494 Heterocyclic Chemistry Diazotisation of 4-amino-pyrazoles, then deprotonation yields isolable diazo-pyrazoles.” HN Me { Nano, ‘ag HEL S °C, en AN wen Sy N 25.12 Synthesis of 1,2-Azoles” 25.12.1 Ring Synthesis There ate parallels, but also methods unique to particular 1,2-azoles, in the principal methods available for the construction of pyrazoles, isothiazoles and isoxazoles: neither the reaction of propene with sulfur dioxide and ammonia at 350 °C, which gives isothiazole itself” in 65% yield, nor a synthesis" from propargyl aldehyde and thiosulfate (shown below) have direct counterparts for the other 1,2-azoles. 25.12.11 From 1,3-Dicarbonyl Compounds and Hydrazines or Hydroxylamine Pyrazoles and isoxazoles can be made from a 1,3-dicarbonyl component and a hydrazine or hydroxylamine, respectively. =e Ho RAS ont Sa RY This, the most widely used route to pyrazoles and isoxazoles rests on the doubly nucleophilic character of hydrazines and hydroxylamine, allowing them to react in turn with each carbonyl group of a 1,3-dike- tone’ or 1,3-Keto-aldehyde, often with one of the carbonyl groups (especially when aldehyde) masked as enol ether," acetal, imine™ or enamine," or other synthon for one of these. Me we Me é ¢ Neh . ‘0 ag NaOH. tt PhNHNAs tte YOM ye 10" : 7 cxoMe cHoMety cHoNes eHioMes cH OMFOMA i ee \, 80°C ag. NaOH. OS ey ae oa 35% xt OF onsen 7 Soe “in0.te t0- a-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis 495 When B-keto-esters are used, the products are pyrazolones"® or isoxazolones;!” similarly, -keto-nitriles with hydrazines give 3(5)-amino-pyrazoles."™ 3(5)-Aminopyrazole itself is prepared via a dihydro precursor formed by addition of hydrazine to acrylonitrile then cyclisation;” hydrolysis of the first eyclic intermedi- ate in this sequence and dehydrogenation via elimination of p-toluenesulfinate allows preparation of 3(5)-pyrazolone. Nt ° cso, nora pf EtOH [ 120. heat vem” ANH HSOn “ogg = CNH Us x te FeCl pyedine tH NaHCO, oe! -“ NH ° o Naover - NaOH ePrOH heap \ py atten Pie nest rn y x Generally speaking, unsymmetrical 1,3-dicarbonyl components produce mixtures of 1,2-azole products."* This difficulty can be circumvented in a number of ways: by the use of acetylenic aldehydes or ketones {as synthons), where a hydrazone ot oxime can be formed first by reaction at the carbonyl group, and this can then be cyclised in a separate, second step." A nice example of this is the formation of S-silyl-pyrazoles and -isoxazoles using silyl-alkynones.""* The regioselective reaction of arylhydrazines with 1,3-diketones shows what can sometimes be achieved by careful choice of reaction conditions and solvent.!"* oF ce ArNHNHSHCI . Xx AA DMA, 1OMHC. et e002 a= () " 7% seas Bn yescion a 2019 SON: Pyrazole itself can be formed by the reaction of hydrazine with propargyl aldehyde.” Using B-chloro-, Bealkoxy-!!°-amino-"" -enones as 1,3-dicarbonyl synthons are other ways to influence the regiochemistry of reaction.""* 2-(Dimethoxymethyl)-ketones react with arylhydrazines at the ketonic carbonyl, thus revers- ing the intrinsic reactivity of a B-keto-aldehyde.!"* er ean ts04 - > Santa tee bo Me Me notin A, M50 yn496 Heterocyclic Chemistry 25.12.12 Dipolar Cycloadditions of Nitrile Oxides and Nitrile Imines Isoxazoles are produced by the dipolar cycloaddition of nitrile oxides to alkynes; pyrazoles result from the comparable interaction of alkynes with nitrile imines. Nitrile oxides (R-C=N'~07),"” which can be generated by base-catalysed elimination of hydrogen halide from halo-oximes (RC(Hal)=NOH), or by dehydration of nitro compounds" (RCH;NO,), readily add (o alkenes and to alkynes, generating five-membered heterocycles. Addition to an alkene produces an isoxazoline, unless the alkene 2 cycloaddition, as shown below. system. 2304 ‘0 incorporates a group capable of being eliminated in a step afler the However, isoxazolines can also be dehydrogenated to the aromatic Be ef ec Ft £100. =pyvaidné” = MeN 8 Me 0" Cycloaddition of a nitrile oxide to an alkyne generates an aromatic isoxazole directly, but mixtures are sometimes obtained. "5" 5 Ph MeO;0, Ph oe LN ‘ Ho! A.useful route to 3-bromo-isoxazoles rests on the cycloaddition of bromonitrile oxide." coe [Br mm, Me0,C Br i). | Assent, 7 CHCl rt N Ch } 40% MeN te > Nitrile imines can be generated in a similar way: the dehydrohalogenation of hydrazonyl halides (from N-halosuccinimide and a hydrazone), or, as in the sequence below, elimination of benzenesulfonate.!™ > \1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis 497 ‘The cycloaddition of diazoalkanes to alkynes gives pyrazoles; the use of stannyl alkynes" produces tin derivatives of the heterocycle (cf. 4.1.6), for use in subsquent electrophilic ipso-displacements, or in palladium(0)-catalysed couplings. Aryl-diazomethanes can be generated in situ, from tosylhydrazones, for formation of pyrazoles.”" E10,CCHN, nn-Buy = 25.12.13 From Oximes and Hydrazones Exposure of ketone oximes that have an c-hydrogen to two mole equivalents of n-butyllithium leads to O- and C-lithiation (syn to the oxygen); reaction with dimethylformamide as electrophile then allows C- formylation and ring closure in sifu to a S-unsubstituted isoxazole." Similarly, reaction of the dianion to an acylating agent (an ester’? or a Weinreb amide'™) leads through to S-substituted isoxazoles, or with diethyl oxalate, to isoxazole-Seesters.!” Displacement of the halogen of an c-bromo-ketone oxime with an alkyne leads to an intermediate, which closes to an isoxazole simply on treatment with mild base." Br Ph Ph — < KO, MeSi SU \) MeOH tt N a HO’ ff vo % Mess An elegant route to pyrazoles, involves forming a ring closure precursor by Horner-Emmons con- densation of a tosylhydrazone-phosphonate with an aldehyde, which becomes the 5-substituent; intramo- lecular Michael addition and then loss of toluenesulfinate as the final aromatising step, completes the sequence.""” LL wienasione 2NaH, THE 0 °C.498 Heterocyclic Chemistry Exercises Straightforward revision exercises (consult Chapters 23 and 25): (a) Compare 1,2- with 1,3-azoles in pairs ~ which is the more basic? Why? (b) What is incorrect about the name: '3-methylpyrazole’? (©) Name some groups that can be used to mask the N-hydrogen in pyrazoles during C-lithiation, (@ For what functionality are isoxazoles synthons if the N-O bond is cleaved? How could one cleave the N-O bond? (©) How are 1,3-dicarbonyl compounds used for the synthesis of isoxazoles and pyrazoles? (8 Describe a method involving an electrocyclic process for the ring synthesis of an isoxazole, (g) Describe a method for the utilisation of the oxime of a dialkyl ketone, to make an isoxazole, More advanced exercises: 1, Suggest structures for the isomeric products, CoH;N,O, formed when I-phenylpyrazole is reacted with: (@ ©. HySOJc. HINO, or (ii) AcO/HINO). Explain the formation of different products under the two conditions. 2. Draw structures for the products obtained by reacting 3,5-dimethylisoxazole with NaNH, then: (i) n- PrBr; (ii) COs; or (iii) PnhCOsMe. 3, Deduce structures for the products obtained by treating S-methylisoxazole with SO,Cl ~> C.H,CINO, and this with aqueous sodium hydroxide —> C,H,CINO (which contains no rings), 4, Draw the structures of the products that would be formed from the reaction of BnNHNH, with MeCOCH,COCO.Me. 5. Deduce structures for the products formed in the following sequence: pyrazole/Me;NSO,CV/ EN — C,HN,O,S, then this with n-BuLi/-70 °C, then TMSCI > C,H,)N,O,SSi, then this with PhCH=O/CSF — C)pH,,N,SO:, 6, Draw the structures of the two products that are formed when hydroxylamine reacts with PhCOCH,CH: suggest an unambiguous route for the preparation of 5-phenylisoxazole. 7. Deduce the structures of the heterocyclic substances produced: (i) CsH.NO, from cyclohexanone oxime with 2 mole equivalents of n-BuLi, then dimethyl formamide; (ii) C\yH)sNOSSi from thien-2-yIC(=NOH) CH,Br and Me,SiC=CLi, then K,CO/MeOH; (iii) CyHi.N, from MeCOC(=NNHPh)Me with (F10),POCH,SEUn-BuLi. 8, Suggest a structure for the heterocyclic product, C;H,sNOSi, formed by reaction of Me,SiC=CC=CSiMe, and hydroxylamine, References ‘Progress in pyazoe chemistry’, Kos, A.N. and Grandber, 1.1, Ad Heterocycl Chem. 196, 6, 47;The Azole, Sshofelé K., Gomes, M. R and Keene, BRT. 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