A primer to heteocyclic chemistry

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A primer to heteocyclic chemistry
Table of Contents
Nomenclature of heterocyclic:………………………………………………
Ring Synthesis………………………………………………………….….
1) Cyclization reactions……………………………………………………
1.1-nucleophilic displacement at a saturated carbonatom (substitution) …
1.2-Intramolecular nucleophilic addition to carbonyl groups……………..…
1.3-Intramolecular addition of nucleophiles to other double bonds……….
1.4-Cyclization onto triple bonds……………………………………….……
1.4.a-Cyclization onto Nitriles………………………………………….……
1.4.b-Cyclization onto Isonitriles………………………………………..…
1.4.c-Cyclization onto alkynes………………………………………….……
1.5-Radical cyclization………………………………………………….…
1.6-Carbene and nitrene cyclization…………………………………….…
1.7-Electrocyclic reactions............................................................................
2) Cycloaddition reactions………………………………………….....……
2.a- 1,3-Dipolar Cycloaddition……………………………………………
2.b- Hetero-Diels-Alder reactions…………………………………………
2.c- [2+2] Cycloaddition……………………………………………………
2.d- Cheletropic reactions...........................................................................
3) Heterocyclic synthesis…………………………………………...………
Pyridine………………………………………………………………………
Quinoline and Isoquinoline…………………………………………….……
Ring systems containing oxygen………………………………………..…
Preparation of Pyrylium salts………………………………………….……
Reactions of Pyrylium salts………………………………………….……
Synthesis of α-Pyrones ………………………………………………………
Diels-Alder reactions of α-Pyrones………………………………..…………
γ-Pyrone…………………………………………………………………...…
References……………………………………………………………..….…

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A primer to heteocyclic chemistry

  1. 1. ‫ﺑﺴﻢ ﺍﷲ ﺍﻟﺮﲪﻦ ﺍﻟﺮﺣﻴﻢ‬ A PRIMER TOPrepared by: Mr. Mohammed H. A. Raidah 2008-200900972599497541 Brkaa2002@hotmail.com
  2. 2. Table of ContentsNomenclature of heterocyclic:………………………………………………. - 2 -Ring Synthesis………………………………………………………….….…- 12 -1) Cyclization reactions……………………………………………………..- 12 -1.1-nucleophilic displacement at a saturated carbon atom (substitution) …...- 14 -1.2-Intramolecular nucleophilic addition to carbonyl groups……………..…- 16 -1.3-Intramolecular addition of nucleophiles to other double bonds………....- 18 -1.4-Cyclization onto triple bonds……………………………………….……- 19 -1.4.a-Cyclization onto Nitriles………………………………………….……- 19 -1.4.b-Cyclization onto Isonitriles………………………………………..…...- 21 -1.4.c-Cyclization onto alkynes………………………………………….……- 23 -1.5-Radical cyclization………………………………………………….……- 25 -1.6-Carbene and nitrene cyclization…………………………………….……- 29 -1.7-Electrocyclic reactions...............................................................................- 33 -2) Cycloaddition reactions………………………………………….....……- 38 -2.a- 1,3-Dipolar Cycloaddition……………………………………………..- 39 -2.b- Hetero-Diels-Alder reactions………………………………………….- 52 -2.c- [2+2] Cycloaddition……………………………………………………- 56 -2.d- Cheletropic reactions..............................................................................- 58 -3) Heterocyclic synthesis…………………………………………...……….- 59 -Pyridine………………………………………………………………………- 59 -Quinoline and Isoquinoline…………………………………………….…….- 65 -Ring systems containing oxygen………………………………………..……- 69 -Preparation of Pyrylium salts………………………………………….…….- 69 -Reactions of Pyrylium salts………………………………………….………- 70 -Synthesis of α-Pyrones ………………………………………………………- 71 -Diels-Alder reactions of α-Pyrones………………………………..…………- 72 -γ-Pyrone…………………………………………………………………...…- 73 -References……………………………………………………………..….….- 74 - -1-
  3. 3. Nomenclature of heterocyclic:Examples of heterocycles with ‘recognized’ trivial names. N N N N N O S N N O H H H Pyrrole Furan Thiophene Pyrazole Imidazole Furazan N N N N N N N O Pyridine Pyridazine Pyrimidine Pyrazine Pyran H H N N N N N O O H H HPyrrolidine Piperidine Piperazine Morpholine Chroman NH N N H N Indole Isoindole Quinoline Isoquinoline -2-
  4. 4. - rules to nomenclature heterocycles-According to Hantzsch-Widman system-follow this steps ( for one ring system):-1-consider priority starting the numbering in this order Oxa(O) then Thia(S) then Aza(Z).2-tend the numbering direction to nearest heteroatom .3-follow the nearest saturated atom.4-write suitable prefixes and stems.Hantzsch -Widman system :common prefixesElement Valence PrefixOxygen II OxaSulphur II ThiaSelenium II SelenaTellurium II TelluraNitrogen III AzaPhosphorus III PhosphaArsenic III ArsaSilicon IV SilaGermanium IV GermaBoron III Borathe final ‘a’ in the prefix is dropped when is followed by a vowel.Stems for the Hantzsch-Widman system:Ring size Unsaturated ring Saturated ring Saturated have ( ) 3 irine irane iridine 4 ete etan etidine 5 ole olane olidine 6 ine inane 7 epine epane 8 ocine ocane 9 onine onane 10 ecine ecane -3-
  5. 5. O H H O O N N N oxazole oxaz ole oxirene oxirane 1H-azirine aziridine Prefixe Stem 2 1 N O H 3 H 1N 1N 1N Cl 4N 5 CH3 2 2 3 23-chloro-4-methyl-1,2,4-oxadiazole N N 1H-diazirine 3H-diazirine 2H-azirine H refer to saturated atom 1 2 1 2 H O N N O N N 4 3 4 3 O 4H-1,2-oxazete azete 2H-1,2-oxazete 1,2-oxazole common as isoxazole H 2 1 Ac 1 O N 4 O N 3 N 3 4 N 2 O 2H-1,3-oxazete 1,2-dihydroazete 4-acetyl-2H-1,3-oxazete 1,3-oxazole common as oxazole H H3C N O N azetidine 2,5-dihydro-5-methyloxazole -4-
  6. 6. 1 saturated 1H 4 saturated Tetrahydro2 saturated Dihydro 5 saturated 1H+tetrahydro3 saturated 1H+dihydro 1 1 O 2 CH3 O 5 CH3 5 2 3 4N N3 HN N4 2-methyl-1,3,4-oxadiazole 2,3-dihydro-5-methyl-1,3,4-oxadiazole 1 O 1 2 5 O 2 5 3 HN N 4 3 N N4naming 1 2,3-dihydro-1,3,4-oxadiazole naming 1 2,5-dihydro-1,3,4-oxadiazolenaming 2 ∆2-oxadiazoline naming 2 ∆3-oxadiazoline priority to double bond oline=half saturation 2 1 N O 3 6 O Ph 4N 5 HN NH H 1,3,4-oxadiazolidine 6-phenyl-4H-1,2,4-oxadiazine 1 1 1 8 2 2 O N O N O 2 N 8 8 3 7 3 N 3 7 7 6 4 4 4 6 6 5 5 5 4H-1,2,8-oxadiazocine 8H-1,2-oxazocine 8H-1,3-oxazocine -5-
  7. 7. When structure of heteroatoms have only one types of atoms start numbering withsaturated heteroatom nearest to another heteroatom,,as followed… 2 1 CH3 CH3 2 1 N N N N 3 5 3 5 4N 4N 1-methyl-1H-1,2,4-triazole H4,5-dihydro-1-methyl-1H-1,2,4-triazole or ∆2-1,2,4-triazole 1 H 2 1 CH3 2 N N N N 3 6 H 3C 3 6 4N 4N 5 5 H1,6-dihydro-1,3-dimethyl-1,2,4-triazine 1,4,5,6-tetrahydro-1,2,4-triazineThe naming of fused ring systems:A very large heterocycles contain two or more fused rings. Some of these haverecognized trivial names,but the vast majority have not. The systematic names offused ring systems are derived by regarding common atoms as belonging to bothring systems. The name is then constructed by combining the names of theindividual rings. N N O O benzoxazole benzene oxazole N N N N N pyrrolo[1,2-a]pyrimidine pyrimidine pyrrole -6-
  8. 8. 3 b a 2 1 N O H furo[2,3-b]pyrrole furo [2,3-b] pyrrole prefixe base component site of fusionBase component are labeled a,b,c,..,etc ,, atoms forming the ring system of thesecond component are numbered in normal way 1,2,3,..Considering in both numbering and labelling toward the nearest heteroatom thento fusion site. Non-standard prefixes in fusion names. Heterocycles ame as prefix Furan Furo Imidazole Imidazo Isoquinoline Isoquino Pyridine Pyrido Quinoline Quino Thiophene Thieno -7-
  9. 9. -Some rules to choose base component-Follow this steps:1) choose the ring have N 3 b a 2 1 O N furo[2,3-b]pyridine 32) No Nitrogen, choose oxa rather bthan thia 1 2 a S O thieno[2,3-b]furan3) choose more than one ring 3 b 2 1 a NH N H pyrrolo[2,3-b]indole4) choose the larger ring 3 b a 2 1 N N H pyrrolo[2,3-b]pyridine c b N5) choose larger number of 2 3 d aheteroatoms N1 4 O H pyrrolo[3,4-d]isoxazole -8-
  10. 10. 3 4 c b6) choose oxaza rather than N2 d a N 1 5thiaza S O isothiazolo[4,5-d]isoxazole N 3 4 c b7) choose 1,2heteroatoms rather 2 d a N 1 5than 1,3heteroatoms O O oxazolo[4,5-d]isoxazole *Numbering the fused ring system: 4 3 3 5 2 6 6 1 -start the numbering from this positions -Consider gives the heteroatoms the lowest combined numbers. -opt the direction the nearest to fusion 5 4 O 4 c 3 1 2 d 6 e b 3 a N 7 O 2 7 1 4H-furo[2,3-e][1,2]oxazineNumbering in this direction gives the three heteroatomsthe lowest combined numbers, (1,2,and 5)the contrary direction gives the three heteroatoms the unpreferable combined numbers (3,6,and 7) -9-
  11. 11. 8 1 7 2 8 N 2 S1 3 b a O c 4 6 3 4 5 4 3,4,4,5,6,8-hexahydrothiopyrano[3,4-c] [1,2]oxazine individial name of the base component CH3 3 4 3 c N 3 4 d b N2 a 5 2 5 1 O O 6 1 63,6-dihydro-3-methyl-oxazolo[4,5-d]isoxazole 5 3 4 4 N3 6 b 5 a c 2 1 S O 2 7 7 N 1 5,6-dihydro-3H-oxazolo[2,3-c] [1,2,4]thiadiazole individual name to the base component 9 10 1 N a 10 2 8 b 2 3 1N c 4 7 4 3 4 6 5 1,4,4,5,6,7,10,10-octahydropyrido[3,4-c]azocine - 10 -
  12. 12. Ring SynthesisThe types of ring-forming reaction available can be divided into two broad groups:-Reaction in which a single bond is formed in the ring-closure process are calledcyclization reaction-Reaction in which two ring bonds are formed, and no small molecules are eliminated inthe process , are called cycloaddition reaction One bond formation Two new σ-bonds1-Cyclization reactionsCyclization reaction can involve any intramolecular version of the common σ-bond –forming processes ,by far the most common are those in which a nucleophilic atominteracts with an electrophile. The predominant reaction types are:--nucleophilic displacement at a saturated carbon atom.-nucleophilic addition to unsaturated carbon . ucleophilic addition elimination .Heterocyclic rings can also be constructed by intramolecular radical, carbene, andnitrene reaction, and by electrocyclic ring closure of conjugated π-electron systems.Doubly electrophilic reagents R δ+ δ+ R RCOCH2COR RCO(CH2)2COR R1R2C CHCOR3 O O δ−R1R2C CHCN Cl2C X (X=O,S,NR ) - 11 -
  13. 13. Doubly nucleophilic reagents RNH2 RNHNH2 RNHOH H2N(CH2)2NH2 XH H2NCNH2 ( X=O,S,NR) X XH Reagents with electrophilic and nucleophilic centres XHNCCH2CN R1CHCOR2 RCOCH2COR XH COR ( X=O,S,NR ) Types of nucleophilic-electrophilic cyclization This is based on the state of hybridization of the atom attacked by nucleophile and on whether the shift of electrons away from that atom in the cyclization reaction is within (endo-) or outside (exo-) the ring being formed. Intramolecular displacement at a saturated carbon atom is an example of an exo-tert process, and nucleophilic addition and addition-elemination reaction of carbonyl compounds are exo-trig process. Y Y X Y X X Z Z Z 3 2 sp X : exo-tert sp X : exo-trig sp X : exo-dig Y Y X X Z Z sp2 Y: endo-trig sp Y: endo-dig - 12 -
  14. 14. 1.1 -nucleophilic displacement at a saturated carbon atom (substitution) . HO O O δ+ Base H2C CH2 H2C CH2 H2C CH2 Cl Cl oxirane δ− H2C OH O Base H2C CH2 oxetane Cl OH O Base Cl tetrahydrofuran 60o H Relative rate N 70 due to strain,banana like the orbitals NH2 NH 1 bad(CH2)n CH2 Br NH 6 x104 most suitable rings to be formed NH 1000 NH 2 - 13 -
  15. 15. Examples of cyclization by Nucleophilic displacement at saturated carbon Reagents likely cyclization Products intermediates (i) RCONH RCONH Cl RCONH CH2Cl N NHOCH2Ph N O O O OCH2Ph OCH2Ph R1 HO R2 OSOCl R1 R2 R1 H(ii) H H ,SOCl2,Et3N R2 HN O H H H N O N O H R3 R3 R3(iii)Feist-Benary Furane synthesis OH O O δ− OH Cl CH2 C R Cl CH2 C R R C CH2 Cl R C CH2 Cl α-Haloketon Base δ+ O+ O C O C O O O C OEt C C OEt N O O C R R C CH2 C OEt R R C CH C OEt β-Keto ester O O R C OEt R HO C OEt O H O(iv) δ+ Me2S CH C CH2 H2C COMe H2C COMe - Me2SCH C CH2 OEt + Me2S Me O O O H O Me MeCOCH2COMe Me C CH C Me Me COMe O Me - 14 -
  16. 16. 1.2-Intramolecular nucleophilic addition to carbonyl groups This type of process is the most common cyclization reaction in heterocyclic synthesis . Internal nucleophilic attack at the carbonyl group of esters, acid chlorides.etc. is followed by displacement of a leaving group, and the carbonyl function is retained in the cyclic product. Attack by a nucleophile on an aldehydic or ketonic carbonyl group is often followed by dehydration of the intermediate, especially when it lead to the formation of a heteroaromatic ring system. Such cyclization may be acid-catalyzed when the nucleophile is a weak one, and the attack is then probably on the protonated carbonyl function. Three types of intramolecular cyclization on to aldehydic and ketonic carbonyl groups,and examples of heterocyclic ring synthesis involving cycization by nucleophilic attack on carbonyl group are illustrated ,below. (a)Aldol-type cycliation O O OH COR1 C R1 C R1 base C R1(i) OH COR2 H OH COR2 O O COR2 Br BrCH2COR2, base dehydration R1 COR2 O(ii) base MeCOCH(NH2)CO2R, Me CO2R O C H2C O Me CO2R O Me H CO2R MeCOCH2CO2R CH Me O Me RO2C N OH RO2C N Me RO2C NH2 H H Me CO2R Me Me CO2R CO2R O CO2R HO H RO2C N Me H Me N RO2C N Me RO2C N Me H RO2C H H H - 15 -
  17. 17. (b) Cyclization through nucleophilic heteroatoms (iii) CH2COR O OH H2/Ni R NO2 R N R N NH2 H (iv) O O H R H R R R C CH2 C R O N HO N N R OH O R O R H2NOH (c) Cyclization onto an ortho position of a benzene ring O base R R OH(v) O H base R H R NH2 N R N R N R R O O O R OH R(vi) RCOCH(Cl)R, R R H PhOH, base, H R R R R then ZnCl2 OH O Cl O O - 16 -
  18. 18. 1.3-Intramolecular addition of nucleophiles to other double bonds Cyclization by nucleophilic addition to double bonds other than carbonyl groups is illustrated below, Activated C=S bond can act as the electrophiles, as in example (i) .In example (ii) the electrophile is activated C=C bond to which an internal conjugate addition reaction can take place, it is worth that in example (ii), the kinetically favored 4- exo-trig reaction is taking place , rather than the feasible alternative, a 5-endo-trig addition. The great majority of cyclization take place by reaction at an electrophilic carbon centre, but ther are a few heterocyclic synthesis which involve cyclization onto electrophilic nitrogen. One such reaction, in which a nitro group act as electrophile ,is shown in example (iii). R R HO R HO R(i) R2C(OH)C(OH)R2 Cl R O R δ− R S R Cl2C S Cl O HO R R S O R R δ+ S δ− Cl α-carbon toward [carbonyl,withdrawal group],its hydrogen is acidic removed easyly by base ,leave carbon very active Nu- . base O O H Cα C H H - 17 -
  19. 19. (ii) O CH(CO2Et) OEt Ph CO2Et CO2Et C Ph N CO2Et (a) C C OEt N CO2Et Ph N Ph N CO2Et O O CO2Et (b) O O CO2Et O CO2Et 4-exo-trig 5-endo-trig Actual product thermodynamic product (a) 4-exo-trig [Kinetic product] the stable product (b) 5-endo-trig the fastest product formed (iii) H NHCOCH2COMe H H N O N O N O NO2 COMe N N COMe N COMe O NaOH aq, O O O 1.4-Cyclization onto triple bonds 1.4.a-Cyclization onto Nitriles Nucleophilic addition to cyano groups provides an important method of synthesis of C-amino-substituted heterocycles, In these reaction the initial product of cyclization is an imine, as shown below, Proton shift then take place to convert this initial product into a mor stable ,aromatic, C-amino compound. If such poton shift cannot occur the imino group is often hydrolysed to carbonyl group during workup. N H C H NH H NH2 Y Y YH imine C-Amino compouds by cyclization of nitriles - 18 -
  20. 20. OH2 H NH H OH H O NH2 Y Y Y imine hydrolysis of imino group to carbonyl group Some Cyclization involving exo addition to nitriles(i) Oδ− Me MeCOCH2NH2, CN Me CN Me CN δ+ NH HO H 2 HO CH2(CN)2 Me C N H C NH N NH2 CH NH2 N H H C C N N(ii) N HN (H2N)2CS CN NH2 NH2 C NH N Tautomerism N Ph C H S H PhCHBrCN Ph S NH2 Ph S NH2 Ph S NH2 NH2 Br NH2 S NH2(iii)EtO2CC NH.OEt,H2NCH2CN N NH NH NH2 CN HN C HN Toutomerism HN EtO2C OEt H2N H EtO2C N EtO2C N EtO2C N H(iv) H2NCR CRCN H2NCH NH N R NH NH2 CN C R NH2 NH2 R R R N H N HN NH2 N H H R N R N R - 19 -
  21. 21. 1.4.b-Cyclization onto Isonitriles Isonitriles undergo endo cyclization reaction readily, and these reaction provide useful methods for the preparation of several five-membered heterocycles containing nitrogen. The Isonitrile cyclizations often give heterocycles with substitution patterns which are not easily available by other methods of ring synthesis. The most common reaction sequence using isonitriles is, A simple isonitrile XCH2NC is deprotonated by a base, and the anion is then made made to react with an unsaturated electrophile.The intermediate so generated can cyclize in a 5-endo-dig process to give the heterocycle which is unsubstituted at the 2-position. N C N C formal charge for N is 5 - 4= 1 formal charge for C is 4 - 5= -1 R1 C Y X X R2 N NX CH2 N C X CH N C X CH N C 1 R1 R R1 C Y R2 Y Y R2 R2 Construction of five-membered heterocycles through isonitriles Tosylmethyl isocyanide (TOSMIC) has found the widest use because of the mild conditions required for its reaction and because the tosyl substituent is often lost in an aromatization step , after cyclization. O O N S C S• O O tosyl (Ts) Tosylmethyl isocyanide - 20 -
  22. 22. Cyclizations of isonitriles(i) TsCH2NC, K2CO3, NC Ts Ts Ts N RCHO N N CH H R C R O R O O H R O(ii) TsCH2NC, K2CO3, Ts NC NR2 Ts R1CH CH Ts N N N R1 C H H N R1 N R1 N C N R2 R2 R2 R2 R1(iii) TsCH2NC, NaH, Ts NC CHCOR2 Ts Ts R1 COR2 R1CH N CH N N R1 H H C CH HC R1 R1 N C CH H COR2 R OC H 2 R1 COR2 COR2(iv) TsCH2NC, R4NOH, Ts NC CS2 CH Ts Ts H Ts N N N S S C C S S S S S S(v) R1O2CCH2NC,NaH, NC R1O2C 2 R COCl R1O2C CH H N R1O2C N R1O2C C C N R2 R2 O R2 O R2 O O Cl - 21 -
  23. 23. (vi) MeNC, BuLi, PhCN H2C NC N H C N N Ph Ph N Ph N Ph N N C H(vii) PhCH2NC, BuLi, PhNCS Ph CH NC Ph Ph N H Ph C N N Ph N C S N S PhN S PhNH S Ph(viii) R1 R1 H R1 R1 LiNR2 NC, C N N N H 1.4.c-Cyclization onto alkynes The exo addition to carabon-carbon triple bonds is not so common , but it has been used to synthesize some five- and six-membered heterocycles, as shown below in examples (i) and (ii) . The reactive intermediate benzyne (1,2-didehydrobenzene) can be regard as a cyclic acetylene, and intramolecular nucleophilic additions to arynes are useful for the synthesis of some benzo-fused heterocycles, an example of this type of cyclization is shown below in (iii) - 22 -
  24. 24. Some Cyclization involving exo addition to alkynes.(i) H2 HC C(CH2)3OH, H2 C C NaNH2 C H2C O CH2 CH O(ii) HC CCMeOH(CH2)3NEt2, Base H HO Me OH Me Me N N NEt2 Et2 Et2 (iii) R OH R CR(OH)CH2NH2 H NH2 Br N H H KNH2 There are significant number of examples of heterocyclic synthesis which involve endo cyclization on to a triple bond. Although such reactions appear to be sterically unfavourable because of the linear nature of the triple bond, it is easily to distort the triple bond to achieve the required transition state geometry. - 23 -
  25. 25. Examples of ring formation by endo attack on carbon-carbon triple bonds(i) O R1COC CR2 R1 R1 R1 1 R C NH2NH2 N CR2 N HN H2N N R2 N R2 NH2NH2 R2 H(ii) RC CC CR, C C C R C C R H2S,Ba(OH) C C R S R R R H2S S(iii) O O R1C CCO2R2, O δ− O δ+ NH H2NOH OR 2 OR2 R1 R1 NH OH NH R1 R1 O HO NH2 OH 1.5-Radical cyclization The intramolecular addition of a radical to a π bonds lead to the formation of a new ring system. Most of the ring system produced by radical cyclization are five- or six-membered, and either partly or fully saturated . The method usually lead to the formation of heterocycles by a process in which a carbon-center radicals becomes bonded to the carbon atom of a π bond. This π bond may be a carbon-carbon double or triple bond, or it may be part of an aromatic ring; there are also a few examples of cyclization onto π bonds containing heteroatoms. A heterocycle is formed if there is a heteroatom present in the linking chain. Less commonly one of the atoms. Unless the radicals are highly stabilized the intramolecular addition step is irreversible. Such reactions are thus kinetically controlled. Five- and six-membered rings are most commonly formed by preferential exo cyclization. - 24 -
  26. 26. The final product isolated from these cyclization depend on the method used to generate the radicals. One of the most common methods of carrying out these reactions is illustrated by example shown in below,, The reaction is a reductive cyclization brought about by tributyltin hydride. A radical initiator, here azobis(isobutyronitrile), decomposes to produce radical initiator (step 1) which abstract a hydrogen atom from tributyltin hydride, breaking the weak tin-hydrogen bond (step 2). The tributyltin radical so formed abstract bromine from the substrate (step 3). The carbon radical then cyclizes to produce a new alkyl radical (step 4) which abstract hydrogen from tributyltin hydride(step 5) ,steps 3-5 are then continued, as a radical chain reaction. H3 C CH3 C C H3CN N N heat N (step 1) C 2 H3C C - N2 CN H3C CH3 azobis(isobutylnitrile) H3C H3 C H + Bu3SnH (step 2) + Bu3Sn H3C tributyltin hydride H3C CN CN O O Bu3Sn + Br + Bu3SnBr (step 3) (step 4) O O CH3 (step 5) + Bu3SnH + Bu3Sn O O Fig. A radical cyclization using tributyltin hydride. - 25 -
  27. 27. Two mor examples of cyclization using tributyltin hydride are shown in the followingexamples.In example (i) an iminyl radical is generated by cleavage of an N-S bond.Example (ii) illustrate the great power of this method in that two successive cyclization takeplace, the product being formed in high yield.Other methods of reductive generation of radicals are illustrated in the remaining examples.In example (iii) samarium iodide(SmI2) is acting as a one-electron reducing agent. Thiscyclization gives better yields if carried out in the presence of one equivalent of an acid,indicating that the protonated aminoalkyl radical is more electrophilic than the neutral species.Similarly, nitrogen-centered radicals tend to be mor electrophilic when protonated ; that is, asaminium radical cations. Example (iv) shows the cyclization of a radical of this type .The cyclization shown in example (v) is typical of many based on aromatic diazonium salts,these being converted into aryl radicals by one-electron reduction followed by loss of nitrogen.Examples of radical cyclization.(i) Me N NSPh, Bu3SnH N(ii) Me Me Me Me N N N SePh ,Bu3SnH N O O O O Me N O - 26 -
  28. 28. (iii) Ph N Ph Ph Me N N H ,ClO-,SmI2,H+(iv) Ph(CH2)3NMeCl, H2SO4,MeCO2H,Fe2+ H+ N H N N N Cl Me Cl H Me H Me H H Me Ph(CH2)3NMeCl Base N N N Cl Me Cl Me Me H H H(v) CONMePh NMe NMe N2 ,HI O O Me N + Cl Cl Me N HR H R Me N H2C N H R H HR H2C N + Me N H2C N H HR Cl H HR HR Cl base H2C N H HR N Cl R Figure Formation of pyrrolidines by the Hofman-Loffler raction. - 27 -
  29. 29. 1.6-Carbene and nitrene cyclization R R R N C C R R Nitrene Singlet carbene triplet carbene consider as biradicalFormation of nitrenes1- the most method of forming nitrenes is photolytic or thermal decomposition of azide ∆ or hv R N3 R N + N2R N N N R N + N N2- O LTA O O O N Lead Tetra Acetate N NH2 NFormation of carbenes1-In α-elimination ,a carbon loses a group without its electron pair, usually aproton, and then a group with its electron pair, usually halide ion: H R -H+ -Cl- C C Cl R C Cl R R R R - 28 -
  30. 30. The most common example is formation of dichlorocarbene by treatment ofchloroform with a base. HO H -Cl- CCl2 CCl2 CCl2 Cl dichloro Cl carbene chloroform trichloro carbanion2-Disintegration of compounds containing certain types of double bonds: R2 C Z R2 C + ZThe two most important ways of forming :CH2 are examples:-the photolysis of ketene. hv CH2 C O CH2 + C O-the isoelectronic decomposition of diazomethane. hv CH2 N N CH2 + N N pyrolysisMonovalent nitrogen intermediates (nitrenes) and divalent carbon intermediates(carbenes) are highly reactive species which can undergo addition reactions withmultiple bonds and can insert into unactivated carbon-hydrogen bonds.Some examples of intramolecular versions of these reactions, leading toheterocycles, are shown in the following figure , - 29 -
  31. 31. In example (i) the thermal or photochemical decomposition of 2-azidobiphenyl, is an important route to carbazole. It has been shown to go by way of the singlet (spin-paired) nitrene, which cyclize onto the ortho position of attached phenyl substituent to give an intermediate, this intermediate can then aromatize to give carbazole by hydrogen shift to nitrogen. It is reasonable to assume that similar modes of cyclization are involved in related process such as those in examples (ii) and (iii). In example (iv) the photodecomposition of vinyl azides to give azirines, can be regarded as an intramolecular nitrene addition to a double bond. In examples (v) to (vii) the ability of singlet carbene and nitrene to insert into unactivated CH bonds is a valuable characteristic of intermediates .Examples of formation of heterocycles by carbene and nitrene cyclization.(i) Ph heat or hv N N3 N N H H N H carbazole intermediate(ii) R R heat N3 R N N H(iii) N Ph N Ph hv N Ph N N N SMe2 H - 30 -
  32. 32. (iv) R1 R2 R1 R2 R1 R2 hv N3 N R3 R3 R3 N(v) Me Me Me CO2Et CO2Et Me CO2Et CO2Et heat insertion N N3 N N Me Me Me Me Me H2C H H Me CH2 Me Me CO2Et CO2Et N N Me Me H H H(vi) Me H N2 Me H H Me Me hv insertion CO2Me CO2Me Et CO2Me Et CO2Me Et Et O O O O O O O O(vii) H N2 N2 N2 H hv N Cl + N Cl H N N H H H H O O O O N O - 31 -
  33. 33. 1.7-Electrocyclic reactions. The cyclization reactions that we have considered so far are all intramolecular versions of well-known σ-forming-processes. Electrocyclic reaction are different, in that they have no direct intermolecular counterpart. The-open chain reagent used in an electrocyclic ring closure must be a fully conjugated π-electron system . Electrocyclic ring closure is the reaction in which a σ-bond is formed at the termini of the π system . The reactions are normally brought about by input of energey in the form of heat or light and without any addition reagent. An equilibrium is set up between the acyclic and cyclic isomers. In many cases the acyclic isomer predominates, so that the electrocyclic reaction may be a ring opening rather than a ring formation. The most important types of electrocyclic reaction found in heterocyclic chemistry are illustrated schematically in the following figure. Reactions (a) and (b) involve the use of open-chain reagents containing four π-electrons, (a) in a 1,3-dipolar species ,or (b) in a heterodiene . Reaction (c) and (d) are the six-π-electrons analogues of (a) and (b). The open-chain species can thus be precursors of saturated or partially saturated heterocycles containing from three to six atoms . Higher-order electrocyclic reaction of system with more than six π-elecrons are also feasible ,but they are not so commonly encountered. Y Y(a) X Z X Z(b) X Y X Y W Z W Z X X(c) W Y W Y V Z V Z W X W X (d) V Y V Y U Z U Z Fig. Electrocyclic reaction involving open-chain isomers containing four or six π- electrons - 32 -
  34. 34. Examples of formation of six-membered heterocycles by electrocyclic ring closure(i) Ph heat Ph O O(ii) Ph O Ph Ph CON3 Ph N heat C N C O R2N O R2N O R2N O N R2N O O Ph O N C R2N O(iii) PhN NHPh NHPh H N N PhNH2 Ph Ph(iv) R1 R1 R1 R1 NR2 NR2 heat NR2 NR2(v) H H hv NR NR NHR O O O - 33 -
  35. 35. Ring opening and cyclization reactions involving three-membered heterocycles (i) N hv Ar C N CR1R2 R1 Ar R2(ii) R2 N R1 R2 hv N R1 O Ar O Ar(iii) R S R R S R S heat R S H N N N N H R R R Fig. Ring opening and cyclization reactions involving three-membered heterocycles The reverse of cyclization, (ring-opening) reactions also occur and are sometimes more useful from a preparative point of view. Example is the revesible ring opening of 2H-Pyrans. R2 R2 R1 R3 R1 R 3 O O R1 R1 - 34 -
  36. 36. X X W Y W Y V Z V Z Six π-electrons cyclization of type are much more common and have been given the general description of 1,5-dipolar cyclization , cyclize thermally to the five- membered heterocycles. The cyclic isomers can also be removed from the equilibria by irreversible tautomerization to a more stable (often aromatic) structure. Examples of 1,5-dipolar cyclization are shown in the following Figure. In examples (ii) and (iii) the primary cyclization products tautomerize to aromatic system and so displace the equilibria in favour of the cyclic forms. In examples (iv) and (v) aromatic heterocycles are formed directly in cyclization. Examples of 1,5-dipolar cyclization(i) heat O O O 1,5-Dipolar intermediates Cyclization product H(ii) tautomerism N N+ N N N N N N vinyldiazomethane 1,5-Dipolar intermediates H Cyclization product(iii) CO2Me Ph MeO2C MeO2C hv tautomerism CO2Me Ph N N Ph N Ph N H(iv) O Ph Ph O hv Ph CHO N N N - 35 -
  37. 37. (v) N N HONO N N N N N NH2NH N3 N N N O N O OH HO N N N N N N N HN N N N N N N N H H H H H H HO N O N N N N N δ− δ+ δ− N N N3 N NA different type of electrocyclization of heterotrienes, leading to the formation ofFive-membered rings, sometimes takes precedence over the usual type of ring closure.The general form of this reaction is shown in the following figure, W X W X V Y Z V Y U U Z N N NPh N N N NPh N Ph Ph N NPh N NPh N O N O Fig, Alternative mode of cyclization of heterotrienes - 36 -
  38. 38. 2-Cycloaddition reactionsReaction in which two ring bonds are formed, and no small molecules areeliminated in the process , are called cycloaddition reactionCycloaddition reaction provide useful synthetic routes to a wide range ofheterocycles, especially those containing four, five, or six atoms in the ringThe most important types of cycloaddition reaction are:- Type name example geometry π-electrons 3+2 5 4+2 πa 1,3-dipolar W W cycloaddition V X V X Y Z Z Y 4+2 6 4+2 πb Diels-Alder V W V W U X U X reaction Y Z Y Z [2+2] W X W X 2+2 4 2+2 πc cycloaddition Y Z Y Z V 4+1 (i) V 5 4+2 π W Z W Z X Y X Yd cheletropic (ii) X X 2+1 3 2+2 π Y Z Y ZFigure 2.1 the major types of cycloaddition process used in heterocyclic synthesis - 37 -
  39. 39. 2.a- 1,3-Dipolar CycloadditionA 1,3-dipole is a three-atom π-electron system with four π-electrons delocalized overthe three atoms.1,3-Dipolar species contain a heteroatom as the central atom. This can be formally sp-or sp2-hybridized, depending upon whether or not there is a double bond orthogonal tothe delocalized π-system. The two types of 1,3-dipole are : R3 R2 1 Y R4 R R1 X Y Z X Z R3 R2 R5 (a) (b) Fig 2.2 Types of 1,3-dipole:(a)with,and(b)without an orthogonal double bond. R1-R5 can be substituents or lone pairs.1,3-dipoles which undergo cycloaddition reactions readily are listed in the table 2.1 .The first six species listed are dipoles of type (a),which formally have a central sp-hybridized atom, but the species are easily bent to permit cycloaddition reactions at thetermini.Compounds which can react with these species in cycloadditon reactions are commonlycalled dipolarophiles. These contain unsaturated functional groups such as C≡C, C=C,C≡N, C=N, C=O, and C=S. - 38 -
  40. 40. Table 2.1 X Y Z Y X Z N N N azide N nitrones C O N N C diazo compounds N C N azomethine imides C N O nitrile oxides N C C azomethine ylides C N N nitrile imides O carbonyl ylides C C C N S nitrile sulphides S thiocarbonyl ylides C N C nitrile ylides C CIn considering the viability of 1,3-dipolar cycloaddition as a route to a particularheterocycle, it is desirable to be able to estimate (i) the reactivity of the componentsunder a given set of conditions and (ii) the selectivity of the reaction in giving asingle isomer where more than one might be formed. - 39 -
  41. 41. QUICK REVISIOHOMO-LUMO InteractionsAs long as the molecules whose interaction we want to consider are far apart, each has its ownset of molecular orbitals undisturbed by the other. These MOs form the unperturbed basis fromwhich the interaction is to be evaluated. As the molecules approach sufficiently closely thatoverlap between their orbitals becomes significant, the new interaction constitutes aperturbation that will mix orbitals of each molecule into those of the other. The strongestinteractions will be between those orbitals that are close to each other in energy, but interactionbetween two filled levels will cause little change in the total energy because one orbital movesdown nearly as much as the other moves up. The significant interactions are therefore betweenfilled orbitals of one molecule and empty orbitals of the other; furthermore, since theinteraction is strongest for orbital pairs that lie closest in energy, the most importantinteractions are between the highest occupied molecular orbital (HOMO) of one moleculeand the lowest unoccupied molecular orbital (LUMO) of the other.These orbitals are sometimes referred to as the frontier orbitals.If HOMO-LUMO interaction cannot occur, for example because the orbitals are of differentsymmetry types, this stabilizing interaction is absent, the small energy increase arising from thefilled level interactions will dominate, and no reaction will occur.It is instructive also to look at an example in which the HOMO levels of the two molecules areof different energies. In the following Figure, the HOMO and LUMO levels are indicated formolecules D and A, D having its highest filled level substantially higher than that of A. This isa donor-acceptor situation, with D the donor and A the acceptor. Note that the HOMO of Dis much closer in energy to the LUMO of A ,but the A HOMO is much farther from the DLUMO. Hence the A HOMO will be relatively little affected, and most of the stabilization willoccur by lowering the D HOMO. As it is lowered, it will mix in substantial amounts of the ALUMO; charge is thereby transferred from D to A. Note that charge transfer occurs primarily tothe lowest antibonding acceptor orbital. LUMO Energy LUMO HOMO HOMO molecule D D....A molecule A Figure: HOMO-LUMO interaction of a donor D with an acceptor A. - 40 -

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