From Thiosemicarbazides

TABI.R 11-21 2-HYDRAZINOTHIAZOLES FROM THIOSEMICARBAZIDES AND a-HALOCARBONYL COMPOUNDS... 

Amino-5-alkyl- or 5-phenyI-l,3,4-thiadiazoles are prepared most conveniently from thiosemicarbazide. For example, benzalthiosemicarbazone by oxidation with iron(III) chloride gives the 5-phenyl derivative. Thiosemicarbazide is also used in the synthesis of 2-amino-5-mercapto-l,3,4-thiadiazole by reaction with carbon disulfide. The product may be alkylated to yield the 5-alkylthio derivatives using a variety of alkylating agents (58MI11201). 

The parent molecule, 1,3,4-thiadiazole (174), was first synthesized in 1956 by a four-step reaction sequence starting from thiosemicarbazide. A second procedure utilizes hydrazine and potassium dithioformate. A later procedure is shown in Scheme 19. Dehydration of DMF with thionyl chloride or phosgene gives the formamidoyl chloride (172) which on... 

Hydrazinothiazoles, synthesis of, from thiosemicarbazides and a-halo-caibonyl compounds, 251, 256... 

Hydrazinylthiazoles, from thiosemicarbazides of nicotinic and isonicotinic acids and o-halocarbonyl compounds. 

Early reports " of 2-imino-l,3-thiazetidines (e.g., 479) being formed from thiosemicarbazide derivatives should be treated skeptically in view of the large dipole moment (8.4 obtained for the compound purported to have structure 479 84oa structure 480 was favored. Further examination of the older work suggests that some of the other structures obtained were 2-amino-5-mercapto-1,3,4-thiadiazoles and not analogs of 479 which, incidentally, violates Bredt s rule. 

The hydrazones of thiocarbohydrazides also react in this manner (304). The 5-amino-.d4-1,3,4-thiadiazoline-2-thiones, which may be prepared from thiosemicarbazides and carbon disulfide, are listed in Table 19-The preparation of these compounds from dithiocarbazic acid esters and isothiocyanates in basic medium is discussed in Section VII.7. It must be pointed out that the numbering of the substituents in Guha s paper (146) is not always very clear so that, for the last three substances in Table 19, there is some doubt about the position of the substituents. 

The 5-R2-amino-J4- l,3,4-thiadiazolinc-2-thioncs (CXVa) formed by cyclization of (CCXXXVII) in alkaline medium (method B) are listed in Table I9. The synthesis of these products from thiosemicarbazides and carbon disulfide (method A) has already been discussed in Section IIL4. 

Thiosemicarbazones are also mostly sparingly soluble and crystallize well. They are obtained from thiosemicarbazide in alcoholic solution. 

Of the ring systems under discussion in this chapter, only the pyrrolotriazoles (2) and (3) and the pyrrolothiadiazoles (7) have been prepared by more than one route. For example, pyrrolo[l,2-6][l,2,4]triazoles (2) have been prepared (i) by cyclization of substituted triazolium salts (Equation (1)), a [5 + 0] synthesis (ii) from cyclic amidrazone (73, Scheme 11), a [4 + 1] synthesis (iii) from thiosemicarbazides (90, Scheme 15), a synthesis involving simultaneous formation of both rings and (iv) from triazolo[4,3-6]pyridazines (94, Scheme 16) by photochemical addition of an alkene. However, as each of these routes yields different groups of products and no individual compound has been prepared by more than one of these routes, it is not possible to compare them in a meaningful manner. The same is true for ring systems (3) and (7). 

Scheme 16.70. Preparation of sulfonamide protected 2-amino-l,3 4-thiadiazoles and 1,3,4-oxadiazoles from thiosemicarbazides.

Thiatriazines. Oxidative cyclization of product from thiosemicarbazides -f (aryl isocyanates (Scheme 30) or benzonitriles (Scheme 31)). 

Hydrogen peroxide potassium hydroxide Semicarbazides from thiosemicarbazides s. 19,129... 

From Thiosemicarbazides. Cyclization of acylthiosemicarbazides. The dehydrative cyclization of acylthiosemicarbazides, one of the oldest syntheses in this field, has now provided compounds of stereochemical interest, viz. trans- and c/j-5-[2-(5-nitro-2-furyl)-l-(2-furyl)vinyl]-2-amino-1,3,4-thiadiazoles (59) and (60). Analogues of type (61) were similarly obtained. ... 

From thiosemicarbazides and thio)phosgene. Sasse has carefully reexamined the old-established synthesis of 1,3,4-thiadiazolines from substituted thiosemicarbazides and (thio)phosgene. 

Diaminotetrazole (35) is prepared from thiosemicarbazide by H2S-elimination with PbO and cycloaddition of hydrazoic acid to the intermediately formed aminocarbodiimide (34) ... 

Azothioformamides from thiosemicarbazides NHNHCSN < N NCSN < 355. CHjO- V-NHNHCSNHCHs -> CH30-/ V-N=N-CSNHCH3... 

The standard synthesis of 5-substituted 2-amino-l,3,4-thiadiazoles from thiosemicarbazides and carboxylic acids has been improved by the use of a mixture (3 1) of polyphosphoric acid and concentrated sulphuric acid as the condensing agent the use of either acid alone produces lower yields. ... 

Horse heart cytochrome c (Sigma, type VI) was purified by chromatography on a Whatman CM-32 column at 4 C as described previously 24 according to the literatures 28 Pyridine aldehyde thiosemicarbazones (PATS) and benzaldehyde thiosemicarbazone (BATS) were synthesized from thiosemicarbazide and corresponding aldehydes , and recrystallized from ethanol. All other reagents were of analytical grade, and used as received. 

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