Heterocyclic Chemistry

212 c
Lectures 1:30h/w/s
Labs. 3h/w/s

Recommended Textbooks:
How Important are
Heterocyclic Compounds?
 More than ½ of the chemical literature deals with such compounds
 Of the 20 highest earning ethical. pharmaceuticals in 1995, 17 (85%)
contain. a heterocyclic ring and total sales of all 17 in 1995 was $26.6
billion.
 Of the 36 new chemical entitles introduced for human therapeutic use in
the world market for the first time during 1995, 25 (69%) contain a
heterocyclic ring.
 Of the 44 compounds currently (May 1997) in all stages of development in
a major UK based pharmaceutical company, 41 (93%) contain a
heterocyclic ring.

Morphine Ergotamine Atropine Thiamine

 Nomenclature
1. Heteroatom prefixes and order of priority.

The following table is in decreasing order of priority:

Valence Prefix
Element

Oxygen II Oxa
Sulfur II Thia
Selenium II Selena
Tellurium II Tellura
Nitrogen III Aza
Phospha
Phosphorus III
2-The Suphix

No. of
Rings containing Rings containing
members
nitrogen no nitrogen
in the ring
Saturatio
Unsaturation Saturation Unsaturation
n

3 -irine -iridine -irene -irane

4 -ete -etidine -ete -etane
5 -ole -olidine -ole -olane
6 -ine -in -ane
7 -epine -epin -epane
8 -ocine -ocin -ocane
3,4,5-Membered Rings
5,6 Membered Rings
3. Fused Heterocyclic Systems

 3.1 - "Ortho-fused" and "ortho- and peri-fused"

ring compounds containing hetero atoms
 (a) A nitrogen-containing component.

 Benz[z]isoquinoline
 not Pyrido[2,3-b]naphthalene
(d) A component containing the largest possible
individual ring.

2H-Furo[3,2-b]pyran
not 2H-pyrano[3,2-b]furan
(e) A component containing the greatest number of hetero atoms of any
kind.

5H-Pyrido[2,3-d]-o-oxazine
not o-Oxazino[4,5-b]pyridine
(f) A component containing the greatest variety of

hetero atoms.

1H-Pyrazolo[4,3-d]oxazole
not 1H-Oxazolo[5,4-c]pyrazole

4H-Imidazo[4,5-d]thiazole
not 4H-Thiazolo[4,5-d]imidazole
 (g) A component containing the greatest number of hetero atoms first

listed in Table B-I.

Selenazolo[5,4-f]benzothiazole
not Thiazolo[5,4-f]benzoselenazole
(h) If there is a choice between components of the same size containing the same number and
kind of hetero atoms choose as the base component that one with the lower numbers for the
hetero atoms before fusion.

Pyrazino[2,3-d]pyridazine
3.2 - If a position of fusion is occupied by a hetero atom, the
names of the component rings to be fused are so chosen as both

to contain the hetero atom.

Imidazo[2,1-b]thiazole
3.3 - The following contracted fusion prefixes may be used: furo,
imidazo, isoquino, pyrido, pyrimido, quino and thieno.

Furo[3,4-c]cinnoline 4H-Pyrido[2,3-c]carbazole
 3.4 - In peripheral numbering of the complete fused systems, the ring system is
oriented and numbered according to the principles of Rule. When there is a choice
of orientations, it is made in the following sequence in order to:

(a) Give low numbers to hetero atoms;

Benzo[b]furan Cyclopenta[b]pyran 4H-[1,3]Oxathiolo[,4-b]pyrrole

(b) Give low numbers to hetero atoms in order of Table B-I, thus:

Thieno[2,3-b]furan
(c) Allow carbon atoms common to two or more rings to
follow the lowest possible numbers.

Imidazo[1,2-b][1,2,4]triazine

not or

(d) Give hydrogen atoms lowest numbers possible:

4H-1,3-Dioxolo-[4,5-d]imidazole
 Aromatic 5-membered
Heterocycles
 Cyclopentadienes – bridged by a heteroatom
with a lone e- pair
 6  electrons
 Hueckel Rule!
 Typical reactivity of pyrroles, thiophenes and
furans
The chemistry of pyrrole, thiophene and furan is
dominated by a readiness to undergo electrophilic
substitution, preferentially at an α -position, but also at
a β-position, should the α-positions be blocked.
• The five-membered heterocycles do not react with electrophiles at
the hetero atom
• Of the trio-pyrrole, furan and thiophene- the first is by far the
most susceptible to electrophilic attack: this susceptibility is linked
to the greater electron-releasing ability of neutral trivalent nitrogen,
and the concomitant greater stability of a positivecharge on
tetravalent nitrogen.

minor minor

Z o/p-director Z m-director
major major

minor
o/p-director m-director

Z Z
major minor major
 

N
H
 Synthesis of Pyrroles pyrrole
 1-From 1,4-dicarbonyl compounds and ammonia or primary
amines
 Paal-Knorr synthesis

Me Me
HO N OH - 2H2O
H
NH3 Me
Me Me PhH/heat Me OH Me N Me
O O O NH2 H
- H2O Me Me
N - H2O 90%
HO
H

Me3SiCl PhNH2
OMe MeO O OMe AcOH/heat N
MeO CHCl3
N Cl Cl Ph
CH2CO2Et 0oC->rt
75%
92%
 2-From a-aminocarbonyl compounds
Me CO2Et Me CO2Et
O CO2Et
aq. KOH aq. KOH
Knorr synthesis CO2Me
N CO2H N
NH2 O H H
53% 60%

Me CO2Et
Me CO2Et Me CO2Et
O aq. Na2S2O4 O
N Me
H Me rt H H
NOH O NH2 O Me
75%

 3-From α -halocarbonyl compounds

 Hantzsch synthesis

CO2Et COOEt
Cl CO2Et Cl CO2Et
aq. NH3 - H+
Me Me Me Me Me Me N Me
O O rt -> 60oC O H2N
Me O NH2
H
 4-From 1,3-dicarbonyl compounds and glycine esters

Et3N EtONa/EtOH
H O
O EtOH/rt O reflux
N CO2Et N CO2Et
Cl H3N CO2Et H H
85%

The Kenner synthesis

Me HO Me Me Me Me
Me
Me Me t-BuOK P4O10 EtONa
t-BuOH/rt N CO2Et N CO2Et N CO2Et
O PhH EtOH/rt
Ts Ts H
TsHN CO2Et 90% 50% 82%
 5-Miscellaneous methods

Grigg has examined the Pd-catalyzed cyclization of

enamines containing b-vinyl bromide functionalities.
1
Br 1 Me CO2R
DMF Br CO2R Pd(OAc)2, PPh 3
1
+ R CO2R
o
NH2 N R K2CO3, DMF, 85 C N R
H H

Grigg, R. et. al., Chem. Commun. 2000, 873.

A facile synthesis of 5-substituted 3-aminopyrrole-2-

carboxylates has been developed wherein condensation of diethyl
aminomalonate with a-cyano ketones which was facilitated by
prior formation of the p-tosyl enol ether.
NH2-HCl 2
2
H2N R
2
NC R Ts2O, TEA NC R EtO2C CO2Et
1
1 MC 1 NaOEt EtO2C N R
O R TsO R
H

Fotsch, C. et. al., J. Org. Chem. 2000, 65, 2603.

 Reactions with Electrophilic Reagents
Whereas pyrroles are resistant to nucleophilic addition and substitution, they are very
susceptible to attack by electrophilic reagents and react almost exclusively by
substitution.

 1- Protonatio
Reversible proton addition occurs at all positions, being by far the fastest at the
nitrogen, and about twice as fast at C-2 as at C-3.
H
H
+
H +H
N H + H+ N N N
H H H H H
most stable least stable
2- Nitration
NO 2
AcONO2
+
N AcOH/-10 oC N NO 2 N
H H H
NO 2 NO 2
51% 13%
Cu(NO3)2 Bu4NF

N Ac2O/rt N THF/rt N

N-Substitution of pyrroles gives rise to increased SiPr 3-i SiPr 3-i H

77% 100%
proportions of b-substitution.
3- Sulfonation; reactions with other sulfur electrophiles
For sulfonation, a mild reagent of low acidity must be used.

Py SO3 HCl
N 100 oC N SO 3- N SO3H
H H H
90%

4-Sulfinylation
O
S
Ph
PhSOCl TsOH
Ph
N MC/0 oC N S PhH/rt N
H H H
O
77% 70%
 5-Thiocyanation
SBn
ClSCN NaOH/BnCl TFA
N AcOH/rt N SCN t-BuOH/rt N SBn N
MC
SO 2Ph SO 2Ph SO 2Ph SO 2Ph
69% 100% 83%

6-Halogenation
Pyrrole halogenates so readily that unless controlled conditions are
used, stable tetrahalopyrroles are the only isolable products.
Cl Cl
1xSO2Cl2 4xSO2Cl2
N Cl Et2O/0 oC N Et 2O Cl N Cl
H H H
80% KI/AcOH
aq.EtOH/H2O2
4xBr2/EtOH
Br Br 0 oC I I

Br N Br I N I
H H
80%
7-Acylation
Direct acylation of pyrrole with acetic anhydride at 200 oC leads
to 2-acetylpyrrole as main product together with some 3-
acetylpyrrole but no N-acetylpyrrole.
Cl3CCOCl NaOMe
CCl 3 OMe
N Et 2O/rt N MeOH/rt N
H H H O
O
79% 92%
Vilsmeier acylation;
Cl H
DMF/POCl3
Cl H
N H NMe 2 N N
H H NMe 2 H NMe 2

MeCOCl H 2O
AlCl3/rt Na2CO3
O O

Me Me
aq. NaOH H
H H Vilsmeier
N N
N H H reaction
H NMe 2 O
O
83%
80%
 Acylation of pyrrole with deactivating substituent requires more forcing
conditions, the presence of a Lewis acid as catalyst.
O O
Me OH
Me Ac2O i) Br2/NaOH
MeCOCl
N BF3 Et2O N AlCl3 N ii) 5N HaOH N
O
SO 2Ph DCE
SO 2Ph SO 2Ph SO 2Ph
rt
83% 93% 78%

8- Alkylation
Mono-C-alkylation of pyrroles cannot be achieved by direct reaction
with simple alkyl halides.
Alkylations with conjugated enones carrying ,-electron-withdrawing
and potential leaving group have considerable synthetic potential.
O
Ph
S
O
O
N N
H H Me
98%
 9- Condesation with aldehydes and ketones
Condensations of pyrroles with aldehydes and ketones occur easily
by acid catalysis.
O O O
Me
Me Me Me Me Me Me
O
n-Pr Me [H]
Me
Me N H3PO2/AcOH Me N Me N
H H H
n-Pr n-Pr
79%
a 2-alkylidenepyrrolium cation

When the pyrrole ring contains an electron-withdrawing substituent

and has only one free -position, dipyrromethanes resulting from
attack by a second mol equivalent of the pyrrole on the intermediate
can be obtained.
EtO 2C EtO 2C CO 2Et
MeCHO/HCl
Me N EtOH/100 oC Me N N Me
H H Me H

83% a dipyrromethane
10-Condensation with imines and immonium ions
The imine and immonium functional groupings are the nitrogen
equivalents of carbonyl and O-protonated carbonyl groups, and their
reactivity is analogous.

CH2=NEt2
Mannich
reaction N N NEt 2
H H
CH2O/Et2NH
62%
AcOH/rt
 11-Reactions with Oxidizing Agents
Simple pyrroles are generally easily attacked by chemical oxidising
agents, frequently with complete breakdown.

12-Reactions with Nucleophilic Reagents

Pyrrole and its derivatives do not react with nucleophilic reagents by
addition or by substitution.

13-Deprotonation of N-hydrogen
Pyrrole N-hydrogen is much more acidic (pKa 17.5) than that of
pyrrolidine (~44).

Boc2O n-BuLi TIPSCl

N DMAP/MeCN N THF/-78 oC N N
H Li
Boc TIPS
81% 92%
14-Reactions of N-Metalated Pyrroles
Lithio, sodio, potassio and magnesio derivatives
N-Metallated pyrroles can react with electrophiles to give
either N- or C-substituted pyrroles: generally speaking the
more ionic the metal-nitrogen bond and/or the better the
solvating power of the solvent, the greater is the
percentage of attack at nitrogen.

O
Ph
N S Ph
N PhMe/-78 oC N O
MgCl H
92%
15- Reactions of C-Metallated Pyrroles
i-Lithio derivatives
Reactions of the species produced by the lithiation of N-substituted
pyrroles are efficient for the introductin of groups to the 2-position.

N Et
Me
65%

n-BuLi B(c-C5H9)3 I2
N THF N Li -78 oC THF N
Me Me Me
85% 73%
Br N

N
N MgBr PdCl2(dppb) N
Me THF Me
71%
Metal/halogen exchange;
Allows the introduction of groups to the pyrrole -
position.
CHO Br
Me2N=CHCl Cl- n-BuLi
N MC/reflux N then DMF N
then aq. NaOH then TBAF
SiPr 3-i SiPr 3-i SiPr 3-i
69% 71%
15-Reactions with Reducing Agents
The pyrrole ring is not reduced by hydride reducing agents,
diborane, or alkali metal/ethanol or /liquid ammonia
combinations, but is reduced in acidic media.

H
Zn/aq. AcOH N
N H
H H
rt 25%
H2
N Pt/AcOH N NaH/THF
H H
then PhSO2Cl NaB(CN)H3
N CF3CO2H/rt N
SO2Ph SO2Ph
75%
16-Reactions with Carbenes
The reaction of pyrrole with dichlorocarbene was at one time a
main route to 2-formylpyrrole.

Cl
CCl2 Cl
-HCl
Cl
N N
H H N

CCl2 H
N H
N CCl 2 N N CHO
H
Cl

H
CHCO2Et CO 2Et
CO 2Et CO 2Et +
N N N N
Me N2CHCO2Et/Cu Me Me Me
5.2:1
Pyrrole Aldehydes and Ketones
These are stable compounds which do not polymerise or autoxidise. For
the most part, pyrrole aldehydes and ketones are typical aryl ketones.

O O
NaBH4

N i-PrOH/reflux
N N
H H H
45%
Pyrrole Carboxylic Acids
The main feature is the ease with which loss of the carboxyl group
occurs. Simply heating pyrrole - or -acids causes easy loss of
carbon dioxide.

Me Me Me Me Me Me
ethanolamine

N CO2H 170oC N CO2 N

H H H
75%
Displacement of carboxyl groups by other electrophiles such as
halogen or nitro is also common.

EtO2C Me EtO2C Me EtO2C Me

I2 H2/Pd-C

HO2C N CO2H aq. NaHCO3 I N I MeOH/pressure N

H H MgO H
90% 70%
Pyrrole Carboxylic Acid Esters
The meta-directing effect of the ester overcomes the normally dominant
tendency for -substitution.
Br
Br2

N CO2Me pyridine/rt N CO2Me

H H
49%
An ester group can also activate side-chain alkyl for halogenation.
Me Et Me Et
Br2

MeO2C N Me AcOH/rt MeO2C N CH2Br

H H
73%
Pyrroles in Clinical Use
Pyrrole tetraamides are potent antibacterials against vancomycin
resistant Enteroccoci and methicillin resistant Staphylococcus
aureus.
 Furans
3()
2()
O
Furans and benzofurans continue to play an important
role in the field of heterocyclic chemistry because their
skeletons are present in many naturally occurring
molecule.
Me HO OH
H
Me HOH2C
O O O O CH2SH
perillene OH furfuryl thiol

secondary plant metabolite ascorbic acid aroma of roasted coffee

NO2

NNHCONH 2 Me2N S
O2N O O N NHMe
H
H

Nitrofurazone Ranitidine
bactericide the treatment of stomach ulcers
 Synthesis of Furans
1-From 1,4-dicarbonyl compounds

The Paal-Knorr synthesis

The most widely used approach to furans is the cyclizing dehydration
of 1,4-dicarbonyl compounds, which provide all of the carbon atoms
and the oxygen necessary for the nucleus.

TsOH cat.
PhH/heat - H2O
t-Bu t-Bu t-Bu t-Bu t-Bu
t-Bu O t-Bu t-Bu
O O O O OH O
H H+
2-From g-hydroxy-,-unsaturated carbonyl compounds
g-Hydroxy- , -unsaturated carbonyl compounds can be dehydrated,
using mineral or Lewis acids, to form furans.

- H2O
H

O O O
H

K2Cr2O7 H - H2O
HOH2C CH2OH H2SO4 H O OH O
HO O
90 oC 62%
 3-From allenyl ketones
Allenyl ketones cyclise to furans with metal ion or metal(0) catalysis.
Et H Et
C
H
Pd(dba)2 S
S S O Et
O Ph3P/100 C o O
37%
4-From a-halocarbonyl and 1,3-dicarbonyl compounds
a-Halocarbonyl compounds react with 1,3-dicarbonyl compounds in the
presence of a base (not ammonia) to give furans.
O O O
OEt H H
O aq. NaOH
H HO OEt OEt

Cl Me Cl O Me O Me
O
Cl O CO2Et CO2Et
OEt (CO2H)2
acetone/•
O
KI cat. Me Me • Me O Me
Me Me O O
O 90%
 Ranitidine
Ranitidine has been synthesised from furfuryl alcohol.

aq. Me2NH3 Cl- HS(CH2)2NH2

Me2N
CH2OH CH2O/rt O CH2OH c. HCl/heat
O

NO2
NO2
MeS NHMe Me2N S
Me2N N NHMe
O CH2S(CH2)2NH2 O
H
Ranitidine

Cyanoketones react with glycolate under Mitsunobu conditions to produce

vinyl ethers which give rise to 3-aminofuran-2-carboxylate esters in good
yields. diethyl azodicarboxylate
O NH2
R O OEt PPh3 R O NaH
HO OEt
+
O DEAD R O COOEt
CN CN

Scott. W. J. Org. Lett. 2000, 2, 2061.

An one-pot reaction of propargyl alcohols with Grignard reagents
followed by treatment with electrophiles producing polysubstituted
furans has been described.

1 2 R R2 R R2
R R -MgX R3CN or DMF
R
OH Mg R1
O R1 R3 O

Fallis, A. G. Tetrahedron Lett. 2000, 41, 17.

Rhodium-catalyzed enyne cycloisomerizations were utilized by Zhang to

prepare alkylidenyltetrahydrofurans with 1,4-diene patterns.
[Rh(dppb)Cl]2 Ph
AgSbF6
Ph
O O

Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490.

Reactions with Electrophilic Reagents
Of the three five-membered systems with one hetero atom, furan
is the 'least aromatic' and gives addition products.

1-Protonation
Furan and simple alkyl furans are relatively stable to aqueous
mineral acids.
H
H H
+ H2O ring-opened
O O products
H O
-protonated cation -protonated cation
which leads
to -exchange

1.5% HCl/MeOH
CH(OMe)2
Me O heat/1 day Me O
40%

H H
H H
aq. AcOH/HBr
Me O Me 100 oC Me Me Me Me
Me O Me O O O
OH
7d
90%
2-Nitration
Sensitivity precludes the use of concentrated acid nitrating mixtures.

AcONO2 H + AcO- Py
O -5 oC O NO2 AcO O NO2 O NO2
60%
Ac2O/c. HNO3
Further nitration of 2-nitrofuran gives 2,5-dinitrofuran as the main
product.
3-Sulfonation
Furan and its simple alkyl derivatives are decomposed by the usual
strong acid reagents.

N
SO3
O DCE HO3S O SO3H
3d 60%
4-Halogenation
Furan reacts vigorously with chlorine and bromine at room temperature
to give polyhalogenated products, but does not react at all with iodine.

Br2/dioxane H + Br- H H - HBr

O 0 oC O Br Br O Br O Br
80%
Br Br
5xBr2/H2O HCONH2 Br
H N
O CHO 0 oC then • O O OH 185 oC
N
94%
60%

Br2/MeOH H H H2/Ni H H
O -10 oC MeO O OMe 100 oC MeO O OMe
77% 2000 psi
1,4-dicarbonyl synthon
5-Acylation
Me
Me Me
DMF/POCl3 (Me2CHCH2CO)2O
H Me
O 0 --> 100 oC BF3
O O
O then aq. K2CO3 Et2O/0 oC O Me
76% 30%

6-Alkylation
Traditional Friedel-Crafts alkylation is not generally practicable in the
furan series, partly because of catlyst-caused polymerisation and partly
because of polyalkylation.

t-BuBr CCl3CHO H
t-Bu t-Bu SiO2/Na2CO3 OH
O O ZnCl2/AcOH O
CCl 3
51% 44%
7-Condensation with imines and immonium ions
Me2N=CH2 Cl-
NMe2
O MeCN O

AcCl 66%

(Me2N)2CH2

CH2O/aq. Me2NH
NMe2
Me O AcOH/95 C o Me O
73%

8-Mercuration
Mercuration takes place very readily with replacement of hydrogen,
or carbon dioxide, from an acid.
Me Me Me
aq. HgCl2 aq. HgCl2
O MeOH O HgCl heat O CO2Na
95% 86%
9-Reactions with Bases
Deprotonation of C-hydrogen
Metallation with alkyllithiums proceeds selectively at an -position.

n-BuLi n-BuLi
O Et2O O Li TMEDA Li O Li
hexane/•
> - 40 oC
Br Li
n-BuLi
O -78 oC/THF O

LDA can effect C-2-deprotonation of 3-halofurans.

Li SMe
(MeS)2

n - BuL i CO2Li O CO2H

2x O
o C/THF 94%
-78
O CO2H
2x L
A D
furoic acid -78 o Me3SiCl
C/TH
F Li CO2Li Me3Si O CO2H
O
87%
Metallation at C-3 can be achieved via metal-halogen exchange. The
greater
stability of carbanion at an -position shows up again in a mono-
exchange of 2,3-dibromofuran with selective replacement of the -
bromine. Br Br
Br 2 180 oC
O CO 2Me aq . NaOH Br CO 2H q uinoline
O Br O
66%

n-BuLi/Et2O Br
-75 oC
then DM F OHC O
50%

Introduction of alkyl groups at the furan -position

B(c-C5H9)3 I2 H c-C5H9
O Li O B(c-C5H9)3 I O B(c-C5H9)2 O
Li+ I-
95%
 3-Lithiofuran can be oxygenated to provide the TMS ether of 3-
hydroxyfuran directly.

Li OSiMe3
(Me3SiO)2
O O

3-Trimethylstannylfuran can be utilized in palladium-catalysed

acylation and arylation.

O
O
Li SnMe3 S S
Cl
Me3SnCl

O -78 oC O PdCl2(Ph3P)2 O
THF/rt 95%
Palladium-catalyzed couplings
Palladium chemistry has been utilized to introduce aryl groups to a furan
-position by substitution of hydrogen, and via boronic acids, and in
Heck-type alkenylations, again at C-2 via 'oxidative' type palladation.
Br

CHO
O Pd(PPh3)4 O
NaOAc/DMF
CHO
150 oC 40%

CO 2Et
Me O Pd(OCOPh) 2 Me O CO 2Et
t-BuO 2COPh
AcOH/100 oC
B(OH)2 Ar
ArBr
O CHO Pd(PPh3)4 O CHO
NaHCO3
81%
aq. DME/•
10-Reactions with Reducing Agents
Most furans are not reduced simply by metal/ammonia combinations,
however furoic acids give dihydro-derivatives.

3x Li/NH3
O CO2H MeOH O CO2H
90%

CO2H H CO2Me
Na/liq. NH3 CH2N2
O i-PrOH O
85%
Oxy- and Aminofurans :Oxyfurans

HO
H
H
H H
H O O
Me O OH Me O O Me O O

-angelica -angelica tetronic acid

2-hydroxy-5-methylfuran
(not detectable) lactone lactone

H
C5H11
CHO O O
C 5H 11 H OH
OTf
TMS o
C 98% (4:1, threo/erythro)
Me3SiCl -78
O O ZnCl2/Et3N O OSiMe3 HC(
OEt)
3 H
55% SnC
l4 H
-40 o O O
C -->
10 oC EtO OEt
90%

2-t-Butoxyfuran can be lithiated at C-5, reaction with a carbonyl

component, then hydrolysis with dehydration, furnishing alkylidene-
butenolides. n-PrCHO H
n-BuLi O
O
O-t-Bu Li O-t-Bu o o
O Et2O O -40 C --> 0 C n-Pr
-40 oC then TsOH cat. 45%
aq. THF/rt
 Thiophenes


S

O
Me
HN NH N
H H S
H N
S (CH 2)4CO 2H

(+)-biotin Banminth
(vitamin H)
Synthesis of thiophenes
1- From 1,4-dicarbonyl compounds and a source of sulfur
1,4-Dicarbonyl compounds can be reacted with a source of
sulfur to give thiophenes.
- H 2S
Me
Ph Me Ph Ph S Me
S S S SH
80%

S S
MeO P P OMe
S S

Lawesson's reagent

2- From thiodiacetates and 1,2-dicarbonyl compounds

The Hinsberg synthesis
Two consecutive aldol condensations between a 1,2-dicarbonyl
compound and diethyl thiodiacetate give thiophenes.
p-An p-An p-An p-An p-An p-An
t-BuOK Cu/300oC
O O
t-BuOH/60oC MeO2C S CO2H MeO2C S
MeO2C S CO2Me 75% 47%
3- From thioglycolates and 1,3-dicarbonyl compounds
Thioglycolates react with 1,3-dicarbonyl compounds (or equivalents)
to give thiophene-2-carboxylic esters.

HSCH2CO2Me NaOMe
MeOH
O
S S CO 2Me
EtOHC O
CO 2Me 64%

4- Preparation of amine-substituted thiophenes

The condensation of activated thiols onto adjacent nitriles is a common
method for the preparation of amine-substituted thiophenes. A three
component condensation was utilized to prepare -aminothiophene.
O Me CO2Et
CO2Et morpholine
+
MeO CN EtOH MeO
S8 S NH2

Pinto, I. L. et. al., Tetrahedron Lett. 2000, 41, 1597.

 Reactions with Electrophilic Reagent
1- Protonation
Thiophene is stable to all very strongly acidic conditions.

Reactions of protonated thoiphenes

The action of hot phosphoric acid on thiophene leads to a trimer.

S
H H+
100% H3PO4 thiophene
S 90 oC H S
S H
S

S S
H
S
40%
2- Nitration
Nitration of thiophene needs to be conducted in the absence of nitrous
acid, which can lead to an explosive reaction.

NO 2
c. HNO3
+
S Ac2O/AcOH S NO 2 S
o
0 C
60% 10%
3- Sulfonation
Use of the pyridine-sulfur trioxide complex is probably the best method.

N
SOCl2 SO 3- Ba(OH)2
Ba2+
S SO 2Cl PCl5 S MC S SO 3-
2
70%
86%
 4- Halogenation
Halogenation of thiophene occurs very readily at room temperature.

I2 Br2/Et2O
S I aq. HNO3 S 48% HBr S Br
90 oC 84%
70%
5- Acylation
The Friedel-Crafts acylation of thiophenes is a much-used reaction and
proceeds generally to give good yields under controlled conditions.
Almost exclusive -substitution is observed, but where both -positions
are substituted, -substitution occurs easily.

PhN(Me)CHO MeCOCl
H Me
S POCl3 S SnCl4/PhH/0 Co
S
O then H2O O
78% 80%
6- Condensation with aldehydes and ketones
Acid-catalysed reaction of thiophene with aldehydes and ketones is not a
viable route to hydroxyalkylthiophenes for these are unstable under the
reaction conditions, Chloroalkylation can be achieved.
HCHO
o
Cl
S c. HCl/0 C S
41%

Cl
HCHO
MeO 2C S Me HCl/ZnCl2 MeO 2C S Me
CHCl
3 93%

7- Condensation with imines and immonium ions

36% aq. HCHO Me2N=CH2 Cl-

NH 2 o NMe 2
S NH4Cl/60 C S MeCN/heat S
45% the MeOH 55%
9- Reactions with Nucleophilic Reagents (Ring Substitution)

N
H
O2N S Br O2N S N

Br MeONa/CuBr OMe 83% (2-)

S MeOH/100 oC 88% (3-)
S
Reactions with bases
1- Deprotonation of C-hydrogen
Monolithiation of thiophene takes place at C-2; two mol
equivalents of lithiating agent easily produces 2,5-dilithiothiphene.
2x n-BuLi m-CPBA
S TMSCl Me 3Si S SiMe 3 then I S I
I2/AgBF4 O2
83%
2-Reactions of C-metalated thiophenes
n-BuLi NTs
S S Li S NHTs
57%

Directed ortho metalation

Directed ortho metalation can be utilized to regiospecifically lithiate the
thiophene ring. For example, the directed lithiation of 2-
amidothiophene with tert-butyllithium followed by treatment with
acetaldehyde gave 3-( -hydroxyethyl)thiophene.

OH
1. t-BuLi
NEt2 NEt2
S S
2. CH3CHO
O O

Grimaldi, T. et. al., Synth. Lett. 2000, 1788.

Organometallic cross-coupling reactions
Arylthiophenes have been produced by palladium-catalysed couplings of
both thiophene-2- and -3-boronic acids and directly from the heterocycle
in an alternative palladium-catalysed process.
Br

NO 2
S Pd(PPh3)4/DMA S
KOAc
NO 2
66%

B(OH) 2
Br S Br S
2
S Pd(PPh3)4 S S
48%
Palladium-catalyzed aminations of halothiophenes have been utilized
to synthesize aminothiophenes
BuNH2 NHBu
Br
Cs2CO3

5 mol% S CO2Me
S CO2Me
Pd2dba3

Luker, T. J. et. al., Tetrahedron Lett. 2000, 41, 7731.

Ring Annelation of Thiophene

The electron-rich thiophene ring system can be elaborated into complex, fused thiophenes
acid-mediated intramolecular annelation reactions. Treatment of a ketone with p-
toluenesulfonic acid resulted in the formation of fused benzo[b]thiophene.
NC
MeS CN
S
p-TsOH MeS
O
S

Junjappa, H. et. al., Tetrahedron 2000, 56, 8153.

Biologically Important Thiophene Derivatives
Thrombin inhibitor: Thrombin is a key clot promoter, thrombin is an enzyme that preside
over the conversion of a substance called fibrinogen to fibrin.

O
Br
N

Takeuchi, K. et. al., Bioorg. Med. Chem. Lett. 2000, 10, 1199.
Takeuchi, K. et. al., Bioorg. Med. Chem. Lett. 2000, 10, 2347.
HO S Sal, D. J. et. al, J. Med. Chem. 2000, 43, 649.
N
O
 4
3()
Indoles
1 2()
7 N
H

indole

Indoles are probably the most widely distributed heterocyclic

compounds in nature.
CO2H HO MeO

NH2 NH2 NH2 NHAc

N N N N
H H H H

tryptophan tryptamine serotonin melatonin

Et2NOC Me
CO2H
NMe
H
CO2H N Me

O
N
H N Cl
H
indol-3-ylacetic acid
Indomethacin
lysergic acid diethylamide
plant growth-regulating hormone
(LSD) for the treatment of
rheumatoid arthritis
 Synthesis of Indoles
Indoles are usually prepared from • non-heterocyclic predursors
• pyrroles
• indolines by dehydrogenation
1-From phenylhydrazones of aldehydes and ketones

H3C ZnCl2/170oC
+ NH3
Ph N Ph
N N
H 76% H
H H
H H
H H +
R1 H R1 R1
R1
R2 R2 R2
R2 N N NH NH2
N N N N
H H2
H H H H+
H+

R1 H H
R1 + R1 H
+H
R2 R2 R1
N R2 N N NH2 R2
H NH3 H NH2 NH2
H
Examples;

110oC/decalin
+ MeNH2
N NMe or N
Me CF3CO2H/rt
Me 74%
CO2Et CO2Et
H
c. H2SO4
Me
- 5oC Me
N NH N
H
H 58%

Et Et
Me Me
o
AcOH/90 C Me
Me +
N N Me N
N Et
H H
90% trace
 2-From ortho-(2-oxoalkyl)anilines
The Reissert synthesis

In the classical Reissert synthesis the acidity of a methyl group

ortho to nitro on a benzene ring is the means for condensation
with oxalate.
CH3 (EtO2C)2 CO2Et H2/Pt
EtOK OK AcOH N CO2Et
NO2 NO2
Et2O/EtOH H
65%

3-From ortho-alkynylanilines
Br SiMe3
H SiMe3 KOH
F3C F3C MeOH
NO2 Pd(PPh3)2Cl2
NO2 heat
Et3N
89%

CH(OMe)2 H2/Pd-C
F3C
F3C CO/MeOH
NO2 N
K2CO3 H
87% 95%
 4-From ortho-toluidides

The Madelung synthesis

Cl Cl Cl
CH3 3x n-BuLi CH2Li
O O
N - 20oC --> rt N N Ph
H Ph Li Ph H
94%

5-From a-arylaminocarbonyl compounds

An a-arylaminoketone is cyclised by electrophilic attack onto the aromatic
ring.
The Bischler synthesis
O o
Me
Me PPA/120 C

N then aq. KOH

COCF3 N
H
64%
From pyrroles
Most follow a route in which a pyrrole, carrying a four-carbon side
chain at the -carbon, is cyclised via an electrophilic attack at the
adjacent pyrrole b-position.

O O
O O
BrMg MnO2 H2SO4
OHC N then i-PrOH/•
H N MeMgBr N
Ts Me
OH Ts Ts
56%
28%

Synthesis of oxindoles
The main synthesis of oxindoles is simple and direct and involves an
intramolecular Friedel-Crafts alkylation reaction as the cyclising step.
Et Et
EtCH(Cl)COCl AlCl3/115oC
Cl
N O
NH PhH/0oC O N
Me Me Me
70%
 Reactions with Electrophilic Reagents
1-Protonation
Indoles, like pyrroles, are very weak bases.

H H
H H
H
CH3
N N H N N
H H H H H

1H-indolium cation 2-H-indolium cation 3H-indolium cation 2-methyl stablises cation

(formed fastest) (stablest)

2-Nitration
Indole itself can be nitrated using benzoyl nitrate as a non-acidic
nitrating agent. NO O N 2 2
PhCO2NO2

0 oC N Me
H N Me
N Me PhCOCl/AgNO3 H
H 35% 84%

H H O2N
c. HNO3 H
H H H
c. H2SO4 Me Me
N Me N N
0 oC H H OSO3H H OSO3H
3-Sulfonation; reactions with other sulfur electrophiles
Sulfonation of indole, at C-3, is achieved using the pyridine-
sulfur trioxide complex in pyridine as solvent. Sulfenylation also
occurs readily, at C-3.

SO3- N+
S
SO3- 2-O2NC6H4SCl

N pyridine/• N PhH/heat
H H N O2N
H
N+
70% OH py 59%
H F/K ri d in
/D M
I2 e/
0 o Br
C 2 Br
I

N N
H
H
93%
64%
4- Acylation
Indole only reacts with acetic anhydride at an appreciable
rate above 140oC, giving 1,3-diacetylindole predominantly.

Ac
Ac2O/AcOH
N N 60%
H H

Ac2O/AcONa Ac2O
aq. NaOH

Ac
Ac2O

N N
Ac Ac
 - The Vilsmeir reaction:
H H H
NMe2 NMe2
Cl - Cl- NMe2
Cl
N N
N H
H H
DMF/POCl3

aq. NaOH/0 oC

CHO H
aq. NaOH
NMe2
N
H N
97%

Indoles, with a side-chain acid located at C-3, undergo cyclising

acylation forming indole -ketones.

BF3

CO2H AcOH
N N
H Ac2O H O
87%
Six-Membered Ring Systems: Pyridines and Benzo Derivatives

CH2OH
CONH2 HO CH2OH N
H Me
N Me N N

niacin pyidoxine (vitamin B6) nicotine

(nicotinamide) plays a key role as the coenzyme
in transaminases

O NHNH 2 CO2Bu-t
EtO2C CO2Et

N N S Me N Me
N H O2 H

Isoniazide Sulphapyridine Lacidipine

a major antituberculosis agent an antibacterial an antihypertensive
Pyridine – Aromatic Imine
 The similarity in delocalized 
bonding between pyridine and
benzene
 lone pair of electrons on the N,
and higher electronegativity of
the N - significant differences
 Unlike benzene, pyridine soluble
in polar solvents, completely
miscible in water due to the
hydrogen bonding
Pyridine
 Lone e- pair not tight up in resonance of
ring
 Weak base pKa: 5.29
preparations and reactions
Ring synthesis
1- From 1,5-dicarbonyl compounds and ammonia
Ammonia reacts with 1,5-dicarbonyl compounds to give 1,4-
dihydropyridines which are easily dehydrogenated to pyridines.
NH3
+
EtOH Me N
Me O
O O H
170oC
H2NOH-HCl
NMe2 HNO3
EtOH/heat

+
Me O - H2O
O
Me N Me N
OH
80%

SMe
Me SMe SMe
SMe N
O NH4OAc
O
N O O AcOH/² N
KOBu-t/THF
N N N N
79%
2- From an aldehyde, two equivalents of a 1,3-dicarbonyl compound,
and ammonia

The Hantzsch synthesis

The product from the classical Hantzsch synthesis is necessarily a
symmetrically substituted 1,4-dihydropyridine.

Me

H O
O O
H H O H Me O O Me O
Me H H Me NH3
Me Me NaNO Me
2
Me O O Me
Me N Me AcOH Me N Me
H
83%
51%
3- From 1,3-dicarbonyl compounds and 3-amino-enones or -nitriles
Pyridines are formed from the interaction between a 1,3-dicarbonyl
compound and a 3-amino-enone or 3-aminoacrylate.

OEt O
CO2Et
OEt 95 oC

EtO OEt H 2N Me N Me
30%

The Guareschi synthesis

The variation which makes use of cyanoacetamide as the nitrogen-
containing component leads to 3-cyano-2-pyridines, from which the
carbonyl group and/or the cyano group can be subsequently removed.
 CN
Me Me
OEt H 2N Me CN

EtO2C O K2CO3 EtO2C N Me

87% acetone
73%

HC(OEt)3
EtOH/TsOH CN
CO2Et CO2Et
O H 2N O CN

(CO2 Et)2 Me O K2CO3

EtONa Me N O
acetone H
Me 84%

Me O CN
MeONa O-Na+
CN
HCO2Et H 2N O

Me O piperidine Me N O
AcOH/² H

59%
Examples of notable syntheses of pyridine compounds
Pyridoxine
Pyridoxine, vitamin B6, has been synthesised by several routes,
including one which utilises a Guareschi ring synthesis.

CN
CH2 OEt CH2 OEt CH2 OEt
H 2N O CN O2N CN
O c. HNO3

Me O EtOH Me N O Ac2O/0oC Me N O
piperidine H H PCl5
heat 32% POCl3
81%

CH2 OEt
CH2 OH CH2 OEt O2N CN
HO CH2 OH H 2N CH2 NH2
48% HB r/² NaNO2
Me N Cl
Me N then Ag Cl HCl/ 90oC Pd/Pt
Me N H2 40%
H2O/²
pyridoxine 40% AcOH
 Reactions with Electrophilic Reagents
1-Addition to nitrogen

When a pyridine reacts as a base or a nucleophile it forms a pyridinium

cation in which the aromatic sextet is retained and the nitrogen acquires
a formal positive charge.
Protonatin of nitrogen
Pyridine itself, with pKa 5.2 in water, is a much weaker base than
saturated aliphatic amines which have pKa values mostly between 9 and
11. Electron-releasing substituents generally increase the basic strength.
Nitration at nitrogen

NO 2+ BF 4- PhH
+
Et2O/rt MeCN/rt
Me N Me Me N Me NO 2 Me N Me
NO 2 BF4-
 Amination of nitrogen
The introduction of nitrogen at a different oxidation level can be
achieved with hydroxylamine O-sulfate.

HI H2NOSO 3H H2O2
K2CO 3 AcOH/65 oC
N N N N
NH2 I
-
NH
- 90 oC -
O
68% 95%

Sulfonation at nitrogen

SO 3 H2O
MC/rt N ²
N N
O S O H HSO 4-
O-
90 %
Halogenation at nitrogen
Pyridines react readily with halogens and interhalogens to give crystalline compounds,
largely undissociated when dissolved in solvents such as CCl4.

Br2
HBr Br2
CC l 4
N N N N N
Br2- 70 % H Br- H Br3-

Acylation at nitrogen

NMe 2 NMe 2

PhCOC l
MeCN/4 oC
N N Ph4B -
NaBPh4
95%
Ph O
 2- Nitration
NO 2
c. HNO3
c. H2SO 4
N N
o
300 C/24 h
6%
Me Me Me
NO2
c. HNO 3

Me N Me oleum/100 oC Me N Me Me N Me
H 90%

3- Sulfonation
Pyridine is very resistant to sulfonation. However, addition of mercuric sulfate in
catalytic quantities allows smooth sulfonation at a somewhat lower temperature.

SO 3H
c. H2SO 4
HgSO 4/220 oC
N N 70%
4- Halogenation
* The bromination process is thought to involve pyridinium-1-sulfonate as the reactive
species, since no bromination occurs in 95% sulfuric acid.

Cl Br2 Br
Cl2
AlCl3 66 % ol eum
N N N
10 0 oC 13 0 oC
33 % 86 %

Substitution in pyridines carrying activating substituents

Electron-releasing groups facilitate electrophilic substitution.
Pyridines carrying an activating substituent at C-3 undergo electrophilic
substitution atC-2.

OH OH
CH 2O/Me 2NH
H2O/10 0 oC
N N CH 2NMe 2
70 %
2-Reactions with Oxidizing Agents
The pyridine ring is generally resistant to oxidising agents. In acidic solution
pyridine is more resistant, but in alkaline media more rapidly oxidised, than
benzene.

Et Et
SeO 2
110 oC/py ridine
N Me N CO 2H
76%

Me CO 2H
O2(4 atm )/DMF

N KOBu-t/rt N 70%

Only - and g-groups are attacked by selenium dioxide.

3-Reactions with Nucleophilic Agents
a-Nucleophilic substitution with 'hydride" transfer
i- Alkylation and arylation
n-BuLi - LiH
H
o
n-Bu N 100 C n-Bu N Bu-n n-Bu N Bu-n n-Bu N
Li Li Pr-n

60%
PhLi PMe/100 oC
H
or O2
N N Ph N Ph
Li 80%
ii- Amination
Amination of pyridines and related heterocycles, generally at a position  to the nitrogen, is
called the Chichibabin reaction, the pyridine reaction with sodamide with the evolution of
hydrogen.
NaNH2
+ + H2
PhNMe 2
N N NH2 N NH- Na+
100 oC
75% (prod uct be fo re worku p)
b-Nucleophilic substitution with displacement of good
leaving groups

Halo, nitro, alkoxysulfonyl, and methoxy substituents at - or g-

positions, but not at -positions, are easily displaced by a wide
range of nucleophiles.

MeON a PhSH
MeOH Et3N
N OMe N Cl N SPh
² 100 oC
95% 93%
Br NH2
Br Br Br NH2
aq. NH 3 aq. NH 3

N 160 oC N N CuSO4
N
140 oC
65% 88%
Reactions of C-Metallated Pyridines
Lithio derivatives

Pyridyl lithium reagents are convenient to prepare and behave as

typical organometallic nucleophiles.

Br Li BEt 2

n-BuLi/Et2O Et2BOMe
-40 oC
N N N

O
Br Li
n-BuLi/Et2O PhCN Ph
-78 oC then aq. H Cl
N N N
61 %
The use of halogen to direct lithiation can be combined with the
ability to subsequently displace the halogen with a nucleophile.

Cl Cl OMe
o
CH O CH O
LDA/-20 C NaOMe
Et
2O MeOH /²
N N N
then HC O2Et
90%

Palladium-catalysed reactions

SiMe 3 SiMe 3 H
Br
H aq. KOH/MeOH
Pd(PPh 3) 2Cl 2/CuI
N N N
Et3N/40-120 oC
80% 58%
Coupling requiring pyridyl organometallic species are best achieved with
boron, zinc, or tin compounds.

Me 3SnCl 4-Br-C 6 H4CO2Me

o
N Li DME /0 C N SnMe3 Pd(PPh 3 )2Cl 2
N
THF/heat 95%
88% CO2Me

Dimerisation
Both sodium and nickel bring about 'oxidative' dimerisations.
O2
H
N N N
Raney Ni
H
N or Na/THF
-2NaH
N N
N
Oxy- and Aminopyridines
Structure

Under all normal conditions, - and g-isomers exist almost

entirely in the carbonyl tautomeric form, and are accordingly
known as pyridones.
O O-

N O N O- N N
H H H H

All three aminopyridines exist in the amino form; the - and g-

isomers are polarised in a sense opposite to that in the pyridones.

N NH N NH2 N NH2
H
Reactions of pyridones
1- Electrophilic addition and substitution
Electrophilic substitution at carbon can be effected more readily with the
three oxy-pyridines than with pyridine itself, and it occurs ortho and
para to the oxygen function.
O
OH

N O N N
H H

The pyridones can be readily halogenated, nitrated and sulfonated

O O
Cl Cl NO 2
Cl2 f H NO3

N O H2O/rt c H2SO 4 N
N O N
H 10 0 oC H
Me Me
38 %
80 %
Replacement of oxygen
The conversion of the carbonyl group in pyridones into a leaving
group has a very important place in the chemistry of these
compounds.

P4O 10 POCl 3
pyrrolidine PCl 5
N N N O heat N OPOCl 2 N Cl
250 oC H H
39% Cl - 85%

Reactions of aminopyridines
Electrophilic addition and substitution
The three aminopyridines are all more basic than pyridine itself and
form crystalline salts by protonation at the ring nitrogen.
NO 2 O 2N
c HNO3
+
c H2SO4
N NH2 N NH2 N NH2
50 -100 oC
20 % 60 %
Reactions of the amino group
-Aminopyridines give normal diazonium salts on reaction with
nitrous acid, but with - and g-isomers, unless precautions are
taken, the corresponding pyridones are produced via easy
hydrolysis.

OH

NH 2 N
N2 N
NaNO2 -naphthol
0.5N HC l 56%
N N N
0oC
 Quinoline

Preparation of Quinolines
1-Aromatic amines and 1,3-dicarbonyl compounds

O -H2O O
H
NH2
O N -H2O
N

2- o-acyl anilines with ketones

O
-2 H2O
NH2 O
N
Baylis-Hillman adducts of o-nitrobenzaldehydes react with TFA
to afford 3-ethoxycarbonyl-4-hydroxyquinoline N-oxides.

OH OH
CO2Et CF3CO2H CO2Et
Xn Xn
NO2 N
O

Kim, J. N. Org. Lett. 2000, 2, 343.

Reactions of Quinoline
1-Nitration

NO2
NO2
CHNO3
HNO3
Ac2O
+
N N H2SO4 N
O N
O
NO2
 H2SO4
2-Sulphonation 220 C
N N
SO3H
 Five Membered Ring Systems: With More Than One N Atom
Pyrazole, imidazole, triazole

N N N
N
N N N
H H H
Pyrazole Imidazole 1,2,4-Triazole

Pyrazoles and Ring-Fused Derivatives

Intermolecular hydrogen bonding is available to only pyrazole. This
association probably takes the form of dimers, trimer and oligomers.
Me Me
H N
N N
N NH
N H N N
H
3(5)-methylpyrazole
 Synthesis of 1,2-Azoles
Ring synthesis
1-From 1,3-dicarbonyl compounds and hydrazines

This, the most widely used route to pyrazoles rests on the doubly
nucleophilic character of hydrazines.
Me Me
N2H4
Me O N
aq. NaOH Me N
O
H
75%

CHO
CH(OEt)2 CH(OEt)2 N2H4
DMF/DMA
N
H3C O Me2N O N
80oC H
66%
,-Unsaturated ketones were condensed with arylhydrazines to
yield dihydropyrazoles which were further alkylated and oxidized
to 1,3,5-triaryl-4-alkylpyrazoles which are novel ligands for the
estrogen receptor.

Ar3 Ar3
O
Ar3NHNH 2-HCl N N 1. LDA, R-I N N
Ar1 Ar2 Ar2
DMSO Ar1 Ar2 2. DDQ or MnO2 Ar1
R

Katzenellenbogen, J. A. Organic Letters 2000, 2833.

Reactions with Electrophilic Reagents

1-Addition at nitrogen
a-Protonation
Direct linking of two hetero atoms has a very marked base-
weakening effect, as in hydrazine and hydroxylamine, and this
is mirrored in the 1,2-azoles.
NH NH
N N
H H
b-Alkylation at nitrogen
The 1,2-azoles are more difficult to quarternise than their 1,3-analogues.

MeI
N N + N
N 100 C o N N Me
H
Me

c-Acylation at nitrogen

AcCl/PhH
N N
N N
H
Ac 80%

Bu-t Bu-t Bu-t

AcCl/pyridine
N NH N
N N N
H
Ac 79%
2-Substitution at carbon
a-Nitration
Pyrazole and isothiazole undergo straightforward nitration, at C-4.

O2N
c. HNO3/Ac2O c. H2SO4
N N N
N AcOH/rt N NO2 0oC N
H H
70%
80%

b-Acylation Only N-substituted pyrazoles react well, perhaps

because of inhibition of N+-salt formation.
Me PhOC Me
PhCOCl
AlCl3
N N
Cl N o
65 C Cl N
C6H4-p-Me C6H4-p-Me

OHC
DMF/POCl3
N N
N o
95 C N
Me Me
then H2O
33%
3-Reactions with Bases
Deprotonation of pyrazole N-hydrogen
The pKa for loss of the N-hydrogen of pyrazole is 14.2, compared with
17.5 for pyrrole.

NaH
N N N
N N N
H

4-Reactions of N-Metallated Pyrazoles

Alkylation of pyrazoles in basic solution involves an N-anion, and
proceeds straightforwardly.

Ph BrCH2CO2Et Ph
NaOEt
N N
N EtOH/rt N
H
CH2CO2Et
84%
Reactions of C-Metallated 1,2-Azoles
The reaction of 5-lithiated-1-substituted pyrazoles allow the
introduction of substituents at that position by reaction with a range of
electrophiles.

CH2O
pyrrolidine n-BuLi PhN=C=O
N N PhHN N
N EtOH/heat N o
-70 C then aq. H + N
H H
O
N 79%
60%

The treatment of 4-bromo-1-phenylsulfonylpyrazole with n-BuLi results in

-deprotonation and not metal-halogen exchange.

Br Br Br
n-BuLi CO2
N N N
N o
-70 C Li N HO2C N
SO2Ph SO2Ph SO2Ph
65%
lithium-halogen exchange

CHO

S OH
Br Li
2 n-BuLi Me
N N S N
N o N
-70 C -> rt N
H Me H
Li
39%
 Imidazoles and Ring-Fused Derivatives
Synthesis of 1,3-Azoles
Ring synthesis

1,2-Diamines have been useful precursors for the syntheses of

imidazoles and benzimidazoles.
H2N R P2S5 N R2 N R2
DMSO
ArCN + Ar Ar
H2N N or N
H H
10% Pd/C

Payard, M. Synthesis 2000, 1814.

Solvent-free microwave assisted synthesis of 2,4,5-substituted imidazoles from

aldehydes and 1,2-dicarbonyl compounds in the presence of ammonium acetate
and alumina has been reported.
R2 R2
Al2O3, NH4OAc
1 2 2
R CHO + R COCOR N NH
Microwave
R1

Usyatinsky, A. Y. Tetrahedron Lett. 2000, 41, 5031.

Metal-promoted cross-coupling reactions of imidazoles
Arylboronic acids reacted efficiently with imidazoles in the presence of a novel
diamine-copper complex to give a variety of N-arylimidazoles.

[Cu(OH)-TMEDA]2Cl2
MC, O2
B(OH)2 N N
R1 R1
HN N R2
R2
Collman, J. P. Org. Lett. 2000, 2, 1233.

3-Iodoimidazo[1,2-a]pyridines underwent facile Suzuki cross-

coupling reactions to afford benzimidazoles.

R1 R1
N R3B(OH)2, Pd(PPh3)4, (5 mol%) N
R2 R2
N N
Na2CO3 (2 eq), DME
I R3

Enguehard, C. J. Org. Chem. 2000, 65, 6572.

Addition of nucleophiles to imidazoles
Amines reacted with 4-hydroxymethylimidazole in refluxing water to
give 4-aminomethylimidazoles.

OH NR2
N R2NH, H2O N

N 100 oC N
H H

Macor, J. E. Tetrahedron Lett. 2000, 41, 2777.

The palladium-catalyzed coupling reaction of immobilized

iodobenzoate with N-methylimidazole gave coupled methyl
ester, after cleavage with sodium methoxide.
I N 1. Cs2CO3, Pd(OAc)2 (10 mol%) N
+ PPh3 (20 mol%), DMF
O N N
MeO Me
Me 2. NaOMe, MeOH, THF
O
O

Kondo, Y. Org. Lett. 2000, 2, 3111.

1,2,4-Triazoles and Ring-Fused Derivatives
Reaction of aromatic nitriles with hydrazine dihydrochloride in the
presence of hydrazine hydrate in ethylene glycol under microwave
irradiation gave 3,5-disubstituted 4-amino-1,2,4-triazoles.

Ethylene Glycol
NH2
NH2NH2-2HCl N
Ar Ar
ArCN
NH2NH2-H 2O N N

Bentiss, F. Tetrahedron Lett. 2000, 41, 1539.

S N N
1 R3NCS NaN3, HgCl2
R
N
H R1 R3 R1 N
N N N N
R2 MC Et3N, DMF 2
R2 H R R3

Powell, D. A. Org. Lett. 2000, 2, 3237.

 Six Membered Ring Systems: With More Than One N Atom
N
N
N
N N N
Pyridazine Pyrimidine Pyrazine

Synthesis of Diazine Heterocycles:

Synthesis of pyridazine ring:
The only general important method for preparation of the pyridazine
ring involves the reaction of 1,4-dicarbonyl compound with hydrazine
(or substituted hydrazine).
Br
OEt O
O Br2
-H2O
O NH
O -EtOH NH AcOH/60 oC
NH2 N N
H2N

-HBr

NH
N
90%
Maleic anhydrides react with hydrazine to give 3,6-di-oxgenated rings.

O
OH
NH2NH2
O
N
O N
H
O
90%
POCl3

H2/Pd-C Cl

N aq. NH3/MeOH N
N Cl N
67% 90%
 Synthesis of Pyrimidine Ring:
The most-used method for the constuction of a pyrimidine ring from
non-heterocyclic precoursors involves the fusion of two three-atom units.

. Pyrimidine can be obtained in the laboratory from uracil in two steps,

the synthesis of which illustrates this general approach . the 1,3-
dicarbonyl component in this examples a-formylacetic (itself produced in
situ by decarboxylation of malic acid with concentrated sulphuric acid)
-H O
and the di-amino component is urea. -CO
2

OH O

O NH malic acid NH

O H2N conc. H2SO4 / 90% N O

H
H
Uracil 55%

POCl3
PhNMe2/D

Cl
N H2/Pd-C N
MgO
N N Cl
78% 87%
Thiourea, imino-ester, amidines and guanidines can be used instead of urea
in this approach. Indeed reactivity in this synthetic procedure is related to the
nucleophilicity of the aminogroups, and list abo represents an increasing
order of reactivity.

Et O
+ -
O NH2Cl MeONa/MeOH NH

H2N  N Me
N H2N
87%
 Synthesis of Pyrazine rings
Pyrazine is not easily made in the laboratory. Commercially, the high
temperature dehydrative and dehydrogenative treatment of precursors,
such as hydroxyethyl ethylenediamine, is utitilized.

H
N N
400 oC
Al2O3-Ni
HO H2N N
60%
Two general methods are available for the preparation of pyrazine rings.
1– From a-amino carbonyl compounds:

H O
NH2 O OH N
glycol
180 oC
HO O H2N O N
H
50%
2.From 1,2-dicarbonyl compounds and 1,2-diamino compounds.

H2N N H N
H -H2O -H2
H H
H2N N N

1-Reactions with Electrophilic Reagents

a-Addition at nitrogen
Protonation

The diazines are essentially monobasic substances, and considerably

weaker, as bases, than pyridine. This reduction in basicity is a
consequence of destabilisation of the mono-protonated cations due to
inductive withdrawal by the second nitrogen atom.
Alkylation
The diazines react with alkyl halides to give mono-quaternary salts,
though somewhat less readily than comparable pyridines.
Et
N Et3O + BF 4- N MeI N
Cl(CH 2)2Cl MeOH
N N N
2BF 4- Et Me I-
86% 85%

Oxidation
All three systems react with peracids, giving N-oxides, but care must be
taken with pyrimidines due to the relative instability of the products
under the acidic conditions. N m-CPBA N
CHCl 3
N N
48%
O-
O-
Me N Me N Me N
H 2O 2/AcOH
+
N Me 60 oC N Me N Me
O- O-
62% 24%
b-Substitution at carbon
Halogenation

It is almost certain that an addition/elimination sequence is involved,

rather than a classical aromatic electrophilic substitution.
N N Cl Br
Cl 2/CCl 4 N Br 2/PhNO 2 N

N 130 oC
N Me N Me N
-
H Cl 85%
67%

c-Reactions with Oxidizing Agents

The diazines are generally resistant to oxidative attack at ring carbon.
Alkyl substituents and fused aromatic rings can be oxidised to
carboxylic acid residues, leaving the heterocyclic ring untouched.
N HO 2C N
aq. KMnO 4

N HO 2C N
75%
 2-Reactions with Nucleophilic Reagents
a-Replacement of hydrogen
Alkylation and arylation
The diazines readily add alkyl- and aryllithiums, and Grignard
reagents, to give dihydro-adducts which can be aromatised by
oxidation. H
Bu-n
n-BuLi Bu-n KMnO 4
N N N
N N Li N
51%

Diazines carrying chlorine or methylthio substituents, attack does not

take place at the halogen- or methylthio-bearing carbon.
N

N Li DDQ
S
N N N Cl
N Cl
N Cl H S
S 83%
 b-Replacement of good leaving groups
All the halodiazines react readily with 'soft' nucleophiles such as
amines, thiolates, and malonate anions, with substitution of the halide.

All cases are more reactive than 2-halopyridines.

X X X
X N
N N
> > > > > >
N N
N N X N N N X N N X

Cl Cl NH 2 NH 2

N NH 3 N N H 2O N
+
N Cl N NH 2 N Cl N O
H
4:6(95%) cytosine

Cl OMe OMe
Cl Cl
MeONa H2
N N Pd-C/MeOH N
Cl N Cl N N
38% 98%
 c-Reactions with Bases
Deprotonation of C-hydrogen

-All three diazines undergo H/D exchange at all ring positions with
MeONa/MeOD at 164 oC. The exchange is faster than pyridines due to
the acidifying, additional inductive withdrawal provided by the second
nitrogen.
-Metallation
Because simple diazines undergo such ready nucleophilic addition,
their direct metallation has not been reported.
Reactions of C-Metallated Diazines
Lithio derivatives
Typically, LTMP has been used for the kinetically controlled metallation
of substituted diazines.
N N Li N CHO
LTMP HCO 2Et
-70 oC
N Cl N Cl N Cl
73%

OMe OH OMe OH
Cl Cl
N LT MP Ph N LT MP Me
Et2O/ 0 oC N -70 oC N
N OMe N OMe Cl N Cl N
then PhCHO then MeCHO
65% 65%

Cl Cl Cl
Li
N LTMP N LTMP N
THF/HMPA Et2O/THF
Li N Cl N Cl N Cl
-70 oC -100 oC
thermodynamic kinetic
Palladium-catalysed reactions
Palladium- (and nickel-) catalysed coupling reactions proceed
normally on halodiazines as with pyridines.

Me Bu 3Sn S Me

N N
PdCl2(PPh3)2 S
Me N Cl Me N
DMF/110 oC
Et3N/K2CO 3 88%

H 2N N CH 2CO 2Et H 2N N CH 2CO 2Et

PhB(OH)2
Pd(OAc)2/dppf
MeO 2C N Br MeO 2C N Ph
Et3N/DMF/90 oC
96%
 In diazine chemistry, tin derivatives have normally been used for
coupling reactions and have the particular advantage that they can
be prepared without the use of organolithium intermediates.

I SnBu 3 Ph
Cl Cl Cl
N n-Bu 3SnCu N PhI N
N SMe THF/-78 oC PdCl 2(PPh3)2
N SMe N SMe
52% 65%

Sonogashira coupling
R
Br OMe (Ph3P)2PdCl2, CuI OMe
+
N N R 75-90% N N

OMe OMe

Djung, J. F. J. Org. Chem. 2000, 65, 5668.

Stille-type cross coupling

N Pd(PPh3)4
+ Br N N Cl
N 80%
Bu3Sn N Cl
N

Fort, Y. Org. Lett. 2000, 2, 803.

Diazine N-Oxides
Pyrimidine N-oxides are more difficult to obtain by oxidation of the
parent heterocycles but they can be prepared by ring synthesis.

NH 2

HON
N
CH(OMe)2 N
N
CH(OMe)2 BF 3 Et2O O-
tol/DM F
79%
 Oxydiazines

O O NH 2 O
R1
Me
NH NH N R2 NH

N O N O N O O N O
H H H H

thymine cytosine barbiturates

uracil
R 1= R2= H=barbituric acid

Reactions of oxydiazines
Reactions with electrophilic reagents

O O O O
ClH2C Br Br
NH (CH2O) n NH Br 2 NH NH
HCl H 2O
N O N O HO N O N O
H H H H
57% 90%
 Reactions with bases
N-Deprotonation

Like pyridones, oxydiazines are readily deprotonated under mild

conditions to give ambident anions which can be alkylated, by phase-
transfer condition.
O
PhOCO OAc F
O NH
O OSi Me3
F PhOCO O N O
NH (Me 3Si)2NH F
N PhOCO OCOPh
(NH4)2SO4 Me 3SiCl /NaI/MeCN
N O N OSi Me3
H PhOCO OCOPh
85%

C-Metallation
N 2x n-BuLi N BnCl N
Bn
H 3C N O THF/TMEDA LiH 2C N OLi N O
H H
58%
Replacement of oxygen
Oxydiazines, with the oxygen  to nitrogen, can be converted into
halo- and thio-compounds.

O Cl O

NH POCl3 N aq . NaOH NH

O N O PhNEt2 Cl N Cl Cl N O
H H
50%
41%

5-Hydroxypyrimidin-2,4-diones react as ketones at the 5-position

and undergo Wittig condensation.

O O
HO Me Me
N Ph3P=CHCO 2Et EtO 2C N
MeCN
N O N O
Me Me
93%
Transition metal-catalysed reactions

OBu-t OBu-t O
O O O
Br
N B(OH) 2 N HCl NH

N OBu-t Pd(PPh3)4/DME
aq . NaHCO3 N OBu-t N O
H
59%
100%
Aminodiazines
Aminodiazines exist in the amino form.
Dimroth rearrangement: the alkali-promoted rearrangement of
quaternary salts via ring-opening process.

warm
N MeI N aq. NaOH N
rearrangement
N NH 2 N NH 2 N NH Me
Me 71%

One amino group is sufficient in most cases to allow easy electrophilic

substitution, halogenation.

Br
N aq . Br 2 N

N NH 2 N NH 2
41%