Heterocyclizations with 4-aminothiazole derivatives

Potentially useful heterocyclic libraries can also be prepared by the application of solution-phase combinatorial chemistry. Although multiple reactions in solution have often been complicated by the difficulties with liquid-liquid extractions the introduction of solid scavengers and equipment to automate these extraction processes allows hundreds of reactions to be managed simultaneously. A typical example is a series of aminothiazole derivatives which has been prepared starting from acyclic precursors (Scheme 3.9). Naturally one-pot multicomponent condensations such as the Ugi (library 84) [332], Passerini or Biginelli reactions present one of the simplest... 

Angyal and Angyal measured the pK of 2-aminothiazoles and 2-imino-4-thiazolines to obtain the protomeric equilibrium constants (Scheme l4) (74). The higher pK values of the imino derivative (9.65) compared with that of 2-aminothiazole (5.68) prove that the amino form is highly predominant, Xp = 2x 10" (72), The limitations of such a method of Kp determination are discussed by Elguero. Marzin and Katntzky in a review of protomeric equilibria in heterocycles (75). 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

In a similar way, 1,3-dinitrogen systems such as diamines, amidines, guanidines, aminothiazoles, aminopyridines, ureas and thioureas react with alkynyl-carbene complexes generating the corresponding heterocycles. Of particular interest is the reaction with ureas, as the process can be applied to the easy synthesis of pyrimidine derivatives [88] (Scheme 41). 

Novel C-4 thiazole kainoid analogues have been synthesised from kainic acid 43. This was converted into the a-bromoketone 44 in three steps, which reacted with thioamides and thioureas to form thiazole and aminothiazole heterocycles 45. All the synthesised thiazole kainic acid derivatives exhibited strong binding to the kainate receptors <00BMCL309>. 

Cyclic amidines (213) react with chlorocarbonylsulfenyl chloride to give bicyclic 1,2,4-thia-diazoles. The product isolated from this reaction depends on the mode of addition. When (213) is added to chlorocarbonylsulfenyl chloride, 3-oxo derivatives (214) are isolated via the postulated intermediate (215). Addition of chlorocarbonylsulfenyl chloride to (213) leads to 5-oxo derivatives (216), via the proposed bis(intermediate) (217) (Scheme 47) <84CHEC-I(6)463). Cyclic amidines (213) have also been treated with 1-chloro-l-phenyliminomethanesulfenyl chloride (210) to afford 2>H-1,2,4-thiadiazoles (218). The other possible product from this reaction, the 2/7-isomer (219) has been shown to be unstable, rearranging to a benzothiazole. Heterocycles (213) which have been used in this transformation include 2-aminopyridine, 3-aminopyridazine, 2-aminobenzothiazole, 2-aminopyrimidine and 2-aminothiazole (Equation (33)) <86S1027>. 

This set of compounds is the most thoroughly studied among derivatives of 2-aminothiazole, thanks to the Beyer group. Heterocyclization methods are most commonly used for their preparation (see Chapter II and Refs. 37, 341, and 513-520). Reaction of 2-diazothiazoles (277) with organometallics provides another synthetic method (Scheme 1711 (521). 2-Hydrazinothiazoles may also be obtained by the action of hydrazine on 2-bromothiazoles (388) or on 2-mercaptothiazoles (522). 

As discussed in Section 3.06.5 aminothiazoles react with alkyl halides to give mainly the product of alkylation at the endocyclic nitrogen when the reaction is conducted in the absence of strong bases with acyl and sulfonyl halides, the exocyclic nitrogen becomes the main nucleophilic site. The reaction of 2-aminothiazoles with heterocyclic or aromatic aldehydes show ample differences depending on the various amine-aldehyde pairs <9lS62i>. In general the azomethine derivatives are obtained by a suitable procedure which has to be followed in each case. The increase of the amine/aldehyde ratio leads to bis-amines as the major products of the reaction. 

In addition to cyclization of 2-mercaptoadenines with dibromoethane to a mixture of [2,3-Z>] and [3,2-a] isomers (86, 85) shown in Scheme 23, the method starting from 2-aminothiazole also produced this heterocycle. This compound—a cyclic isothiourea—was condensed with ethyl nitrosocyanoacetate to 5-amino-6-nitroso-thia/o 1 o[3,2-nitroso group with sodium dithionite to 6-amino derivative 91 followed by acylation with acyl chloride yielded 5-amino-6-acylaminothiazolo[3,2-u]pyrimidin-7-one (92). Heating 92 with polypho-sphoric acid produced 2-aryl- or 2-heteroaryl-thiazolo[2,3-/)]purin-4(3//)-ones 93. 

Supports 3e and 3f derived from a related linker with only one me-thoxy group ortho to the aldehyde have been reported [140] to have a more reactive aldehyde group than 3c or 3d due to lower steric hindrance. Resin 3e was used to synthesize aminothiazoles, which were cleaved under acidic conditions [141]. Thus, amines were anchored reductively to 3e and converted to resin-bound thioureas by reaction with Fmoc-isothiocyanate followed by deprotection. Cyclization by reaction with a-bromomketones gave the desired heterocycles, which were cleaved from the resin by treatment with TFA-H2O (19 1) (Scheme 4). 

The interaction of enamines with sulphur in conjunction with carbon disulphide, isocyanates, or isothiocyanates results in the production of sulphur-containing heterocyclics. Cyanamide has now been shown to participate in this reaction. Treatment of enamines of type (24) with sulphur and cyanamide at room temperature in ethanol produces a range of 2-aminothiazoles (27) in 30—70% yield no catalyst is required. Initial formation of the thiolated intermediate (25) is probably followed by addition of cyanamide, yielding (26) elimination of amine finally produces the observed thiazoles (27). Since AW-dialkylcyanamides do not undergo this reaction, cyanamide may react as the tautomeric carbodi-imide. An actual example of the reaction employing the enamine derived from cyclohexanone and morpholine is also shown [(28) - (29)]. ... 

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