Fused-ring heterocyclic chemistry

Heterocyclic ring systems common in drug structures

Rings contain in addition to carbon, other atoms like nitrogen, oxygen, sulfur

Benzo-fused heterocycles:Indole

Indole is an important heterocyclic system because it is built into proteins in the form of the amino acid tryptophan. It is the basis of important drugs such as indomethacin, and because it provides the skeleton of the indole alkaloids—biologically active compounds from plants including strychnine and LSD

Indole : Such bicyclic heterocyclic structures which has a benzene ring and a pyrrole ring sharing one double bond.

Medicinal compounds contain indole

Serotonin is a monoamine neurotransmitter (derived from Trp) synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal (GIT)tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.

Serotonin antagonists

Antiemetic: treatment of vomiting

Medicinal compounds contain indole

LSD stands for LySergic acid Diethylamide. It is the hallucinogenic drug ‘acid’. When people walk off a building claiming that they can fly, they are probably on LSD. It contains an indole ring made up of a benzene ring and a pyrrole ring fused together.

Isoindole is more basic than indole

According to lewis definition

Acid e

Base e

The lone pair of sp3 N in indole are delocalized into the aromatic ring, thus less available to give.

While in isoindole it is not delocalized into the aromatic ring, thus available to give.

Indole is more stable than isoindole.

Six-memberedring correspondsto benzene

Six-memberedring does not havesame pattern ofbonds as benzene

Rxns of Indole in Electrophilic Aromatic Substitution (EAS)

The chemistry of Indole is similar to that of pyrrole ring with a relatively unreactive benzene ring due to the electron withdrawing effect of the nitrogen.

However, pyrrole reacts with electrophiles at all positions but prefers the 2- and 5-positions, while indole much prefers the 3-position.

WHY????

In indole: reaction at the 3-position simply involves the rather isolated enamine system in the five-membered ring and does not disturb the aromaticity of the benzene ring.

Nitration

Sulphonation

Halogenation

Fischer indole synthesis The Fischer indole synthesis, which was first discovered in 1883, is still considered as the most popular, general and efficient approach.

The aryl hydrazones are easily obtained by condensation of a ketone with an aryl hydrazine

The acid-catalyzed cyclization of aryl hydrazones generate indole with loss of ammonia.

The method can be used to generate substituted endols at 2-position (R2 in figure below) which is difficult to obtain by EAS

R1

R1

R2

R1

R2

R1

R2

Basicity of purine Purine has three basic, pyridine-like nitrogens with lone-pair electrons in sp2 orbitals in the plane of the ring. The remaining purine nitrogen is nonbasic and pyrrole-like, with its lone-pair electrons as part of the aromatic p electron system.

Although this N is sp3 hybridized, the lone e are involved in the aromatic p system. Thus the lone

e are not available.

Basicity of sp3 N in Indole and purine

The indole sp3 N is more basic than that of purine. Since purine has three aromatic sp2 N withdrawing the electrons, the sp3 N has less electron to give (less basic)

Electron withdrawing

13

Purine Two purine bases of nucleic acids:(pyrimidinoimidazole)

N

N

N

NH

NH2

adenine6-aminopurine

N

N

N

NH

OH

H2N

guanine2-amino-6-hydroxypurine

xanthine2,6-dihydroxypurine

hypoxanthine6-hydroxypurine

N

N

N

NH

OH

N

N

N

NH

HO

OH

uric acid (2,6,8-trihydroxypurine)

N

N

N

NH

–OH

HO

OH

N

N

N

NH

O– NH4+

HO

OH

ammonium hydrogen urate lactim form lactam form of uric acid

N

N

N

NH

–OH

HO

OH

N

N

N

NH

N

N

N

NH

–OH

HOHO

OHOH

N

N

N

NH

1

2

3

4

67

8

9

5

atypical numbering!

Lactam is cyclic amide (NH-C=O) which undergo tautomerism to lactim (N=C-OH)

DNA base pairing

15

OH

allopurinol

N

NN

NH mercaptopurine

N

N

N

NH

SH

caffeine1,3,7-trimethyxanthine

theophylline1,3-dimethylxanthine

theobromine1,7-dimethylxanthine

Methylxanthines are N-methyl derivatives of xanthines, known alkaloids in coffee, tea, and cocoa.

Allopurinol is an isomer of hypoxanthine, which is used in treatment of hyperuricacidaemia and gout. It inhibits xanthine oxidase – the enzyme that transforms hypoxanthine and xanthine to urate.Mercaptopurine (6-sulfanylpurine) inhibits the biosynthesis of purine bases and is used in chemotherapy of cancer.

Purine synthesis

4,5-diaminopyrimidine 8-methyl-9H-purine

3-methyl-5-aminoimidazole-4-carbonitrile

Traube synthesis:

Reacting 4,5-diaminopyrimidine with formic acid to give purine, or acetic anhydride to give methyl substituted purine at imidazole ring.

Or

Reacting substituted imidazole with formamide to give substituted purine at pyrimidine ring

Quinoline and Isoquinoline A benzene ring can be fused on to the pyridine ring in two ways giving the important heterocycles quinoline, with the nitrogen atom next to the benzene ring, and isoquinoline, with the nitrogen atom in the other possible positionQuinoline forms part of quinine (anti-malarial alkaloid) and isoquinoline forms the central skeleton of the papaverine (antispasmodic opium alkaloid).

Numbering

The presence of nitrogen in this structure produces an irregular distribution of the electron density in both heterocyclic and carbocyclic rings, a situation that alters the physicochemical properties and reactivity.

Napthalene Quinoline

Basicity of quinolone and isoquinoline

Both N are sp2

The lone-pair electrons of N are close to benzene ring and thus get involved with the p

electrons of benzene(play with neighbor kids)

The lone-pair electrons of N are far from benzene ring and thus get not involved with the

p electrons of benzene(no neighbor kids to play with)

Basicity depends on the ability of N to give electrons for

Reactivtiy of quinolines The chemistry quinolines = pyridine

Quinoline and isoquinoline both have

1. Have basic, pyridine-like nitrogen atoms, which undergo electrophilic substitutions.

2. Are less reactive toward electrophilic substitution than benzene because of the electronegative nitrogen atom that withdraws electrons from the ring.

3. Electrophilic substitution occurs on the benzene ring rather than on the nitrogen-containing pyridine ring, and a mixture of substitution products is obtained.

In quinolone and isoquinoline the N withdraw electrons in pyridine ring thus few are available for EAS, therefore Br prefers to go to benzeneNote: EAS reactivity for the fused benzene ring in both of quinolone and isoquinoline is much lower than that for non-fused benzene (Because of the deactivating effect of N) While pyrrole ring of indole is most reactiveto EAS

This N is sp3 hybridized, thus electrons are swimming away from their mother (nucleus) ,

thus wolf can attack

This N is sp2 hybridized, thus electrons are swimming close

to their mother (nucleus), thus wolf can not attack

This is a hateful electron greedy wolf

Here we pull e by protonation, to destroy any

hope for NO2 to come to pyridine ring

Rxns of quinoloneElectrophilic substitution

Quinoline chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring.

So nitration of quinoline gives two products—the 5- nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinolone).

Rxns of quinoloneElectrophilic substitution

Acridine, with two benzene rings, which gives four nitration products, all on the benzene rings.

IF you want electrophils to come to pyridine ring, then give the ring some electrons, e.g. by formation of N-oxide.

The acridine-N-oxide gives just one product in good yield—nitration takes place at the only remaining position on the pyridine ring.

Here we fuel N with e to enable EAS at

pyridine

Rxns of isoquinolineElectrophilic substitution

The nitration of isoquinoline is rather better behaved, giving 72% of one isomer (5-nitroisoquinoline) at 0 °C.

Synthesis of quinolines Anilines Plus 1,3-Dielectrophiles:

Condensation of a 1,3-dielectrophile, in the simplest case a 1, 3-dicarbonyl derivative, with an aniline furnishes a β-aminoenone, which can evolve to an aromatic derivative by treatment with concentrated acid.

Cβ

Cα

o-Acylanilines Plus Carbonyl Compounds

o-Acylanilines condense with enolizable carbonyl (keto group with adjacent H) to give quinolines.

The outcome of the condensation was found to be dependent on the type of catalyst (acid or base)

Synthesis of quinolines This Zigzag bond indicate unknown

isomer

Here we have tautomerizatoin also

Synthesis of quinoline Skraup reaction

conjugate addition of the amine. Under acid catalysis the ketone now cyclizes to give a dihydroquinoline after dehydration. Oxidation to the aromatic quinoline is an easy step accomplished by many possible oxidants.

Unsaturated keton

Aniline

Synthesis of quinoline Simple example of Skraup reaction

Traditionally, the Skraup reaction was carried out by mixing everything together and letting it rip. A typical mixture to make a quinoline without substituents on the pyridine ring would be the aromatic amine, concentrated sulfuric acid, glycerol, and nitrobenzene all heated up in a large flask at over 100 °C with a wide condenser.

The glycerol was to provide acrolein (CH2=CH·CHO) by dehydration, which provide the necessary 3C to close the ring

The nitrobenzene was to act as oxidant

Synthesis of isoquinoline Alkylation of phenylethylamine by acyl halide, then electrophile is made from an amide and POCl3 to close the ring and generate dihydroisoquinoline, which is then reduced to isoquinoline