Thiazole Carbonylation

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... 

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 saturated systems such as dihydro, tetrahydro, or perhydro oxopyrrolo[2,l-fi]thiazoles, carbonyl absorption appears in the normal range. Only in 3,5-dioxoperhydropyrrolo[2,l-fi]thiazole do carbonyl absorptions appear at higher values, at 1782 and 1720 cm <87JMC498>. 

Fluorophenyl)indol-l-ylzinc chloride 3-(Pyridin-3-yl)-l /7,3-f -pyrrolo[l, 2-c]thiazole-7-carbonyl chloride >45 [8]... 

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. 

The 4-Hydroxy-thiazoles are characterized by infrared absorption near 1610 cm (KBr) (3) or 1620 to 16.S0cm (CCI4) (8), indicating a strongly polarized carbonyl group. H-5 resonates near 5.6 ppm in the NMR spectrum like similar protons in other mesoionic compounds (3). Two fragmentations of the molecular ion are observed in the mass spectra. The first involves rupture of the 1,2 and 3,4 bonds with loss of C2R 0S . In the second, the 1,5 and 3,4 bonds are cleaved with elimination of C2R 0. ... 

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

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 well known that in nitrogen-containing heterocyclic compounds the reactivity of alkyl groups is enhanced. In the thiazole series, alkyl groups in the 2-position are reactive towards carbonyl compounds and condensations may be realized. 

The alkyl derivatives of thiazoles can be catalytically oxidized in the vapor phase at 250 to 400°C to afford the corresponding formyl derivatives (21). Molybdenum oxide, V2O5, and tin vanadate are used as catalysts either alone or with a support. The resulting carbonyl compounds can be selectively oxidized to the acids. 

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). 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

As shown in Scheme 2, two heteroatom-carbon bonds are constructed in such a way that one component provides both heteroatoms for the resultant heterocycle. By variation of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the use of the appropriate oxidation level in the carbonyl-containing component, further oxidized derivatives of these ring systems result. These processes are analogous to those utilized in the formation of five-membered heterocycles containing one heteroatom, involving cyclocondensation utilizing enols, enamines, etc. 

The thiazole-2,4-dione 105a has been obtained optically active, demonstrating the existence of the dioxo form. Rhodanines are usually written in the carbonyl form (106, R, R = H or alkyl) (cf, reference 117), and this formulation is supported by infrared, ultraviolet, ... 

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). 

In NRPs and hybrid NRP-PK natural products, the heterocycles oxazole and thiazole are derived from serine and cysteine amino acids respectively. For their creation, a cyclization (or Cy) domain is responsible for nucleophilic attack of the side-chain heteroatom within a dipeptide upon the amide carbonyl joining the amino acids [61]. Once the cyclic moiety is formed, the ring may be further oxidized, to form the oxazoline/thiazoline, or reduced, to form oxazolidine/thiazolidine (Figure 13.20). For substituted oxazoles and thiazoles, such as those... 

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. 

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. 

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