Carbonylation reaction thiazoles

The carbonylation of imidazole derivatives with several olefins takes place in high yields with the aid of an Ru3(CO)i2 catalyst.112,112a The carbonylation occurs exclusively at the a-position to the sp2 nitrogen (Equation (85)). A wide range of olefins can be utilized in this reaction, and a variety of functional groups are compatible under the reaction conditions. The (/i-H)triruthenium clusters such as 12 are proposed as a key species in this carbonylation reaction. Other five-membered A-heteroaromatic compounds, such as pyrazoles, oxazoles, and thiazoles, can be used for the carbonylation reactions, where the carbonylation takes place at the a-C-H bond to the sp2 nitrogen. 

This type of C-H carbonylation is also feasible at C-H bonds in five-membered N-heteroaromatics, such as imidazoles 3 (Scheme 2), thiazoles 5, oxazoles 6, and pyr-azoles 7 [3], Functional group compatibility was extensively studied in the reaction of 3, and it was found that a variety of functional groups, for example ketone, ester, cy-ano, acetal, N, O-acetal, ketal, and silyl groups, were tolerated under the reaction conditions, indicating that C-H carbonylation reactions have now reached a satisfactory level in organic synthesis. The reactivity of the five-membered N-heteroaromatics is significantly affected by the pK, of conjugate acid of the N-heteroaro-... 

There have been some studies of the diazo coupling and carbonyl reactions with imi-dazo[2,1 -b ]thiazol-3 (2//)-ones (67CHE706), 2,3 -dihydrothiazolo[4,3-c ]-s-triazol-5-ones (76ZN(B)853) and 2,3-dihydroimidazo[2,l-6]thiazol-3(2//)-ones (81ZN(B)50l). Oxidation of 2,3-dihydrothieno[3,2-fc]pyrrole with chloranil to thieno[3,2-fc]pyrrole has been reported (72CHE1428). 

The carbonylation reaction is also applicable to other five-membered N-hetero-cycles, such as thiazoles, oxazoles, and pyrazoles [36], The reactivity of the substrates increases with increasing pfCa values of the conjugate acids of the N-heterocycles according to the series imidazole (pfCj 7.85) > thiazole (pfCa 3.37) > oxazole (pKa 2.91) > pyrazole (pKa 2.09). This indicates that the coordination of the substrates by the sp nitrogen to the ruthenium center is the key step in the carbonylation of C-H bonds in N-heterocycles. 

Both carbonyl groups of terephthaldehyde are reported to react with the exocyclic nitrogen of 2-aminothiazole yielding 1.4-phenylene bis(2-methyleneamino)thiazole. The same report describes the reactions of 2-amino-4-phenylthiazole with terephth aldehyde and salicylaldehyde as yielding 64 and 65, respectively (Scheme 45) (215), whose structures are based on ultraviolet and infrared spectra. 

As in the case of the thiazoles, a variation on the Hantzsch s method has been used. This consists of using a nonhalogenated carbonyl derivative directly in the presence of iodine in the reaction with selenourea (Scheme 7) (20). However, in this case the reaction with selenourea is slower than with thiourea, and normally an excess of carbonyl compound is used. 

The thermal decomposition of thia2ol-2-yl-carbonyl peroxide in benzene, bromobenzene, or cumene affords thiazole together with good yields of 2-arylthiazoles but negligible amounts of esters. Thiazol-4-ylcarbonyl peroxide gives fair yields of 4-arylthiazoles, but the phenyl ester is also a major product in benzene, indicating reactions of both thiazol-4-yl radicals and thiazol-4-carbonyloxy radicals. Thiazole-5-carbonyl peroxide gives... 

Active Raney nickel induces desulfurization of many sulfur-containing heterocycles thiazoles are fairly labile toward this ring cleavage agent. The reaction occurs apparently by two competing mechanisms (481) in the first, favored by alkaline conditions, ring fission occurs before desul-, furization, whereas in the second, favored by the use of neutral catalyst, the initial desulfurization is followed by fission of a C-N bond and formation of carbonyl derivatives by hydrolysis (Scheme 95). 

The reaction of phosphorus pentasulfide with a-acylamino carbonyl compounds of type Ilia also yields thiazoles. Even more commonly, a mercaptoketone is condensed with a nitrile of type IVa or a-mercaptoacids or their esters with Schiff bases. This ring closure is limited to the thiazolidines. In the Va ring-closure type, /3-mercaptoalkylamines serve as the principal starting materials, and ethylformate is the reactant that supplies the carbon at the 2-position of the ring. These syntheses constitute the most important route for the preparation of many thiazolidines and 2-thiazohnes. In the Vb t3fpe of synthesis, one of the reactant supplies only the carbon at the 5-position of the resultant thiazole. Then in these latter years new modern synthetic methods of thiazole ring have been developed (see Section 7 also Refs. 515, 758, 807, 812, 822). 

An unusual reaction was reported in which 2-(4-pyridyl)-4-carboxyethylthiazole (50) prepared from thioisonicotinamide (49) and ethylbromopyruvate (48) was converted to 51, which upon treatment with KNCS in the presence of NaHCOj gave 52 (618). This was again cyclized with 48 to yield 2-(4-pyridyI)-4-(4-ethoxycarbonyl-2-thiazolyl hydrazino-carbonyl)thiazole (S3) (Scheme 24). 

It is possible to reduce thiazole carbonyl derivatives with aluminium isopropoxide (56, 57). For example, 4-methyl-5-acetylthiazole gives 4-methyl-5-(a-hydroxyethyl)thiazole. With aluminium amalgam one obtains a duplication like to the pinacol reaction, and the yield is genaally poor... 

Thiazoles are desulfurized by Raney nickel, a reaction probably initiated by coordination of the sulfur at Ni. The products are generally anions and carbonyl compounds (see Section 4.02.1.8.4). 

Hydroxy-imidazoles, -oxazoles and -thiazoles (484 Z = NR, O, S) can isomerize to 2-azolinones (485a). These compounds all exist predominantly in the azolinone form and show many reactions similar to those of the pyridones. They are mesomeric with zwitterionic and carbonyl canonical forms e.g. 485a 485b Z = NR, O, S). 

A methyl group in the 2-position of the selenazole ring shows the same reactivity as the analogous thiazoles toward carbonyl compounds. By reaction of 2,4-dimethylselenazole with benzaldehyde in the presence of anhydrous zinc chloride catalyst, 4-methyl-2-styryl-selcnazole (9), mp 74-75°C, could be prepared. ... 

J ,3J ,4J ,5J )-2,5-bis(benzyloxy)-3,4-dihydroxy-Nd -bis (lS)-2-methyl-l-[(methylamino)carbonyl]propyl hexanediamide is a C2-symmetric HIV-1 protease inhibitor [29]. Derivatization in the para positions of the benzyl-oxy groups via microwave-assisted Stille reaction on the corresponding di-brominated inhibitor smoothly yielded the desired heteroarylated derivatives (Scheme 10). Interestingly, the 1,3-thiazole derivative showed a higher antiviral activity on the wild type virus than the lead compound. The activity remained at the same level in the presence of seriun. Unfortimately, a low activity was observed on mutants. 

Reaction of /3-carbonyl amides with the Lawesson s reagent under microwave irradiation gave thiazoles in acceptable yields [37]. The reaction was the same one previously reviewed for the synthesis of thiophenes and was also employed for the preparation of thiadiazoles (Scheme 10, X = NH, Y = CH). 

The rate of the base-catalysed condensation of carbonyl compounds with alkyl groups activated by Jt-deficient aromatic systems is enhanced by the addition of quaternary ammonium salts. For example, 2-methylbenzoxazole, 2-methylbenzo-thiazole and 4-nitrotoluene react with a range of substituted benzaldehydes to produce the corresponding 2-styryl derivatives (62-80%) at room temperature over 1 -2 hours [61, 62]. The intermediate alcohol can also be isolated after a short reaction time. 

When artemisinin 9a was treated with 2-lithiothiazole followed by in situ O-acetylation, the thiazole carbonyl adduct 161 was formed chemoselectively in good yield (Scheme 22) the same reaction with PhLi produced a mixture of uncharacterized products. When this acetyl adduct 161 was exposed to TMSOTf, the corresponding elimination product 162 was formed, which was converted in three steps without purification of intermediates into aldehyde 163. This was reacted with high chemoselectivity in reactions with organometallics ( -BuLi, PhMgBr) and with phosphonium ylides in a Wittig procedure <1999T3625>. 

In a similar vein, reaction of the thiobenzamide (100-1) with 4-bromoacetoacetate (100-2) in the presence of a base starts by the displacement of bromine by sulfur to afford a transitory substimtion product such as (100-3). This can then undergo internal imine formation between basic nitrogen and the adjacent carbonyl goup to afford the thiazole (100-4). Saponification then leads to the NSAID fenclosic acid (100-5) [110]. 

A. Medici, G. Fantin, M. Fogagnolo, and A. Dondoni, Reactions of 2-(trimethylsilyl)thiazole with acyl chlorides and aldehydes. Synthesis of new thiazol-2-yl derivatives, Tetrahedron Lett. 24 2901 (1983) A. Dondoni, G. Fantin, M. Fogagnolo, A. Medici, and P. Pedrini, Synthesis of (trimethylsilyl)thiazoles and reactions with carbonyl compounds. Selectivity aspects and synthetic utility, J. Org. Chem. 53 1748 (1988). 

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