Hydrazine heterocycle synthesis

The chemistry of these very electron-deficient rings mostly concerns nucleophilic attack and displacement of leaving groups such as Cl by nucleophiles such as alcohols and amines. To introduce this subject we need to take one heterocyclic synthesis at this point, though these are properly the subject of the next chapter. The compound maleic hydrazide has been known for some time because it is easily formed when hydrazine is acylated twice by maleic anhydride. 

In the same domain of heterocyclic synthesis, much effort has been devoted to understanding the selectivities in the synthesis of indoles starting from phenylhydrazine and ketones, i.e. the Fischer indole synthesis. With phenyl-hydrazine, l-phenyl-2-butanone and zeolite H-Beta, the slimmer product 2-phenyl-3-methylindole dominates over the more bulky isomer (13) ... 

Reactions of acetylenes with hydrazines in synthesis of N-heterocycles ... 

Cyclization of an o-benzoyl-isothiocyanate occurs at low temperatures on treatment with a primary amine or hydrazine, the latter behaving as a monofunc-tional reagent. The use of isothiocyanates in heterocyclic synthesis has been reviewed 13593, 3990]. 

We are going to look at these compounds briefly here. Pyrimidine is more important than either of the others because of its involvement in DNA and RNA— you will find this in Chapter 42. All three compounds are very weak bases—hardly basic at all in fact. Pyridazine is slightly more basic than the other two because the two adjacent lone pairs repel each other and make the molecule more nucleophilic (the a effect again see p. 513). The chemistry of these very electron-deficient rings mostly concerns nucleophilic attack and displacement of leaving groups such as Cl by nucleophiles such as alcohols and amines. To introduce this subject we need to take one heterocyclic synthesis at this point, although these are properly the subject of the next chapter. The compound maleic hydrazide has been known for some time because it is easily formed when hydrazine is acylated twice by maleic anhydride. 

Heterocycle Synthesis. The reaction of hydrazine with a,p-unsaturated ketones yields pyrazoles. Although the products can be isolated as such, they are useful intermediates in the synthesis of cyclopropanes upon pyrolysis of cyclopropyl acetates after treatment with Lead(IV) Acetate (eq 11). 

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

Heterocyclics. One of the most characteristic and useful properties of hydrazine and its derivatives is the ability to form heterocycHc compounds. Numerous pharmaceuticals, pesticides, explosives, and dyes are based on these rings. A review of the appHcation of hydrazine in the synthesis of heterocychcs is available (91). For further information in the field of heterocycHc chemistry, see the General References. 

Hydrazine and its derivatives find considerable use in the synthesis of biologically active materials, dyestuff intermediates and other organic derivatives. Reactions of aldehydes to form hydrazides (RCH=NNH2) and azines (RCH=NN=CHR) are well known in organic chemistry, as is the use of hydrazine and its derivatives in the synthesis of heterocyclic compounds. 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

The preparation of pyrazoles from heterobut-l-en-3-ynes and hydrazine provides the main pathway to the synthesis of these fundamental heterocycles [67HC (22)284 74MI2],... 

Amino-5-hydrazinopyrazole dihydrochloride 300 is a good source for the synthesis of this type of heterocyclic compound [78JCS(P1)885] and it was prepared by reaction of malononitrile with two equivalents of hydrazine. Reaction of 300 with ethyl pyruvate afforded 301. Unstable hydra-zone 302 formed when 300 was boiled with diacetyl rapidly cyclized to 303. Reaction of 300 with benzil gave 304 directly, which gave an acetyl derivative and resisted reductive deamination. On the other hand, a polymer was isolated from the reaction of 300 with glyoxal (Scheme 65). 

The potential of such reaction sequences for the generation of molecular diversity was also demonstrated by the synthesis of a library of heterocycles. Epoxide ring-opening with hydrazine and subsequent condensation with (3-diketones or other bifunctional electrophiles gave rise to a variety of functionalized heterocyclic structures in high purity [34]. A selection based on the substrate derived from cyclohexene oxide is shown in Scheme 12.12. 

Hydrazides (RCONHNH2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5... 

Recent studies have been directed towards the synthesis of heterocyclic hydrazones which have lower toxicities than thiosemicarbazones [44], It has been proposed that the hydrazinic N-H group is essential for activity since it might be involved in a crucial radical formation step important in the mechanism of RDR. This is supported by the loss of antileprotic activity for this series of compounds when the hydrazinic hydrogen is replaced by a methyl group [44]. The heterocyclic hydrazones, like thiosemicarbazones, behave as tridentate ligands. 

Heterocycles can be employed as precursors for the synthesis of pyrazoles. Pyrazoles can be synthesized by three-membered ring substrates. For example, allyl amines 12 and pyrazoles 13 could be obtained by hydrazinolysis of 2-ketoaziridines 11 <06TL255>. Regioselective ring opening of 3-aryl-2-benzoyl-l,l-cyclopropanedicarbonitriles 14 with hydrazine provided a new process for the synthesis of 5-aryl-3-phenylpyrazoles 15 <06JHC495>. 

Synthesis of a great variety of heterocyclic structures becomes possible on utilization of hydrazines. Diazaphospholanes (64) and (65) were obtained by the interaction of bis(hydroxymethyl)phosphine with hydrazines [Eq. (32)] (81TL229). 

This group of nucleosides could also be named glycerolyl heterocycles. A modified procedure for the synthesis of the pyrazole nucleoside 1026 was carried out by the hydrazinolysis of the epimeric hydrazine 1025, obtained from 1024, by hydrolysis with HCl. The use of 1025 is more efficient than using 1027 obtained from the hydrazinolysis of 1023, which in turn was obtained from 1022 [75JHC75 85JCS(P1)1425]. 

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