Thiourea 5-hydroxy

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

The addition of thioureas to l,4-ben2oquinones is an excellent preparation of 5-hydroxy-l,3-ben2oxathiol-2-ones (94). Monosubstituted l,4-ben2oquinones give good yields (92% in eq. 6) and high regioselectivity. 

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked improvement, Varma et al. have synthesized the title compounds by the simple reaction of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-wave irradiation (Scheme 6.43) the process is solvent-free in both the steps [147]. 

Phenylamino-l,3-thiazolines have been synthesized from /V-(2-hydroxy-ethyl)-/V -alkyl thioureas by a one-pot intramolecular Mitsunobu reaction. 

Alternative precursors for the synthesis of NHCs are thiourea derivatives of type 3. The preparation of such thiones with a symmetrical substitution pattern is achieved by the reaction of a-hydroxyketones like 3-hydroxy-2-butanone with suitable 2-thiones (Fig. 3d) [31] or by reaction of a diamine with thiophosgene [32, 33]. Unsymmetrically substituted thiones 4 possessing a saturated heterocycle have also been described (Fig. 3e) [34, 35]. 

Ethyl 2-ethylthio-4-chloro-5-pyrimidinecarboxylate (XXIIa), as well as the corresponding4-hydroxy-(XXIIb) and 4-amino-(XXIIIa) derivatives, possess-anti-cytogenic activity on Neurospora crassa [223, 224]. Compounds (XXIIIa, b and c) were found to inhibit the conversion of orotic acid to the uridine nucleotides [202]. Ethyl 2-methylthio-4-(halo-substituted anilino)-5-pyrimidinecarboxylates (XXIV), particularly the o-bromo- and the o-chloro- derivatives, substantially inhibit the growth of five experimental mouse tumours (Krebs-2 ascites carcinoma, Ehrlich carcinoma clone 2, leukaemia L-1210, carcinoma 755 and lymphocytic neoplasm P-288) [225]. Compounds of this type are usually prepared by the base catalysed condensation of ethoxymethylenemalonic esters or related derivatives with urea, thiourea, guanidine, or substituted amidine-type analogues [212, 225-237]. 

When the 3-thiourea derivative (59) was heated in boiling ethanol for 3 h, and then the evaporated reaction mixture was treated with 10% NaOH solution at 100°C for 20 min, anhydro 2-methyl-3-mercapto-4-hydroxy-5,6,7,8-tetrahydro[l,2-6]pyridazinium hydroxide (61) was obtained (71CPB159). The mercapto group was alkylated with benzyl bromide and was treated with HgCla in boiling ethanol to yield the 3-chloromercurithio derivative. Anhydro 3,4-dihydroxy-2-methyl-5,6,7,8-tetrahydropyrido[l,2-f ]pyridazinium hydroxide (62) was O-acylated with acetic anhydride, but the structure of the product was not elucidated (71CPB159). 

In 2007, another departure from carbonyl-type activation was marked by Kotke and Schreiner in the organocatalytic tetrahydropyran and 2-methoxypropene protection of alcohols, phenols, and other ROH substrates [118, 145], These derivatives offered a further synthetically useful acid-free contribution to protective group chemistry [146]. The 9-catalyzed tetrahydropyranylation with 3,4-dihydro-2H-pyran (DHP) as reactant and solvent was described to be applicable to a broad spectrum of hydroxy functionalities and furnished the corresponding tetrahydro-pyranyl-substituted ethers, that is, mixed acetals, at mild conditions and with good to excellent yields. Primary and secondary alcohols can be THP-protected to afford 1-8 at room temperature and at loadings ranging from 0.001 to 1.0mol% thiourea... 

Scheme 6.19 Synthesis of polystyrene-bound thiourea derivatives 17 and 18 screened in the THP protection of hydroxy substrates.

These experimental results suggested a hydrogen-bonding mediated cooperative Bronsted acid catalysis mechanism (Scheme 6.28). Thiourea cocatalyst 9 is viewed to coordinate to mandelic acid 20 through double hydrogen-bonding, stabilizes the acid in the chelate-hke cis-hydroxy conformation, and acidifies the a-OH proton via an... 

Scheme 6.82 Proposed reactive complex of the Petasis reaction utilizing a-hydroxy aldehydes, amines, and organic boronic acids (A) and bifunctional mode of action of chelating thiourea catalyst 65 in the enantioselective Petasis-type 2-vinylation of N-acetylated quinolinium ions (B).

The Deng group identified QN-derived thiourea 121 and QD -derived thiourea 124 to be also efficient promoters of enantio- and diastereoselective Diels-Alder reactions between the 2-pyrone diene 3-hydroxypyran-2-one and the dienophiles fumaronitrile, maleonitrile as well as acrylonitrile, while various C9-hydroxy acylated and alkylated (dihydro)cupreines and (dihydro)cupreidines failed for the same reactions under identical conditions (e.g., 97% yield, 15% ee, 64 36 endoxxo) [289], Catalysts 121 and 124 (5mol% loading), however, produced the corresponding Diels-Alder adducts 1-3 with synthetically useful enantioselectivities (85-... 

The transformations of 8-hydroxy-a,P-enones to the corresponding internal Michael adducts were performed at 20mol% loading of C9-epi-quinine-thiourea 121 in toluene at increased reaction temperature (50°C) using 3,4,5-trimethoxy-phenylboronic acid for ahphatic and phenylboronic acid for aromatic enones. Under these conditions, this protocol furnished the desired (R)-configured adducts 1-5 in yields ranging from 73 to 86% and ee values of 84—96% (Scheme 6.143) [294]. Product 5 in Scheme 6.143 was identical in all respects with (+)- S)-streptenol A, one of four known streptenols produced by Streptomyces luteogriseus that has attracted attention as an immunostimulant as well as an inhibitor of cholesterol biosynthesis and tumor cells [295]. 

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