquid-liquid phase extraction (LPE) and liquid-solid phase extraction (SPE). 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

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

E)-Chalcones 4 were prepared via Claisen-Schmidt condensation of methyl ketones with different aromatic aldehydes. Cycloaddition reaction of 4 with thiourea yielded the eorresponding thioxypyrimidine 5 derivatives. Compounds 5 were condensed with chloroacetic acid to yield thiazolopyrimidine 6. Also thione 5 were also condensed, in one pot reaction, with chloroacetic acid and aromatic aldehyde to yield arylmethylene derivatives 7 which could also be prepared directly by condensation of 5 with aromatic aldehydes (Scheme 2) [14-20]. 

Aminolhtazoles were synthetized from thiourea by three methods Method A, from a-haloketones or aldehydes designated as (Cl) or (Br) Method B, from ketones and iodine (fj) or bromine (Btj) Method C, from iodomercuriketones. Method D consists in condensing ketones with cyanamid and sulfur. 

A variation of the general method for the synthesis of 2-amino-selenazoles is to avoid the use of the free a-halogenocarbonyl compound and in its place react the corresponding ketone and iodine with selenourea.This procedure is also taken from thiazole chemistry. By contrast with thiourea, the reaction with selenourea needs a longer reaction time and the work up of the reaction mixture is somewhat more difficult. Usually an excess of the ketone is used. In the preparation of 2-amino-4-( n-nitrophenyl)selenazole, a very high yield, calculated on the amount of iodine used, was obtained. To explain this peculiar result, the oxidative action of the nitro group was invoked. This liberates free iodine from some of the hydrogen iodide eliminated in the condensation reaction, and the free iodine then re-enters into the reaction. 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar quantities of thiourea and a-halo ketones or aldehydes to yield the corresponding 2-aminothiazoles (Scheme 167) (l888LA(249)3l). The reaction occurs more readily than that of thioamides and can be carried out in aqueous or alcoholic solution, even in a distinctly acid medium, an advantage not shared by thioamides which are often unstable in acids. The yields are usually excellent. A derived method condenses the thiourea (2 mol) with the non-halogenated methylene ketone (1 mol) in the presence of iodine (1 mol) or another oxidizing agent (chlorine, bromine, sulfuryl chloride, chlorosulfonic acid or sulfur monochloride) (Scheme 168) (45JA2242). 

Condensation of thioamides or thiourea with, -unsaturated ketones is a general method for the construction of the 1,3-thiazine skeleton . -Chlorovinyl ketones 343 and the thioamide 344 in the presence of perchloric acid give intermediate thioimidium salts 345, which cyclize to yield 1,3-thiazinium salts 346 (Scheme 160) <1982T937>. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

The standard method for formation of 2-imino-l,3-oxathioles (328) is condensation of a substituted phenacyl bromide, Ar COCH2Br, with either a dithiocarbamate (327 X = SR) <83PHA441, 84EGP215313) or a thiourea (327 X = NMc2) <92Mi 3io-02> (Equation (54)). Compounds of this type can also be prepared from rhodium-catalyzed decomposition of an a-diazo ketone (312) in the presence of an isothiocyanate, R NCS to give (329) (Equation (55)) <92BCJ3088>. 

Condensation of alpha-halo ketones or aldehydes with thioureas in neutral, anhydrous solvents to give 2-amino thiazoles. 

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