杂环化学市公开课金奖市赛课一等奖课件

1、6 Six-membered Heterocycles芳香六元杂环化合物第1页芳香六元杂环化合物类型第2页芳香六元杂环化合物类型第3页6.1 PyridinePyridine is the simplest heterocycle of the azine type. It is derived from benzene by replacement of a CH group by an N-atom. The pyridinium ion is isoelectronic with benzene. Methylpyridines are known as picolines, dimet

2、hylpyridines as lutidines and 2,4,6-trimethylpyridine as collidine.第4页6.1 PyridineElectrophilic reactions on nitrogen第5页6.1 Pyridine Electrophilic substitution reactions第6页6.1 Pyridine -NitrationElectrophilic substitution reactionsNitration of pyridine with HNO3/H2SO4 occurs under drastic conditions

3、 (ca. 300C), but yields only ca. 15% of 3-nitropyridine. N2O5, however, gives rise to good yields of 3-nitropyridine (ca. 70%) when reacted in CH3NO2 or SO2.第7页6.1 Pyridine -SulfonationElectrophilic substitution reactionsSulfonation of pyridine with oleum at 250C with Hg(II) catalysis yields the pyr

4、idine-3-sulfonic acid in 70% yield第8页6.1 Pyridine -HalogenationElectrophilic substitution reactionsHalogenation of pyridine occurs with elemental chlorine or bromine at high temperature. 3-Halo- and 3,5-dihalopyridines are formed at ca. 300C as a result of an ionic SEAr process.At higher than 300C,

5、2-halo- and 2,6-dihalopyridines are produced, probably by a radical mechanism.第9页6.1 Pyridine Nucleophilic substitution reactions and metalationAs expected, N-, O-, S- and C-nucleophiles attack the ring C-atoms of pyridine. Addition of the nucleophile and elimination of a pyridine substituent as lea

6、ving group occur in a two-step process.第10页6.1 Pyridine Nucleophilic substitution reactions and metalation第11页6.1 Pyridine Nucleophilic substitution reactions and metalation第12页6.1 Pyridine Nucleophilic substitution reactions and metalationPyridine shows complex behaviour towards GRIGNARD reagents.第

7、13页6.1 Pyridine Additions of nucleophiles to pyridinium ionsN-Alkylpyridinium ions add hydroxide ions reversibly and exclusively in the 2-position, forming 2-hydroxy-l,2-dihydro-N-alkylpyridines which can be oxidized by mild oxidizing agents to N-alkyl-2-pyridones第14页6.1 Pyridine Side-chain reactivi

8、ty of pyridineAlkylpyridines undergo reactions analogous to benzene such as side-chain halogenation and oxidative functionalization.第15页6.1 Pyridine Side-chain reactivity of pyridine第16页6.1 Pyridine Side-chain reactivity of pyridine第17页6.1 Pyridine Side-chain reactivity of pyridine第18页6.1 Pyridine R

9、eactions of pyridine N-oxidesN-Oxidation of pyridine is carried out with peroxy acids and deoxygenation back to pyridine is brought about by a redox reaction with phosphorus(III) compounds such as PCl3, PPh3 or P(OC2H5)3第19页6.1 Pyridine Reactions of pyridine N-oxidesPyridine- 1 -oxide undergoes elec

10、trophilic and nucleophilic substitution reactions at the 2- and 4-positions, as predicted from its resonance description第20页6.1 Pyridine Reactions of pyridine N-oxides第21页6.1 Pyridine Reactions of pyridine N-oxidesPyridine-N-oxides undergo alkylation and acylation at oxygen. O-Alkylation occurs most

11、 readily with benzyl halides under mild conditions and leads to 1-benzyloxypyridinium ions which in a basic medium, e.g. aqueous alkali, undergo disproportionate into arylaldehydes and pyridine第22页6.1 Pyridine OxidationThe pyridine ring is remarkably stable towards oxidation. Therefore, pyridine ser

12、ves as a solvent for oxidation reactions in the Collins oxidation with CrO3. Aqueous KMnO4, preferably in a basic medium, oxidizes pyridine to CO2; peroxy acids bring about N-oxidation to pyridine-1-oxide.第23页6.1 Pyridine Reduction第24页6.1 Synthesis of PyridinePyridine synthesis by cyclocondensation第

13、25页6.1 Synthesis of PyridinePyridine synthesis by cycloaddition第26页6.1 Synthesis of PyridineHetero-Diels-Alder reaction第27页6.1 Synthesis of PyridinePyridine synthesis via ring transformations第28页6.2 QuinolineQuinoline is derived from naphthalene by replacement of one of its a-CH groups by nitrogen.

14、2-and 3-Methylquinoline (quinaldine and lepidine), 2-quinolone (carbostyril), 4-quinolone and the quinolinium ion are important derivatives of quinoline.第29页6.2 QuinolineElectrophilic substitution reactionsNitration第30页6.2 QuinolineElectrophilic substitution reactions第31页6.2 QuinolineElectrophilic s

15、ubstitution reactions第32页6.2 QuinolineNucleophilic substitution reactions第33页6.2 QuinolineNucleophilic substitution reactions第34页6.2 QuinolineSide-chain reactivity第35页6.2 Quinoline Oxidation第36页6.2 Quinoline Reductions第37页6.2 Quinoline Reductions第38页6.2 Synthesis of Quinoline第39页6.2 Synthesis of Qui

16、noline第40页6.2 Synthesis of Quinoline第41页6.2 Synthesis of Quinoline第42页6.2 Synthesis of Quinoline第43页6.2 Synthesis of Quinoline第44页6.2 Synthesis of Quinoline第45页6.2 Synthesis of Quinoline第46页6.2 Synthesis of Quinoline第47页6.2 Synthesis of QuinolineMeth-Cohn synthesis第48页6.2 Synthesis of Quinoline第49页6

17、.2 Synthesis of Quinoline第50页6.2 Synthesis of QuinolineQuinolines are accessible by ring transformation of other heterocyclic systems.第51页6.2 Synthesis of Quinoline第52页6.3 Isoquinoline 异喹啉Isoquinoline is derived from naphthalene by replacement of a -CH group by nitrogen. The isoquinolinium ion and 1

18、-isoquinolone isoquinolin-1(2H)-one, isocarbostyril are important derivatives of isoquinolines.第53页Electrophilic substitution reactions第54页Nucleophilic substitution reactions第55页Nucleophilic substitution reactions第56页Nucleophilic substitution reactions第57页Side-chain reactivity第58页Oxidation第59页Reduct

19、ion第60页Synthesis of isoquinoline第61页Synthesis of isoquinoline第62页Synthesis of isoquinoline第63页Synthesis of isoquinoline第64页Synthesis of isoquinolinePomeranz-Fritsch synthesis第65页Pictet-Spengler synthesis第66页Synthesis of isoquinoline第67页Synthesis of isoquinoline第68页6.4 Dibenzopyridines吖啶菲啶第69页Reactio

20、ns of dibenzopyridines第70页Reactions of dibenzopyridines第71页Reactions of dibenzopyridines第72页Reactions of dibenzopyridines第73页Reactions of dibenzopyridinesPhenanthridine is oxidized to 6-phenanthridone and quinoline-3,4-dicarboxylic acid by the action of ozone, followed by treatment with alkaline H2O

21、2 solution:第74页Synthesis of acridines and phenanthridinesUllmann synthesis第75页Synthesis of acridines and phenanthridinesBernthsen synthesis第76页Synthesis of acridines and phenanthridines第77页Synthesis of acridines and phenanthridines第78页Synthesis of acridines and phenanthridines第79页6 Six-membered Hete

22、rocycles芳香六元杂环化合物( 2 )第80页6.5 磷杂苯 Phosphabenzene第81页6.5 磷杂苯 Phosphabenzene第82页6.5 磷杂苯 Phosphabenzene第83页Synthesis of phosphabenzenes第84页6.6 哒嗪 Pyridazine第85页6.6 哒嗪 PyridazineReactions of pyridazine also show analogies to pyridine. Electrophiles attack the ring N-atoms,for instance in protonation, al

23、kylation or N-oxidation. SEAr reactions at the ring C-atoms are difficult to carry out, even in the presence of activating substituents due to the deactivation by the additional N-atom. However, N-oxidation facilitates the substitution in some cases.第86页6.6 哒嗪 Pyridazine3-Substituted pyridazine-1-ox

24、ides react with cyanide by analogy to a REISSERT reaction functionalizing the C-6 position。第87页Synthesis of pyridazines第88页Synthesis of pyridazinesSchmidt-Druey synthesis第89页Synthesis of pyridazines第90页6.7 嘧啶 PyrimidineIn its reactions, pyrimidine behaves as a deactivated heteroarene. Its reactivity

25、 is comparable to that of 1,3-dinitrobenzene or 3-nitropyridine. Electrophiles attack on nitrogen in protonating and alkylating reactions. Electrophilic substitutions at carbon are not observed in the parent compound. Electron-donating substituents (OH, NH2) increase the SEAr reactivity in the pyrid

26、midine system (two substituents give a reactivity corresponding to benzene, three to that of phenol) and enable nitration,nitrosation, aminomethylation and azo-coupling to take place at the 5-position。第91页6.7 Reactions of Pyrimidine第92页6.7 Reactions of Pyrimidine第93页6.7 Reactions of Pyrimidine第94页6.

27、7 Reactions of Pyrimidine第95页6.7 Synthesis of PyrimidinePinner synthesis第96页6.7 Synthesis of Pyrimidine第97页6.7 Synthesis of PyrimidineShaw synthesisRemfry-Hull synthesis第98页6.7 Synthesis of PyrimidineIn a novel principle of 1,3-diazine formation phosphazenes like 20 containing an amidine moiety unde

28、rgo an aza-WlTTlG reaction with a,-unsaturated aldehydes followed by oxidative electrocyclic ring closure to pyrimidines.第99页6.7 Synthesis of Pyrimidine第100页6.8 吡嗪 PyrazineThe symmetrical 1,4-diazine structure is reflected in the 1H- and 13C-NMR spectra (CDCl13) with one signal for the ring protons

29、(S= 8.60) and one for the ring C-atoms (S= 145.9). Pyrazine shows UV maxima at 261 (3.81), 267 (3.72) and 301 nm (2.88) (H2O).第101页6.8 吡嗪 PyrazinePyrazine is more reactive than pyridine towards nucleophiles. Although the CHICHIBABIN animation is unsatisfactory, substitution of the halogen in 2-halop

30、yrazine occurs readily by ammonia, amines, amide, cyanide, alkoxide and thiolate.第102页6.8 吡嗪 Pyrazine第103页6.8 吡嗪 PyrazineLike the other diazines and pyridine, alkylpyrazines can undergo base catalysed C-C bond-forming reactions of the CH groups adjacent to the heteroatom. 2-Methylpyrazine, after dep

31、rotonation with NaNH2 in liquid NH3 via anion 13, can be alkylated, acylated and nitrosated:第104页Synthesis of pyrazine1 ,2-Dicarbonyl compounds and 1 ,2-diaminoethanes cyclocondense (with double imine formation) to afford 2,3-dihydropyrazines 20 which are conveniently oxidized to pyrazines 21 by CuO

32、 or MnO2 in KOH/ethanol:第105页Synthesis of pyrazineThe classical pyrazine synthesis involves the self-condensation of two molecules of an a-aminocarbonyl compound furnishing 3,6-dihydropyrazine followed by oxidation, usually under mild conditions, to pyrazine.第106页Synthesis of pyrazinePyridazine deri

33、vatives can also be obtained from dioxopiperazines by oxidation with trialkyloxonium salts forming bislactim ethers. On oxidation with DDQ, they are dehydrogenated providing 2,5-dialkoxypyridazines.2.3-dichloro-5,6-dicyanobenzoquinone2,3-二氯-5,6二氰苯醌 第107页Synthesis of pyrazineA regioselective synthesi

34、s of alkylpyrazines starts from a-hydroxyimino ketones.第108页6.9 嘌呤 PurineFor historical reasons, the numbering of purine (imidazo4,5-dpyrimidine) does not comply with IUPAC rules.第109页6.9 嘌呤 Reactions of PurinePurine undergoes reactions with electrophiles and nucleophiles. Protonation of purine occu

35、rs at N-l, but alkylation at N-7 and/or N-9. This is shown by its reactions with dimethyl sulfate, iodomethane and vinyl acetate:第110页6.9 嘌呤 Reactions of PurineNucleophilic substitution can be carried out on purine itself as well as on halo-, alkoxy- and alkylsulfanylpurines. The CHICHIBABIN reactio

36、n of purine with KNH2 in liquid ammonia leads to 6-aminopurine (adenine).第111页6.9 嘌呤 Reactions of PurineHalogen substituents in the purine system display a leaving group ability which decreases in the series C-6 C-2 C-8. This is demonstrated by the synthetic steps leading from 2,6,8-trichloropurine

37、to guanidine(鸟嘌呤):第112页Synthesis of PurineTraube synthesis第113页Synthesis of PurineIn some cases, purines are prepared from 4,5-disubstituted imidazoles by cyclocondensation with formic acid or its equivalents. the 9-alkylpurin-6(H)-one from l-alkyl-5-aminoimidazole-4-carboxamide and formic acid.第114

38、页Synthesis of PurinePurine is formed by the thermolysis of formamide, or by interaction of N-(cyanomethyl)phthalimide with tris(fomiamino)methane, or with formamidine acetate in formamide or butanol第115页Synthesis of Purine第116页6.10 碟啶 PteridineThe spectroscopic data, especially the strong downfield

39、shifts of the H- and C-atoms in the NMR spectra, are characteristic of pteridine as a strong p-deficient heteroaromatic system. Pteridines are coloured (yellow to red), the parent compound being yellow.第117页6.10 Synthesis of pteridinesGabriel-hay synthesis4,5-Diaminopyrimidines cyclocondense with sy

40、mmetrical 1,2-dicarbonyl compounds to give pteridines第118页6.10 Synthesis of pteridinesTimmis synthesis第119页6.10 1,2,3-三嗪 1,2,3-Triazine1,2,3-Triazines undergo hydrolysis and oxidation. At room temperature, monocyclic 1,2,3-triazines are stable towards aqueous acid; at higher temperature, ring fissio

41、n occurs to form 1,3-dicarbonyl compounds。第120页Synthesis of trisubstituted 1,2,3-triazines.(1) Oxidation of 1-aminopyrazoles(2) Thermal rearrangement of cyclopropenyl azides3-Substituted l,2,3-benzotriazin-4(3H)-ones are obtained by cyclization of the diazonium salts derived from the N-substituted a

42、nthranilic acid amides第121页6.11 1,2,4-三嗪 1,2,4-Triazine第122页Reactions of 1,2,4-triazinesAmong the reactions of the 1 ,2,4-triazines, the hetero-DlELS- ALDER reactions with electron-rich alkenes and alkynes are of special importance in preparative chemistry。第123页Reactions of 1,2,4-triazines第124页React

43、ions of 1,2,4-triazines1,2,4-triazines react as 1,3-diazadienes across the ring positions N-2 and C-5 with alkynylamines, also in a 4+2 cycloaddition:第125页Synthesis of 1,2,4-triazines.(1) The cyclocondensation of symmetrical 1,2-dicarbonyl compounds with amide hydrazones is universally applicable to

44、 the synthesis of 3,5,6-trisubstituted 1,2,4-triazines第126页Synthesis of 1,2,4-triazines(2) a-Keto-N-acylhydrazones, which are accessible from 1,2-dicarbonyl compounds and acid hydrazides, undergo cyclocondensation with NH3 affording 1,2,4-triazines either directly or after conversion into a-chloroaz

45、ines.第127页Synthesis of 1,2,4-triazines(3) A frequently used method is the cyclocondensation of a-acylamino ketones with hydrazine providing 4,5-dihydro-l,2,4-triazines followed by dehydrogenation to triazines.第128页6.12 1,3,5-Triazine 1,3,5-三嗪 The H- and C-atoms are strongly deshielded in the NMR spe

46、ctra (comparable to the 2-position in pyrimidine) because of the alternating ring N-atoms 1H-NMR: S= 9.25; 13C-NMR: 8 =166.1 (CDC13). The UV spectrum (cyclohexane) shows maxima at 218 (2.13) and 272 (2.89) nm.1,3,5-Triazine has few absorption bands in its IR spectrum due to its D3h symmetry, with four main band at 15