Bithiazole

NCN=C(SR)S (R = alkyl) react with chloroacetamide to give the amino-thiazoles (583). Irradiation of 2-phenyl-2-thiazoline (584) in acetonitrile leads to a mixture of the corresponding thiazole, benzonitrile, and ethylene sulphide. Heating the dithiobiuret Me2NCSNHCSNH2 with phenacyl bromide affords the 2,5 -bithiazole (585) in excellent yield. ... 

In the reverse reaction, thioheteroaryl amides reacted under reflux in alcohol with haloketones or aldehydes to give the corresponding 2-heteroarylthiazole derivatives (238, 271, 482, 550, 751, 765, 776, 781). 2,2 -Bithiazoles (4,4 -disubstituted) have been obtained in 80 to 90% yield by cyclocondensation of 1 mole rubeanic acid with 2 moles of a-bromoketones in polyphosphoric acid at 95 to 135 C (780). Some multiheteroaryl substituted thiazoles have been also reported (704). 

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

The irradiation a 1 1 Cu-peplomycin complex, an antibiotic of the bleomycin family (Fig. 15), leads to a product of an isomerization of a thiazole ring. In this case, the compound converted from a 2,4 -bithiazole to a 4,4 -bithiazole derivative. When a 5 1 Cu - peplomycin complex was used, the product was a 3-isothiazolyl-4-thiazole derivative (86JA7089 87JA938). 

This behavior has been verified with bithiazole derivative 94 (Scheme 36). Neither acetophenone nor benzophenone sensitized the reaction, in agreement with an ICI mechanism via the excited singlet state (86TL6385 87JA938). 

FtG. 16. Relative energy of the excited states of bithiazole derivative 94 and of some reactive intermediates. 

Eungicide antibiotic micothiazoles (4,4 -bithiazole derivatives with (3-me-thoxyacrylic acid fragment as a substituent) as cell respiration inhibitors 98UK595. 

The same lithium salts with copper(I) chloride react through the stage of the anionic C-coordinated complexes 100, which on protonation with hydrochloric acid give the corresponding 2,2 -bithiazoles, with triflic acid— the N-coordinated species 101, and on methylation with methyl triflate they give carbenes of structure 102. 

Bis(aminoalkyl)bithiazoles are useful as DNA cleavage agents. Bleomycin contains a 2,4 -bithiazole moiety which plays an important role in the interaction with double stranded DNA during the cleavage reaction. The 2,2 -bis(aminomethyl)-4,4 -bithiazole (70) has been synthesised by the condensation of l,4-dibromobutane-2,3-dione with Boc-glycinethioamide... 

In the presence of Cu (II), the bithiazole (70) is a simple DNA cleaving agent, the first example of a 4,4 -bithiazole having this property <96CPB1761>. 

The 2,2/-bi-2/-thiazolines 16 17 18 (Dq(Ni2+) values 1160, 1120 and 1160 cm-1, respectively) are related to the bithiazoles, and the perchlorate salts of the [Fe N6]2+ derivatives of all three systems are low spin at room temperature but their behaviour above room temperature has not been reported. The low spin configuration for [Fe 173](C104)2 in particular appears inconsistent with the behaviour of related systems containing substituents adjacent to the donor atoms, and with its relatively low Dq(Ni2+) value. Nelson and co-workers have pointed out that the steric effect here is not so pronounced because the methyl substituents are not coplanar with the diimine group [21]. 

Bithiazole, 2,2 -btz = (96), is a diimine, but it coordinates much less strongly than bipy to Fe2+ 9 [Pe(2,2 -btz)3](C104)2 exists in two modifications with slightly different magnetic proper-... 

Bithiazole, 4,4 -btz = (97), is not a diimine its iron(II) complex [Fe(4,4 -btz)3] is only weakly colored but its magnetic properties and Fe—N bond distances 1.970-1.973A suggest that the ligand field effect of 4,4 -btz is not enormously less than that of bipy. ... 

Fe (thiazole)6], in the form of its [Fe 20Cl6] salt, is the product of reaction of an excess of thiazole with FeCl3. Several complexes of bithiazole and other thiazole-containing ligands are... 

A 100-ml Schlenk flask was charged with the step 1 product (0.231 mmol), 5,5 -bis(5-bromo-2-thienyl)-4,4 -dihexyl-2,2 -bithiazole (0.231 mmol), tris(dibenzy-lideneacetone)dipalladium (0) (0.00231 mmol), triphenylphosphine (0.0162 mmol), and Aliquot 336 (0.0855 mmol). The flask was evacuated and refilled with argon... 

The structure for the step 2 reagent, 5,5 -bis(5-bromo-2-thienyl)-4,4 -dihexyl-2,2 -bithiazole, (I), is indicated below. 

The formation of 2,4 -bithiazoles, a structural motif found in a series of natural products exhibiting a diverse spectrum of biological activities, can also be achieved through the use of the Negishi coupling protocol. 4-Bromo-... 

Stereochemically controlled synthesis of this subunit, which contains five stereogenic centers, is important to an efficient bleomycin synthesis. (2S,3S,4i )-4-(/er/-Butoxycarbonyl-amino)-3-hydroxy-2-methylpentanoic acid (15) was obtained via a stereoselective syn aldol addition of a boron Z-enolate with (27 )-2-(tert-butoxycarbonylamino)propanal (Scheme 4). Similarly, the L-threonine subunit 18 was prepared by diastereoselective syn aldol addition of an N- acy I ox azo I i di n one stannous Z-enolate with acetaldehyde. The bithiazole unit 19 was prepared using a direct DCC-promoted condensation of 3-(methylsulfanyl)propylamine. Convergent access to tetrapeptide S was obtained by coupling of acid 15 and deprotected 18 to give dipeptide 20, followed by further coupling with the bithiazole 19 to ultimately give tetrapeptide S (21). 

Aminoethyl)-V-[3-(methylsulfanyl)propyl]-2,4 -bithiazole-4-carboxamide (19) pl Bithiazole 19 was prepared by a modification of the procedure of Sakai and co-workers.1"1... 

A soln of the acid from hydrolyzed dipeptide 20 (40 mg, 0.115 mmol) in DMF (lmL) was treated with bithiazole 19 (30 mg, 0.088 mmol), HOBt (12 mg, 0.088 mmol), EDC (17.8 mg, 0.093 mmol), and NaH-C03 (30 mg, 0.35 mmol) at 0°C, and the mixture was stirred at 25 °C for 50 h. Brine was added, and the mixture was extracted with EtOAc (5x5 mL). The extracts were washed with sat. aq NaHC03 and brine, dried (MgS04), and concentrated. Chromatography (silica gel, preparative TLC, CH2Cl2/MeCN 2 1 and MeCN/CH2Cl2/MeOH 3 6 0.2) gave the jV-Boc tetrapeptide methyl sulfide yield 50 mg (85%). This was methylated with Mel/MeOH in 97% yield and then deprotected in 99% yield to give tetrapeptide S (21). 

Such design concepts were first reported utilizing 2,2 -bithiazole and 2,2 -bi-pyridine units, respectively, as postpolymerization metal coordination sites [349, 350]. Subsequently, a poly(p-phenylenevinylene)-based polymer 69 containing ionic ruthenium centers bound to bipyridyl (BPY) units incorporated into the polymer backbone was reported. This system, depicted in Scheme 68, exhibits enhanced photoconductivity relative to the parent organic polymer [351] (Yu). 

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