We can learn the synthesis

1. ORGANIC REACTIONS IN HETEROCYCLIC
CHEMISTRY
Presented by
Suraj N. Wanjari
M. Pharm. First Semester Pharmaceutical Chemistry
Department Of Pharmaceutical Sciences
Rashtrasant Tukadoji Maharaj Nagpur University
Nagpur-440 033

2. Content
• Debus – Radziszewski Imidazole synthsis
• Knorr Pyrrole Synthesis
• Pinner Pyrimidine Synthesis
• Combes Quinoline synthesis
• Bernthsen Acridine synthesis
• Smiles Rearrangement Synthesis
• Traube Purine Synthesis
• Refrences
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3. Debus – Radziszewski Imadazole
synthsis
• This reaction is named after Heinrich Debus & Bronislaw leonard Radziszwski
• It is an organic multicomponent reaction used for the synthesis of imidazole from carbonyl ,
an aldehyde and ammonia .
• The dicarbonyl component is commonly gloyoxal but can also include various 1 ,2-
diketones & ketoaldehyde .
• The reaction can be viewed as occuring in two stages .
• In first stage , the dicarbonyl and ammonia condense to give an diimide ( shown with unsual
orientation of N-H group )
Dicarbonyl comp. Ammonia Diimide 11/22/2018
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4. • In the second stage diimine condenses with aldehyde gives Imadazole.
• A modification of this general method where one equivalent of ammonia is replaced by an
amine affords N-Substituted imidazoles in good yield. .
Dimine aldehyde Imadazole
Carbonyl comp. aldehyde Ammonia1ryAmmine
Imadazole
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5. Application
• It is the important precorsor for the synthesis of systemic antifungal agent .
• Imidazoles has been used extensively as corrosion inhibitor on transition metals
such as copper .
• Imidazoles can also be used as organic structure directing agent to synthesize
zeolites .
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6. Knorr Pyrrole Synthesis
• This reaction was used for the synthesis of substituted pyrroles .
• The method involve the reaction of an alfa amine ketone and compound containing an
alectron – withdrawing group (eg.an ester )
• The mechanism requires zinc & acetic acid as catalyst . It will proceed at room tempreture .
Because alfa-amino-ketone self condense very easily , they must be prepared in situ .
• The usual way of doing this is from the relevant oxime via the Neber rearrangement .
Zn2+
CH3COOH
alfa amine ketone An ester Pyrrole
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7. • The original knorr synthesis employed two equivalents of ethyl acetoacetate , one of which
was convert to ethyl 2-oximinoacetate by dissolving it in glacial acetic acid & slowly
adding one equivalent of saturated aqueous sodium nitrite under external cooling. Zinc
dust is then stirred in reducing the oxime group to the amine. This reduction consumes two
equivalents of zinc and four equivalents of acetic acid.
ethyl acetoacetate 2-Nitro ethyl
acetoacetate
Pyrrole
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8.  Mechanism of Knorr Pyrrole synthesis
alfa amine ketone
HCOOC2H5
Pyrrole 11/22/2018
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ethyl acetoacetate

9. Application
• It was the important precursor for the drug tolmetin ( NSAID ) .
• It was also found in many drug such as atorvastatin , ketorolac & sunitinib .
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10. Pinner Pyrimidine Synthesis
• Condensation of 1,3-dicarbonyl compounds with amidines catalysed by acid or
bases to give pyrimidines derivatives is regarded as Pinner Pyrimidine synthesis .
• Amidines are the oxaacid derivative ,much more basic than amide and are the
strongest unionised base .
1,3 – dicarbonyl compounds Pyrimidines
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11. • Protonation occurs onto the sp² hybridized nitrogen. This occurs because the positive charge
can be delocalized onto both nitrogen atoms .
• Resulting cationic species is known as amidinium ion .
• The condensation of amide derivative with other β-Keto esters, malonic esters and β-
Ketones proceed similarly .
amidine amidineAmidinium Ion Amidinium Ion
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12. Mechanism of Pinner Pyrimidine Synthesis
1,3 – dicarbonyl
compounds
Amidinium Ion
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13.  Application
• Sulfur containing pyrimidine have the folic acid antagonistic activity specially 2-
Amino-4-hydroxypyrimidines .
• It was also used as the antibiotic such as amicitin .
• It was also used as ati-viral agent such as iododeoxyuridine .
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14. Comes Quinoline Synthesis
• Comes quinoline synthesis is a chemcal reaction which was first reported by combes in
1888 .
• It is use to synthesize quinoline often used to prepare the 2,4,-substituted Quinoline
backbone and is unique in that it uses a β-diketone substrate which is different from other
quinoline preparation .
Aniline Quinoline
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15. Mechanism of Combes QUINOLINE Synthesis
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1,3 – dicarbonyl
compounds

16.  Application
• It was used for the manufacturing of dyes .
• It is also used as a solvent for resin & terpines .
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17. BERNTHSEN ACREEDINE SYNTHESIS
• The Bernthsen acridine synthesis is the chemical reaction of a diarylamine heated with
a carboxylic acid (or acid anhydride) and zinc chloride to form a 9-substituted acridine .
• Using zinc chloride, one must heat the reaction to 200-270 °C for 24hrs.
• The use of polyphosphoric acid will give acridin products at a lower temperature, but
also with decreased yields.
• Chemical name of acridine is 2,3-Benzoquinoline .
Diarylamine carboxylic acid acridine
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200-2700 C

18. Mechanism of Bernthsen synthesis
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Diarylaminecarboxylic acid
acridine

19. ACREEDINE
• Many acridine have antiseptic properties .
• It was use in the preparetion of Dyes .
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20. SMILES REARRENGEMENT
• It is an organic rearrangement reaction.
• It is an intramolecular nucleophilic aromatic substitution type of reaction .
• X in the arene compound can be a sulfur , a sulfisde , an ether or any substituent capable
of dislodging from arene carrying a negative charge .
• The terminal functional group in the chain end Y is able to act as a strong nucleophile for
instance an alcohol , amine or thiol .
• As in other nucleophile aromatic substitution the arene requires activation by electron –
withdrawing group preferebly in the aromatic ortho position . 11/22/2018
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21. • This particular reaction requires the interaction of the alkyllithium group ortho to
the sulfone group alkin a directed ortho metalation .
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22. • In one modification called true- smiles rearrangement the incoming nucleophile is
sufficiently strong that the arene does not require this additional activation for
example when the nucleophile is an organolithium .
• This reaction is exemplified by the conversion of an aryl sulfone into an sulfonic
acid by action of n-butyllithium .
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23. TRAUBE PURINE SYNTHESIS
• Preparation of 4,5-diaminopyrimidines by introduction of the amino group into the
5-position of 4-amino-6-hydroxy- or 4,6-diaminopyrimidines by nitrosation and
ammonium sulfide reduction, followed by ring closure with formic acid or
chlorocarbonic ester .
4,6-diaminopyrimidines 4,5-diaminopyrimidines
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24. MECHANISM OF TRAUBE PURINE SYNTHESIS
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4,5-diaminopyrimidines
HO
HO HO
HO
HO
HO

25. REFRENCES
• Quin D. L. Tyrele A. J. , Fundamental of heterocyclic
chemistry Page number 225 to 240
• https://scholar.google.com date of search 28/09/2018
• https://en.wikipedia.org date of search 27/09/2018
• https://www.google.com date of search 27/09/2018
• https://www.slideshare.net date of search 27/09/2018
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26. THANK YOU
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