1.2.5- Thiadiazole reduction

It is noteworthy that the strain introduced by substituents at the carbon atoms C3-C4 can have a dramatic effect on the stereochemical outcome of the thiadiazole reduction (Equations (4) and (5)). In these cases, Na/EtOH will also reduce the 1,2,5-thiadiazole but with a reversal of stereochemistry (trara-diamine predominates) <91JHC55, 91JHC289>. 

Isothiazoles are reductively desulfurized by Raney nickel, e.g. as in Scheme 31 (72AHC(l4)l). 1,2,5-Thiadiazoles are subject to reductive cleavage by zinc in acid, sodium in alcohol, or Raney nickel, e.g. Scheme 32 (68AHC(9)107). 

Azole 7V-oxide groups are readily removed by reduction with Zn/HOAc, HI or PCI3, e.g. in the pyrazole series. 1,2,3-Thiadiazole 3-oxides isomerize on irradiation to the corresponding 2-oxides. 

Pyridinium iodide, 4,4 (l,3,4-thiadiazole-2,5-diyl)-bis(l-methyl)-reduction, 6, 564 Pyridinium ion, Af-methyl-as metabolite of pyridine, 1, 234 Pyridinium ions hydrogen bonding to water mass spectrometry, 2, 135 magnetic circular dichroism, 2, 129 NMR, 2, 121... 

Step D Chemical Reduction Preparation of 3-Morpholino-4-(3-tert-Butylamino-2-Hydroxy-propoxyl-l,2,5-Thiadiazole — The 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole (0.01 mol) is dissolved in isopropanol (10 ml). To the solution is added sodium borohydride in portions until the initial evolution of heat and gas subsides. The excess sodium borohydride is destroyed by addition of concentrated hydrochloric acid until the mixture remains acidic. The precipitate of sodium chloride is removed, ether is added, and the solution is concentrated to crystallization. The solid material is removed by filtration and dried thus providing 3-morpholino-4-(3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 161° to 163°C (as hydrochloride). 

Alternative Step D Reduction with a Reductate — Sucrose (1 kg) is dissolved in water (9 liters) in a 20-liter bottle equipped with a gas trap. Baker s yeast Saccharomyces cerevisiae, 1 kg) is made into a paste with water (1 liter) and added to the sucrose solution with stirring. After lively evolution of gas begins (within 1 to 3 hours), 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole hydrogen maleate [1.35 mols, prepared by reaction of the 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole with an equimolar quantity of maleic acid in tetrahydrofuran]. The mixture is allowed to stand until fermentation subsides, after which the bottle is kept in a 32°C incubator until all fermentation has ended (in approximately 1 to 3 days). The yeast is filtered off with addition of diatomaceous earth and the filtrate is evaporated to dryness to give S-3-mor-pholino-4/3-tert-butylamino-2-hydroxypropoxy)-1,2,5-thiadiazole, MP 195° to 198°C (as hydrogen maleate), according to U.S. Patent 3,619,370. 

Simple 1,2,3-thiadiazoles show three absorption bands in the ultraviolet (UV) 211-217 (emax 4380-5300), 249-253 (1460-2100), 290-294 (195-245) nm <1996CHEC-II(4)289>. The ESR spectrum for the radical anion generated by the electrochemical reduction of the 1,2,3-thiadiazolium ion 8 has been reported. A number of 5-substituted derivatives were also examined and the splitting constants in the ESR spectrum were analyzed <1998MRC8>. 

Mesoionic derivatives are generally synthesized from the parent 1,2,3-thiadiazoles. A new method based on the rearrangement of oxadiazoles under reductive conditions has been reported. For example, the oxadiazole 70 when... 

Reactions of 1,2,4-thiadiazoles with radicals and carbenes are virtually unknown. Catalytic hydrogenations and dissolving metal reductions usually cleave the N-S bond in a reversal of the oxidative cyclization procedures used in synthesis of 1,2,4-thiadiazoles (see Section 5.08.9.4). 

Thiadiazolidines cannot be prepared by reduction of the corresponding thiadiazoles or thiadiazolines because cleavage of the ring would occur in preference to reduction as a consequence of the harsh conditions required. No preparations of 1,2,4-thiadiazolidines have been reported. 

Electrochemical reduction of various 3,4-disubstituted-l,2,5-thiadiazole 1,1-dioxides (3,4-diphenyl- 10, phenanthro[9,10]- 51, and acenaphtho[l,2]- 53) gave the corresponding thiadiazoline 1,1-dioxides <1999CJC511>. Voltammetric and bulk electrolysis electroreduction of 3,4-diphenyl-l,2,5-thiadiazole 1-oxide 9 at ca. —1.5 V, in acetonitrile, gave 3,4-diphenyl-l,2,5-thiadiazole 8 (50%) and 2,4,6-triphenyl-l,3,5-triazine 54 (30%) (Equation 3) <2000TL3531>. 

Stereoselective hydride reduction of 1,2,5-thiadiazoline 1,1-dioxides 60 generates unsymmetrical 1,2,5-thiadiazol-idine 1,1-dioxides 61 <1998SL623> that can be readily converted to unsymmetrical vicinal diamines 62 with HBr in the presence of phenol (Scheme 5) <1996TL2859, 1998SL623>. The unsymmetrical thiadiazolidine 1,1-dioxides 63 can also be converted into 1,2-diketones 64 on treatment with selenium dioxide followed by alkaline hydrolysis (Equation 7) <1997SL671>. 

The olefin metathesis of 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 and a McMurry coupling reaction (Ti3+ under reductive conditions) of the aldehyde 114 were both unsuccessful <2004TL5441>. An alternative approach via a Wittig reaction was successful. With the use of the mild heterogenous oxidant 4-acetylamino-2,2,6,6-tetramethyl-piperidine-l-oxoammonium perfluoroborate (Bobbitt s reagent), the alcohol 113 was converted into the aldehyde 114. The phosphonium salt 115 also obtained from the alcohol 113 was treated with the aldehyde 114 to give the symmetrical alkene 116 (Scheme 16) <2004TL5441>. 

In combination with the use of tetrasulfur tetranitride, trithiazyl trichloride, or any equivalent source of N-S-N , the technique of functionalizing a two-carbon source such as active methylene, alkene, or alkyne into thiadiazole (see Section 5.09.9.1.4) followed by reduction (see Section 5.09.5.6) provides a rapid route to 1,2-diamines. 

Bakulev et al. reported the synthesis of 5//-[l,2,3]triazolo[5,l-i>] [l,3,4]thiadiazines starting from 5-N-nitrosylamino-l,2,3-thiadiazole 68. Reduction of 68 with SnCh and 1A/HC1 and then subsequent reaction with a ketone gave the imine 69. Treatment of 69 with thionyl chloride at -80 °C led to the formation of the isolable triazolothiazine 70 which on further reaction with thionyl chloride at room temperature gave the corresponding chloro derivative 71 <00MC19>. 

The Vilsmeier-Haack reaction of 2,6-dimethylimidazo[2,T. ][l,3,4]thiadiazole 169 gives aldehyde 170, which after reduction with sodium borohydride affords 2,6-dimethyl-5-hydroxymethylimidazo[2,TA [l,3,4]thiadiazole 171 (Scheme 2) <2000AF550, 2006BMC3069, 2006TL2811>. 

A reductive ring opening of a linearly fused thiadiazole derivative 92 was reported by Nawrocka and Stasko <1997PJC792>. Reaction of this compound with sodium borohydride in methanol under heating afforded the iV-aminoquinazolone-thione 93. 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

Reduction of 3,5-diphenyl-l,2,4-thiadiazole (39) results in loss of sulfur and formation of the benzamidine (40) (Equation (9)). 

Hydrazino-l,2,4-thiadiazoles (124), which can be prepared by reduction of the corresponding nitrosamine (123) (Scheme 29) with LAH, are stable in acid and base and readily form hydrazone derivatives on reaction with suitable carbonyl compounds <65AHC(5)ll9>. In contrast, 3-hydrazino-1,2,4-thiadiazoles (125), which are synthesized by ring closure methods, are very sensitive to acid... 

Metallation of 3,4-dimethyl-l,2,5-thiadiazole (55) to the anion (56) was accomplished with the use of a nonnucleophilic base, lithium diisopropylamide <82JHC1247>. Nucleophilic attack at sulfur resulted in an alkyllithium reagent <70CJC2006>. The lithiomethyl derivative (56) was carboxylated to (57) with carbon dioxide and converted to the vinyl derivative (58) via an esterification, reduction, mesylation, and base elimination sequence (Scheme 12). 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel rafts reaction, thiadiazole acetic acid derivatives, and halo ketones via the Arndt Eistert synthesis and carbinols by hydride reduction <68AHC(9)107>. The dialkylcadmium conversion of acid chlorides into ketones fails in the 1,2,5-thiadiazole series. The major product is either a tertiary carbinol or the corresponding dehydration product, by virtue of the high reactivity of the intermediate ketone. 

Herz salts (89) made from 3-aminopyrazoles (Section 4.11.8.5) give pyrazolo[3,4-r/]-l,2,3-thia-diazoles (90) when subjected to reduction by sodium dithionite followed by nitrozation (Equation (12)) <84JOCl224>. If the reduction is carried out in an inert atmosphere the disulfide (91) is formed which upon nitrozation gives (90) in 63% yield. Notably, benzo-fused Herz salts give benzo-1,2,3-thiadiazoles simply on treatment with nitrozating mixture <84CHEC-I(6)916>. 

The electrophilic substitution of the 3-aryl compounds (265, R = Ar, R = H) exemplified by the formation of 5-bromo- (265, R = Ar, R = Br) and 5-nitro derivatives (265, R = Ar, R = NOj) has been put forward as evidence against the meso-ionic formulation 265. lliis approach is unacceptable since ground state charge distribution cannot be deduced from reaction products. The aluminum-amalgam reduction of meso-ionic l,2,3-thiadiazol-4-ones (265) yields either N-mercaptoacetyl-A-arylhydrazines or Ar-acyl-A-arylbydrazines. Triethyl-oxonium tetrafluoroborate and meso-ionic l,2,3-thiadiazol-4-ones (265) yield 1,2,3-thiadiazolium tetrafluoroborates (267). The effect of solvent on the ultraviolet spectra of meso-ionic l,2,3-thiadiazol-4-ones (265) has been reported. ... 

Phenyl-5-ethoxy-l,2,4-thiadiazole 74 has been synthesised as a by-product (13%) in the reaction of phenylbromodiazirine 73 with potassium ethyl xanthate and was suggested to have arisen by a radical mechanism. As expected, the major product formed in the reaction (87%) was benzonitrile, arising by reduction of the bromodiazirine <99TL29>. 

Reversible electrochemical reduction of the [l,2,5]thiadiazolo[3,4-f][l,2,5]thiadiazole 6 led to the long-lived radical anion 7 and further to the dianion 8. The radical anion 7 was also obtained by the chemical reduction of the parent 6 in an ESR tube with 2 equiv of /-BuOK in degassed absolute MeCN at 50 °C for 20 min (Scheme 9). Electrochemical approaches to generation of the radical cation 12 failed <2005IC7194>. 

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