Type G Syntheses

Type G Syntheses [C—N—S + C—N]. Nitrile sulphides R—C N- S have recently become available as reactive intermediates in the thermolysis (at ca. 190 °C) of 5-substituted l,3,4-oxathiazol-2-ones they may be trapped by 1,3-dipolar cycloadditions, e.g. with acetylenes, resulting in S,N-heterocycles. Cycloaddition of nitrile sulphides R CNS to nitriles R CN provides a new general synthesis of 3,5-disubstituted 1,2,4-thiadiazoles (62). Yields are moderate, but are satisfactory when electrophilic nitriles are used in conjunction with aromatic nitrile sulphides. Minor amounts of (63) are formed as by-products. 

Physical Properties.—The spectral properties of a series of 3-amino-4-aryl-5-aryl(or alkyl)-imino-4,5-dihydro-l,2,4-thiadiazoles are in accord with the proposed structures. The n.m.r. spectra indicate the preferred existence of the dihydro- rather than the tautomeric tetrahydro-thiadiazole structure. Mass spectral fragmentation patterns were proposed for these, and for compound (70).  

investigation of the energy barrier to internal rotation of the dimethylamino group in five-membered heterocyclic compounds has included a 1,2,4-thiadiazole (65) and variously substituted 1,3,4-thiadiazoles (6Q. Compound (65) is iso- r-electronic with 4-dimethylaminopyrimidine, and is comparable 

An X-ray analysis of 2,4-dimethyl-l,2,4-thiadiazolidine-3,5-dithione has shown its hetero-ring to be planar, due presumably to conjugation, which does 

Chemical Properties.—Alkylation. Treatment of 3,5-diethoxy-l,2,4-thiadiazole (67) with benzyl bromide in boiling acetonitrile ( Hilbert-Johnson reaction ) slowly yields a monoalkylation product (68). Chloromethyl benzyl ether effects the alkylation rapidly in good yield. The use of ribosyl halides should make novel nucleosides accessible.  

Type G (C—C—S—C— N) Syntheses.— The reaction of ethyl thiocyanoace-tate with an amine and aromatic aldehyde produces variously substituted 5-arylidene-2-iminothiazolidin-4-one derivatives (231) and (232). Condensation proceeds differently in benzene-acetic acid and ethanol, with the results shown.  

In conclusion, brief reference is made to numerous thiazolidines that have been synthesized in the course of biological screening programmes, by well-established cyclization reactions. They include 2,2-dialkyl- and 2-spiro-thiazolidines, 2-alkyl(or aryl)-2-ethoxycarbonylthiazolidines, and 3-substituted 2-imino-5-carboxymethylthiazolidin-4-ones. Substituted 

Hayashi, H. Yasuda, and A. Sakurai, Nippon Kagaku Zasshi, 1971, 92, 867 

Fatome, P. Poutrain, R. Granger, H. Orzalesi, Y. Robbe, and M. Randon, Chim, Thirapie, 

2- [(3-thiazolidinyl)alkyl]thio pyridines have been prepared from the preformed hetero-nucleus.  

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Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

Type G Syntheses (N-C-S-C-C). Various 2,4,5-trisubstituted thi-azoles have been prepared in good yield from thiocyanates R COCHR SCN (R2,R =H,alkyl,Ar,alkoxycarbonyl, acyl.benzoyl) and active methylene compounds CH-RR (R.R rCN, HCO,N00,alkanoyl,... 

Type G Syntheses (C6//5—5—C—A). The reaction between 2-thiocyanato-cyclohexen-3-one and aniline gives the partially reduced benzothiazole (104). ""... 

The principal difficulty associated with this type of synthesis is in the availability of a-aminoacyl compounds, e.g. a-aminoaldehydes, a-aminoketones, etc., and most type B syntheses rely on the generation of these compounds in situ, where the self-condensation occurs spontaneously. A large number of research groups have addressed themselves to this problem and a variety of routes are now available. 

Type K Syntheses (C—C—N—C—S). The reaction between jS-(ethoxycar-bonyl)acryloyl isothiocyanates (obtained from the acid chloride and lead thiocyanate) and aromatic amines gives the 2-arylamino-A -thiazolin-4-ones (48) in good yield.2-(Substituted amino)-A -thiazolines may also be obtained in high yields by allowing vicinal iodo-isothiocyanates to react with amines e.g. PhCH(NCS)CH2l with amines, in the absence of light, gives (49). ... 

Synthesis.—Type A Syntheses S—C—N + C—C). The reaction between thioamides, e.g., MeC(0)CH2C(S)NHPh, and bis(perfluoroketimines) (F3CN=CF)2 in the presence of a fluoride acceptor gives 4,5-bis(trifluoro-... 

Recently the total synthesis of mucronine-B (150) 147), of the 4(15)-mucronine-A-type, and zizyphine-A (27) 148), the major representative of the 5(13)-type, was achieved. Total synthesis of dihydro derivatives of cyclopeptide alkaloids was more fruitful dihydro-zizyphine-A and -B 149) of the 5(13)-type, dihydro-mauritine-A 150) of the 5(14)-amphibine-B-type and dihydro-zizyphine-G 151, 152) of the 4(14)-amphibine-F-type were synthesized. The total synthesis of the linear peptide alkaloid hexaacetyl-celenamide-A was also achieved (156) 153). 

The first group of methods involves end-group analyses. Many types of syntheses leave a special group on one or both ends of the molecule, such as hydroxyl and carboxyl. These can be titrated or analyzed instrumentally by such methods as infrared. For molecular weights above about 25,000 g/mol, however, the method becomes insensitive because the end groups are present in too low a concentration. 

The anionic polymerization of 9-vinylanthracene gives only low molecular weight products [342], which agrees with Rembaum s and Eisenberg s results [355]. Stolka et al. [342] found no proof of the proposed [337,355] across-the-ring addition instead, the IR and UV spectra of their polymers indicated the conventional 1,2-addition pattern. 2-Propenyl-l-anthracene could not be polymerized anionically [342], Attempts to initiate polymerizations by means of electron-transfer-type initiators (e.g., sodium naphthalene and sodium biphenyl) were unsuccessful [341,342,353,354], The polymerization of 1-vinylpyrene initiated by electron-transfer initiators showed the characteristics of a living polymer system [356,357], Block copolymers of the AB and ABA type were synthesized with ethylene oxide, styrene and isopropene [357],... 

The results are relevant to a number of practical situations. The most important applications will be found in the development of chemical reactors for liquid phase reactions which are not very fast, such as we often encounter in the synthesis of organic products. For this type of syntheses, we can easily design, e.g., large scale continuous stirred tank reactors on the basis of data obtained with small scale batch-reactors. Examples of these are discussed in Chapter 10. 

The toxicity is based on the heteroaromatic amino function. The amines are genotoxic after oxidative metabolic conversion to a strong electrophile, e. g., a nitrene. Nitrenes of this type are synthesized for model experiments as shown in Formula 1.56. According to these experiments, MelQ, IQ and MelQx have an especially high genotoxic potential. The compounds listed in Table 1.6 can be deaminated by nitrite in weakly acid solution and thus inactivated. 

Synthesis.—As in the past, the majority of the synthetic routes to 1,2,4-thia-diazoles are ultimately based on ring-closures involving suitably placed imino- and mercapto-groups (Type C). Additional types of syntheses, classified according to the fragments from which the hetero-ring is constructed (see Vol. 3, p. 679) are listed as methods F and G. 

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