Synthesis from aryl diazonium salts

The profitable conversion of thiouronium salts into dialkyl thioethers (see Section 4.1) is less successful for synthesis of diaryl thioethers. For example, l-chloro-4-nitrobenzene reacts with bis-thiouronium salts of the type (H2N)2CS(CH2) SC(NH2)2+ under soliddiquid and liquidrliquid conditions to produce the desired bis-thioethers, ArS(CH2) SAr, (20-35%), together with the diaryl sulphide, Ar2S (5-15%). Higher yields of the diaryl sulphide are observed under liquiddiquid conditions whereas, under solidiliquid conditions, the diaryl disulphide, (ArS)2, (20%) is also formed [56], Diaryl disulphides are the sole products (>65%) from the stoichiometric reaction of aryl diazonium salts with benzyltriethylammonium tetrathiomolybdate [57],... 

Formazans are conveniently produced under phase-transfer catalytic conditions from Af-aryl hydrazones and aryl diazonium salts [24], Yields vary from ca. 50% to 70%, but the procedure is superior to the standard synthesis. 

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

Due to the potential explosive nature of aryl diazonium salts, the reader is urged to consult the original literature before attempting any BS synthesis. For example, a great difference exists in the stability of the diazonium tetrafluoroborates derived from the isomeric aminopyridines, aminoquinolines, and aminoisoquinolines. Thus, whereas the diazonium tetrafluoroborate from 2-aminoquinoline decomposes as it forms at room temperature, the same diazonium salt from 3-aminoquinoline is stable enough to be isolated and dried, decomposing only at 95 °C.32... 

When Pschorr reported more than a century ago on the first intramolecular homolytic aromatic substitution [25], he showed that biaryls could be readily prepared by intramolecular homolytic aromatic substitution using reactive aryl radicals and arenes as radical acceptors. The aryl radicals were generated by treatment of arene-diazonium salts with copper(l) ions. Today, this reaction and related processes are referred to as Pschorr reactions. It was later found that radical biaryl synthesis could be conducted without copper salts by photochemical or thermal generation of the aryl radical from the corresponding diazonium salt [26], Moreover, the reduction of aryl diazonium salts offers another route to generate reactive aryl radicals. Hence, electrochemistry [27], titanium(lll) ions [28], Fe(II)-salts [29], tet-rathiafulvalene [30] and iodide [31] have each been used successfully for the reduction of diazonium salts to generate the corresponding aryl radicals [32]. As an example, the iodide-induced cycUzation of diazonium salt 6 to phenanthrene derivative 7 is presented in Scheme 13.3 [31]. For further information on the... 

SCHEME 15 HRC one-pot synthesis of 2-quinolone from 2-(2-nitrophenyl)acrylates and aryl diazonium salts catalyzed by in situ generated Pd/C. 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

Heck olefination of a diazonium salt is a key step in the industrial synthesis of sodium 2-(3,3,3-trifluoropropyl)benzenesulfonate, en route to Novartis sulfonylurea herbicide Prosulfuron (Scheme 15) [46]. Pd(dba)2 (0.5-1.5 mol%, prepared in situ from PdCl2), is used as catalyst. After completion of the arylation step, charcoal is added, thus directly providing a heterogeneous catalyst for the subsequent hydrogenation step and enabling easy removal of the now supported catalyst by filtration. 

Among the early synthetic works, we wish to mention here the synthesis of polyporic acid (3) [115] and thelephoric acid (82) [78]. As summarised in Scheme 3a, several terphenylquinones have been synthesized with moderate yields starting from 2,5-dichlorobenzoquinone by arylation with V-nitrosoacetanilides or diazonium salts and subsequent alkaline hydrolysis. This method allowed preparation of symmetrical and unsymmetrical terphenylquinones, this latters with low yields. 

Diazonium intermediates have also been employed in the synthesis of pyrazoles. A convenient one-pot procedure for the preparation of 3-phenyl- or 3-pyridylpyrazoles 27 from the 1,3-dipolar cycloadditions of phenylacetylene or 3-(pyridyl)acetylene with diazo compounds 26 generated in situ from aldehydes 25 has been reported <03JOC5381>. Cyclization of ortho-(arylethynyl)benzene diazonium salts 28 having substituents at the para-position of the aryl ring furnished indazoles 29 <03TL5453>. 

The advantages of the synthesis of aryl halides from diazonium salts will be discussed in detail in Sec. 25.3. Aryl fluorides and iodides cannot generally be prepared by direct halogenation. Aryl chlorides and bromides can be prepared by direct halogenation, but, when a mixture of 0- and p isomers is obtained, it is difficult to isolate the pure compounds because of their similarity in boiling point. Diazonium salts ultimately go back to nitro compounds, which are usually obtainable in pure form. 

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