Lactones, reaction with hydrazine

Reaction of the Lactone Group with Hydrazine and Derivatives... 

Most of the isobenzofurans that have been used as substrates for phthalazine syntheses are in practice either l,3-dihydro-l,3-isobenzofurandiones (i.e., phthalic anhydride derivatives) or 1,3-dihydro-l-isobenzofuran-l-ones (i.e., the lactonic phthalides), both of which normally undergo ring fission and reaction with hydrazine or the like to give phthalazinones. Discussion of these syntheses is subdivided according to the type of substrate used. 

It was found that the reaction of the lactone glycosides (5/ )- and (5S)-5-methoxy-5-(2,3,5-tris-(9-benzoyl-/3-D-ribofuranosyl)-2(5//)-furanone270and271 with hydrazine hydrate in methanol gave two products the pyridazinone 272 and a mixture of diastereomeric A -aminopyrrolinones 273, which could not be separated, in yields of 26 and 71%, respectively (Scheme 70) (87JOC4521). 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Finally, the amino metabolites of the NMs have been synthesized by researchers and used as standards. These synthesis methods include reduction of NMs with hydrogen in the presence of Pd/charcoal to form the amino metabolites [ 15,16,23] or reaction of NMs with hydrazine hydrate and Raney nickel [ 14,23]. A metabolite of HHCB, HHCB-lactone, has also been synthesized and used as a standard [17]. 

Sugar lactones react readily with hydrazine to give crystalline derivatives useful for isolation and identification (127). Thus, addition of hydrazine to a reaction mixture containing an aldonolactone facilitates isolation of the product. The lactone may be regenerated from the hydrazide by treatment with nitrous acid (128). The phenylhydrazides obtained on treatment of aldonolactones with phenylhydrazine are also useful for characterization (129,130). 

The 2,5-dibromo-2,5-dideoxy-D-xylono-1,4-lactone (6) (Scheme 2) can also be selectively reduced to give 5-bromo-2,5-dideoxy-D-fhreo-pentonolactone (7) by reaction with either aqueous hydrazine as mentioned above, or by consumption of 1 mole of hydrogen [ 14]. Further reaction with hydrogen and Pd/C leads to 3-hydroxypentanoic acid by an initial reductive elimination [15]. Reduction of the primary bromine in these cases can be obtained by means of tributyltin hydride [25] to give 8. 

Only one example of a derivative of this ring system has been reported. This compound, 2,6-dimethyl-3,4-dioxo-2,3,4,6,7,8-hexahydropyridazino[4,3-c]pyridazine 4-(p-bromo-phenylhydrazone) (149), was obtained in the reaction of the lactone (148) with methyl-hydrazine. A proposed mechanism for this unusual reaction is shown (80JHC617). 

Deoxy-D-vy/o-hexuronic acid was obtained in good yield via the reaction of 1,2-0-cyclohexyliden-5-0-(methylsulfonyl)-a-D-glucofuranurono-1,4-lactone with hydrazine.196... 

Eschenmoser s pyrone 38 on treatment with cyclopropenone ketal 39 in refluxing benzene afforded lactone 40 (73%). Lactone 40 on hydrolysis with acetic acid at 100°C afforded, after deprotection and decarboxylation, tropone 37 (70%). Introduction of the tropolonic hydroxyl group was achieved with hydrazine hydrate in ethanol, to give a mixture of deacetyl-colchiceinamides 41 (53%) and 42 (37%), followed by reaction with ethano-lic potassium hydroxide, which afforded tropolones 43 and 44, respectively. Tropolone 43 was converted to 44 which, therefore, became the major reaction product. Methylation of 44 gave a mixture of enol ether 18 and 45 which were separated by chromatography. 

The lactones 81 and 82 on heating with hydrazine hydrate gave rise to the diazepinones 83 and 84, respectively.68 Treatment of 83 and 84 with glacial acetic acid and sodium nitrite caused loss of a nitrogen atom with formation of a lactam.68 This loss of a nitrogen has been noted above for other 1,2-diazepines and appears to be a fairly general reaction under a variety of conditions. A somewhat more complex quinobenzodiazepine has also been prepared.69... 

Five-membered heterocycles have been used as substitutes for the y-lactone ring of cardenolides. Thus, the 17 -(5 -isoxazolyl)- and 17)8-(3 -pyrazolyl)-cardenolides (526) and (527) have been prepared from 20-ethoxy-21-formyl-3 -acetoxy-17)8-pregna-5,14,20-triene (528) by reaction with hydroxylamine and hydrazine hydrate, respectively. The isomeric 14a,15a- and 14) ,15/S-epoxides (529) and (530) in both series were then obtained by peracid treatment or alkaline cyclization of the respective 14,15-bromohydrin. 

Apart from the A-methylated compound,1 examples for derivatives of the fully conjugated pyridazino[4,3-c]pyridazine or the unsubstituted compound 1 itself are not known. Attempts to synthesize 4,8-diphenylpyridazino[4,3-c]pyridazine-3,7-diol (3) by reacting pulvinic acid lactone 2 with an excess of hydrazine failed, instead 6-benzyl-4-phenylpyridazine-3,5-diol (4) was produced. The reaction is thought to proceed via the attack of hydrazine on one lactone ring and water on the other, followed by decarboxylation.4... 

Reaction of 5-hydroxy- or 5-ethoxy-y-lactones with hydrazine has been developed as a route to... 

Diastereoselectivity is also observed in reactions of carbanions derived from imines and hydrazones, when those species contain a chiral center or a chiral auxiliary (sec. 9.4.F). Asymmetric imines can be used, and chiral oxazoline derivatives have also been prepared and used in the alkylation sequence (sec. 9.3.A). Meyers showed that chiral oxazoline 478 could be alkylated to give the ethyl derivative, 479. A second alkylation generated the diastereomeric product 480, and hydrolysis provided the chiral lactone (481) in 58% yield and with a selectivity of 70% ee for the (R) enantiomer. 53 As pointed out in Section 9.4.F.ii, hydrazone carbanions can be used for alkylation or condensation reactions. In a synthesis of laurencin. Holmes -l prepared the asymmetric hydrazone 483 (prepared by Enders by reaction of cycloheptanone and the chiral hydrazine derivative called SAMP, 482-A-amino-(2S)-(methoxymethyl)pyrrolidine)- - and showed that treatment with LDA and reaction with iodomethane gave an 87% yield of the 2-ethyl derivative in >96% de. Ozonolysis cleaved the SAMP group to give (/ )-2-ethylcycloheptane (484) in 69% yield. The enantiomer of 482 is also known (it is called RAMP, A-amino-(27 )-(methoxymethyl)pyrrolidine). 

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