1.3.4- Thiadiazoles, alkoxy

In principle, alkoxy-1,3,4-thiadiazoles should be available through reaction of alkoxides with suitable halogenothiadiazoles. However,... 

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

Alkoxy-l,3,4-thiadiazoles can be dealkylated under acidic conditions to give l,3,4-thiadiazol-2(3//)-ones. The selective and clean dealkylation of the ethoxy group in thiadiazole 109 was achieved with HBr in refluxing ethanol to give the thiadiazolone 110 (90%) (Equation 33) <1999H(51)2739>. 

In the intense search for inhibitors of gastric acid secretion a new class of potent histamine H2-receptor antagonist was discovered. These 1,2,5-thiadiazole-l-oxides (27) were prepared by nucleophilic addition of primary amines to 3,4-dialkoxy-l,2,5-thiadiazole 1-oxide (25). Sequential addition of two different amines to positions C(3) and C(4), respectively, could be achieved via the 3-alkoxy-4-amino adduct (26) (Scheme 5) <82JMC207,82JMC210>. 

Due to the lack of suitable aliphatic starting materials, the synthesis of aromatic forms of monocyclic 1,2,5-thiadiazoles was not accomplished for more than 70 years after the first report of the benzo analogues. General synthetic methodology for monocyclic 1,2,5-thiadiazoles was devized which readily leads to a variety of substituted derivatives, alkyl, aryl, halo, hydroxy, alkoxy, cyano, and amino as well as the parent system. A general model for substrates applicable in these syntheses... 

The reaction of alkoxy benzenes with S4N4 has been shown to be an effective method for conversion of phenols <85JCR(S)346,88JCS(P1)1869,89BCJ3127> and naphthols <91BCJ68> to 1,2,5-thiadiazoles. For example, phenol gives (1) and 2-naphthol gives (42). 

Graubaum et al. studied the reaction of 5-aminothiatriazole (10) with chloroformates in the presence of base and isolated 1,2,4-thiadiazoles (104 R = OR) <89M997, 90JPR208). In the reaction between 5-aminothiatriazole and chlorothioformates in the presence of base the main products were trithiapentalenes (116) (Scheme 21). However, in the absence of base the intermediary 5-alkoxy-and 5-aryloxy-3-imino-A -1,2,4-dithiazoline (115) hydrochlorides are isolated. These reactions are analogous to those of (10) and acid chlorides (Section 4.19.6.1.2). 

Suitable monothiobiurets are convertible into 3-hydroxy-l,2,4-thiadiazoles by the general reaction as expected. Thus, 4-alkyl- 1-aryl-(or alkyl)-2-thioisobiurets (116) are smoothly dehydrogenated, by bromine or acidified hydrogen peroxide, to 3-alkoxy-5-aryl(or alkyl)-... 

Guanidine cannot be thioacylated by O-alkylchlorothioformates (RO—CS—Cl) the action of dialkylthiocarbonates [(RO)2CS], however, yields unstable intermediates (130) which are cyclized by bromine to 5-alkoxy-3-amino-l,2,4-thiadiazoles (131) in low yield (14.5% when R = Et).92... 

In alkaline media, 3-halogeno compounds appear to be less stable 3-chloro-5-phenyl-l,2,4-thiadiazole is decomposed completely by 1 Jf-alcoholic potassium hydroxide and by hydrazine.178 Nucleophilic substitution of the 3-halogen atom by alkoxy groups can be achieved, however, by means of sodium alkoxide in the appropriate alcohol 3-methoxy-, 3-benzyloxy-, and 3-(2 -hydroxyethoxy)-5-phenyl-l,2,4-thiadiazole are obtainable by this route in good yield.178... 

Hydroxy-5-methylamino-l,2-4-thiadiazole is sufficiently basic to yield a picrate, as are the 3-alkoxy homologs.180... 

Hydroxy-l,2,4-thiadiazoles possess phenolic character they give red to purple colors with ferric chloride, and fail to afford ketonic derivatives.130,178 They resist the action of hot alkaline sodium plumbite.130 The 3-alkoxy homologs are neither alkali soluble nor give colors with ferric chloride.130... 

III,D, 1). In spite of this, differences in the spectra of 5-anilino-3-hydroxy- and 3-alkoxy-5-anilino-l,2,4-thiadiazoles suggest that ketonic tautomers of the hydroxy compound contribute to the resultant absorption curve. Similar observations are made with 3-hydroxy-5-phenyl-l,2,4-thiadiazole.122 The spectra of 4-methylpyrimid-2-one and 2-methoxy-4-methylpyrimidine led to similar conclusions.170... 

A number of phenolic ethers of this series show the expected properties. 5-Amino-3-ethoxy-l,2,4-thiadiazole is considerably more soluble in water than its 3-methoxy homolog (3.24 and 0.76 g/100 ml, respectively).88 Their ultraviolet spectra resemble those of the 3-alkyl (or aryl)-5-amino-l,2,4-thiadiazoles.88 3-Alkoxy(or aryloxy)-l,2,4-thiadiazoles are more sensitive towards acids than are the 3-alkyl(or aryl) analogs.88... 

D. Amino-1,2,4-thiadiazoles 1. 3- and 5-Amino-1,2,4-thiadiazoles a. Physical Properties. 3-Substituted 5-amino-1,2,4-thiadiazoles are generally stable, colorless, odorless compounds.6,88,86,128 Their thermal stability (as reflected by their melting points), solubility, and resistance to acids are influenced by the nature of the 3-substituent. 5-Alkoxy-3-amino-l,2,4-thiadiazoleB sublime without decomposition.83... 

Alkoxy derivatives are attacked more rapidly by 2N hydrochloric acid, with liberation of sulfur, than are the 3-alkyl derivatives.88 3-Alkylthio groups also increase the sensitivity of 5-amino-l,2,4-thiadiazoles to hydrolysis the 3-phenylthio homolog, for example, tends to decompose on crystallization from boiling water.85... 

Although 3-amino-l,2,4-thiadiazoles (e.g. the 5-phenyl homolog) fail to yield nitrosamines under the usual conditions,126 5-nitrosamines are well known.81, 5,190,191 Thus, 3-alkoxy-,8 3-alkylthio-,85 3-dialkyl-amino-,87 and 3-alkylsulfonyl-5-amino-86 (243) as well as 3-aryl-5-arylamino-l,2,4-thiadiazoles,74 on treatment with the calculated quantity of sodium nitrite in dilute mineral acid, or concentrated formic acid, yield crystalline nitrosamines (244). Their unusual stability has permitted a close study of their formation and properties. 170 Their positive Liebermann reaction85,87,170 and the results of their methylation (outlined in the reaction scheme) show that nitro-sation occurs in the side-chain and not in the nucleus.170... 

Oxidation, by chromic-acetic acid, of the hydroxylamine 272 yields the azoxy-thiadiazole 276 quantitatively, presumably via a primary nitrosamine the interaction of the hydroxylamine (272) with suitable nitrosamines does indeed afford mixed azoxy-thiadiazoles (277), but their exact structure is not known. Alkaline hydrolysis of s-azoxy-thiadiazole (276) yields the 1,2,4-thiadiazole diazotate 278 and hydroxy(or alkoxy)-1,2,4-thiadiazole 279, depending on the hydrolytic reagent employed170 (see also ref. 190). 

Amino-1,2,4-thiadiazoles79 and their 3-alkoxy-, 3-alkylmercapto-, and 3-dialkylamino derivatives84 have been claimed to be useful intermediates in the manufacture of dyes,84 pharmaceuticals,84 and materials valuable in pest control.79 Mono-azo dyes derived from diazotized 5-amino-l,2,4-thiadiazoles and coupling components of the benzene series are especially suitable for dyeing polymeric materials such as acetate rayon, polyamides, polyurethanes, polyesters, and... 

Similar reactions have been carried out with amidines (67NEP6610627). Thus tri-chloroacetamidine (309) reacts with chlorothioformate esters to produce thioacyl products (310) which are readily oxidized to 5-alkoxy-3-trichloromethyl-l,2,4-thiadiazoles (311). The yields in both steps are about 80% (Scheme 111). The bromine oxidation of N-thiocarbamyl derivatives (312) of cyclic amidines (2-aminopyridine, 2-aminothiazole, 2-aminopyrimidine) yields thiadiazolium salts (313) (71JPR1148). In the 2-aminopyridine series, products of type (230 Scheme 81) are obtained in 20-73% yield when R is an ethoxycar-bonyl group (750PP55). 

Alkoxy-l,2,4-thiadiazoles (311 R = alkyl) have been prepared in good yields by the oxidation of AT-alkoxythiocarbonylamidines (310), as indicated in Scheme 148 (also see Scheme 111) (67NEP6610627). 

The 1,3,4-thiadiazole ring system, with three heteroatoms, does not exhibit tautomerism in its fully conjugated form. However, when certain substituents are present, tautomerism is possible. l,3,4-Thiadiazolin-2-ones (39 X = 0) and -2-thiones (39 X = S) exist in the oxo and thione forms, respectively, as shown by spectroscopic and LCAO-MO calculations. 2-Amino-l,3,4-thiadiazoles exist in the amino form in solution and in the solid state the Kt value is 10s as shown by basicity measurements. UV spectroscopy and LCAO-MO calculations show that the amino tautomer is also the main species when there is an alkoxy group in the 5-position (40 R1 = alkoxy, R2 = NH2), or if the exocyclic nitrogen atom is part of a hydrazone group (40 R2 = NHN=CR2). 

The reaction products of cyanogen with alcohols, dialkyl oximidates (44) and alkylcyanoformimidates (45), also available through the reaction of sodium cyanide with chlorine in aqueous alcohol, both react with the sulfur chlorides forming the appropriately substituted thiadiazole. Wen reported the synthesis of diethoxy-1,2,5-thia-diazole (46) from 44 and sulfur dichloride. Several analogs of 45 were converted to 3-chloro-4-alkoxy-l,2,5-thiadiazoles (46a) by treatment with sulfur monochloride. 

In some cases a reagent can be used for cyclizing thiohydrazides, which itself provides an amino group. Thus thioncarbazates (40) are cyclized by cyanogen chloride and cyanogen bromide to 2-alkoxy-5-amino-1,3,4-thiadiazoles (41). ... 

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