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……………………………………………………………..….…

1. ‫ﺑﺴﻢ ﺍﷲ ﺍﻟﺮﲪﻦ ﺍﻟﺮﺣﻴﻢ‬
A PRIMER TO
Prepared by:
Mr. Mohammed H. A. Raidah
2008-2009
00972599497541 Brkaa2002@hotmail.com

2. Table of Contents
Nomenclature 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. 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 H
Pyrrolidine Piperidine Piperazine Morpholine Chroman
NH
N N
H N
Indole Isoindole Quinoline Isoquinoline
-2-

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 prefixes
Element Valence Prefix
Oxygen II Oxa
Sulphur II Thia
Selenium II Selena
Tellurium II Tellura
Nitrogen III Aza
Phosphorus III Phospha
Arsenic III Arsa
Silicon IV Sila
Germanium IV Germa
Boron III Bora
the 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. 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 2
3-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. 1 saturated 1H 4 saturated Tetrahydro
2 saturated Dihydro 5 saturated 1H+tetrahydro
3 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 N4
naming 1 2,3-dihydro-1,3,4-oxadiazole naming 1 2,5-dihydro-1,3,4-oxadiazole
naming 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. When structure of heteroatoms have only one types of atoms start numbering with
saturated 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
H
4,5-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
H
1,6-dihydro-1,3-dimethyl-1,2,4-triazine 1,4,5,6-tetrahydro-1,2,4-triazine
The naming of fused ring systems:
A very large heterocycles contain two or more fused rings. Some of these have
recognized trivial names,but the vast majority have not. The systematic names of
fused ring systems are derived by regarding common atoms as belonging to both
ring systems. The name is then constructed by combining the names of the
individual rings. N N
O O
benzoxazole benzene oxazole
N N
N N
N
pyrrolo[1,2-a]pyrimidine pyrimidine pyrrole
-6-

8. 3
b
a 2 1
N O
H
furo[2,3-b]pyrrole
furo [2,3-b] pyrrole
prefixe base component
site of fusion
Base component are labeled a,b,c,..,etc ,, atoms forming the ring system of the
second component are numbered in normal way 1,2,3,..
Considering in both numbering and labelling toward the nearest heteroatom then
to 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. -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
3
2) No Nitrogen, choose oxa rather b
than thia 1 2 a
S O
thieno[2,3-b]furan
3) choose more than one ring 3
b 2 1
a NH
N
H
pyrrolo[2,3-b]indole
4) choose the larger ring 3
b
a 2 1
N N
H
pyrrolo[2,3-b]pyridine
c b N
5) choose larger number of 2 3 d a
heteroatoms N1 4 O
H
pyrrolo[3,4-d]isoxazole
-8-

10. 3 4 c b
6) choose oxaza rather than N2 d
a
N
1 5
thiaza S O
isothiazolo[4,5-d]isoxazole
N
3 4 c b
7) choose 1,2heteroatoms rather 2 d
a
N
1 5
than 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]oxazine
Numbering in this direction gives the three heteroatoms
the lowest combined numbers, (1,2,and 5)
the contrary direction gives the three heteroatoms
the unpreferable combined numbers (3,6,and 7)
-9-

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
6
3',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. Ring Synthesis
The 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 called
cyclization reaction
-Reaction in which two ring bonds are formed, and no small molecules are eliminated in
the process , are called cycloaddition reaction
One bond formation Two new σ-bonds
1-Cyclization reactions
Cyclization reaction can involve any intramolecular version of the common σ-bond –
forming processes ,by far the most common are those in which a nucleophilic atom
interacts 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, and
nitrene 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. Doubly nucleophilic reagents
RNH2 RNHNH2 RNHOH H2N(CH2)2NH2
XH
H2NCNH2 ( X=O,S,NR)
X XH
Reagents with electrophilic and nucleophilic centres
XH
NCCH2CN 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. 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. 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. 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. (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. 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],it's hydrogen is acidic removed easyly
by base ,leave carbon very active Nu- .
base
O O
H
Cα C
H H
- 17 -

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. 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. 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 N
X 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. 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. (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. 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. 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. 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 H3C
N 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. Two mor examples of cyclization using tributyltin hydride are shown in the following
examples.
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 take
place, 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. This
cyclization 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, as
aminium 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. (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. 1.6-Carbene and nitrene cyclization
R R
R N C C
R R
Nitrene Singlet carbene triplet carbene
consider as biradical
Formation of nitrenes
1- the most method of forming nitrenes is photolytic or thermal decomposition of azide
∆ or hv
R N3 R N + N2
R N N N R N + N N
2-
O LTA O
O O
N Lead Tetra Acetate N
NH2 N
Formation of carbenes
1-In α-elimination ,a carbon loses a group without its electron pair, usually a
proton, 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. The most common example is formation of dichlorocarbene by treatment of
chloroform with a base.
HO
H
-Cl-
CCl2 CCl2
CCl2
Cl dichloro
Cl carbene
chloroform trichloro
carbanion
2-Disintegration of compounds containing certain types of double bonds:
R2 C Z R2 C + Z
The 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
pyrolysis
Monovalent nitrogen intermediates (nitrenes) and divalent carbon intermediates
(carbenes) are highly reactive species which can undergo addition reactions with
multiple bonds and can insert into unactivated carbon-hydrogen bonds.
Some examples of intramolecular versions of these reactions, leading to
heterocycles, are shown in the following figure ,
- 29 -

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. (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. 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. 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. 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. 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. (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 N
A different type of electrocyclization of heterotrienes, leading to the formation of
Five-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. 2-Cycloaddition reactions
Reaction in which two ring bonds are formed, and no small molecules are
eliminated in the process , are called cycloaddition reaction
Cycloaddition reaction provide useful synthetic routes to a wide range of
heterocycles, especially those containing four, five, or six atoms in the ring
The most important types of cycloaddition reaction are:-
Type name example geometry π-electrons
3+2 5 4+2 π
a 1,3-dipolar W W
cycloaddition V X V X
Y Z Z Y
4+2 6 4+2 π
b 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 π
c cycloaddition
Y Z Y Z
V 4+1
(i) V 5 4+2 π
W Z W Z
X Y X Y
d cheletropic
(ii) X X
2+1 3 2+2 π
Y Z Y Z
Figure 2.1 the major types of cycloaddition process used in heterocyclic synthesis
- 37 -

39. 2.a- 1,3-Dipolar Cycloaddition
A 1,3-dipole is a three-atom π-electron system with four π-electrons delocalized over
the 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 to
the 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 the
termini.
Compounds which can react with these species in cycloadditon reactions are commonly
called dipolarophiles. These contain unsaturated functional groups such as C≡C, C=C,
C≡N, C=N, C=O, and C=S.
- 38 -

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 C
In considering the viability of 1,3-dipolar cycloaddition as a route to a particular
heterocycle, it is desirable to be able to estimate (i) the reactivity of the components
under a given set of conditions and (ii) the selectivity of the reaction in giving a
single isomer where more than one might be formed.
- 39 -

41. QUICK REVISIO
HOMO-LUMO Interactions
As long as the molecules whose interaction we want to consider are far apart, each has its own
set of molecular orbitals undisturbed by the other. These MO's form the unperturbed basis from
which the interaction is to be evaluated. As the molecules approach sufficiently closely that
overlap between their orbitals becomes significant, the new interaction constitutes a
perturbation that will mix orbitals of each molecule into those of the other. The strongest
interactions will be between those orbitals that are close to each other in energy, but interaction
between two filled levels will cause little change in the total energy because one orbital moves
down nearly as much as the other moves up. The significant interactions are therefore between
filled orbitals of one molecule and empty orbitals of the other; furthermore, since the
interaction is strongest for orbital pairs that lie closest in energy, the most important
interactions are between the highest occupied molecular orbital (HOMO) of one molecule
and 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 different
symmetry types, this stabilizing interaction is absent, the small energy increase arising from the
filled 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 are
of different energies. In the following Figure, the HOMO and LUMO levels are indicated for
molecules D and A, D having its highest filled level substantially higher than that of A. This is
a donor-acceptor situation, with D the donor and A the acceptor. Note that the HOMO of D
is much closer in energy to the LUMO of A ,but the A HOMO is much farther from the D
LUMO. Hence the A HOMO will be relatively little affected, and most of the stabilization will
occur by lowering the D HOMO. As it is lowered, it will mix in substantial amounts of the A
LUMO; charge is thereby transferred from D to A. Note that charge transfer occurs primarily to
the 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 -

42. ase
-ph
t -of LUMO
ou
bine
com
2x
co
mb
in ei
n-
ph
as
e
HOMO
The allyl system
the allyl cation
H H
H H H H
+ Br
H Br H H H
antibonding
Ψ3 molecular orbital
higher in energy
than a p orbital
increasing nonbonding this is the
Ψ2
energy 3x molecular orbital Lowest Unoccupied
of orbitals Same energy Molecular Orbital
as a p orbital (LUMO)
three degenerate
2p orbitals combine Ψ1 bonding orbital. this is the
to form three energy lower Highest Occupied
molecular orbitals than p orbital Molecular Orbital
(HOMO)
- 41 -