Heterocyclic Chemistry For Pharmacy Students PDF

Dr. Solomon Derese [email protected] Chemistry Department; Room 118 Dr. Solomon Derese UPC 213 1 UPC 213 (Pharmaceutical Chemistry II) Heterocyclic Chemistry n = 1,2,3, …… Where Z is different (hetero) from carbon Dr. Solomon Derese UPC 213...

Dr. Solomon Derese [email protected] Chemistry Department; Room 118 Dr. Solomon Derese UPC 213 1 UPC 213 (Pharmaceutical Chemistry II) Heterocyclic Chemistry n = 1,2,3, …… Where Z is different (hetero) from carbon Dr. Solomon Derese UPC 213 2  Course outline Introduction to heterocyclic chemistry Nomenclature of Heterocycles Structure, reactions and synthesis of aromatic heterocyclic compounds Dr. Solomon Derese UPC 213 3 Department of Chemistry facebook page www.facebook.com/kemiauon Like it Share it Post Comment Dr. Solomon Derese UPC 213 4  Scope of the course Study Nomenclature, Structure, Reaction and Synthesis of aromatic heterocyclic compounds. Aliphatic heterocycles Dr. Solomon Derese UPC 213 5 Aromatic heterocycles Dr. Solomon Derese UPC 213 6 We will study the chemistry of heterocyclic compounds i.e. Cyclic organic compounds containing not just carbon atoms, but oxygen, nitrogen, sulfur etc. It may seem strange that this rather narrowly defined class of compounds deserves a whole unit, but you will soon see that this is justified both by the sheer number and variety of heterocycles that exist and by their special chemical features. Dr. Solomon Derese UPC 213 7 Why bother with heterocycles? A recent analysis of the organic compounds registered in Chemical Abstracts revealed that as of June 2007, there were 24,282,284 compounds containing cyclic structures, with heterocyclic systems making up many of these compounds – about two third of organic compounds are heterocyclic. Most pharmaceuticals are based on heterocycles. An inspection of the structures of the top-selling brand- name drugs in 2007 reveals that 8 of the top 10 and 71 of the top 100 drugs contain heterocycles. Dr. Solomon Derese UPC 213 8 The history of medicine can be defined by heterocyclic compounds. As early as 16th century The first synthetic drug have been used to treat (1887) (used for malaria. reduction of fevers) Dr. Solomon Derese UPC 213 9  The first multi-million pound drug (1970s), antiulcer drug. The first effective antibiotic (1938). Dr. Solomon Derese UPC 213 10 Dr. Solomon Derese UPC 213 11  Approved in 1997 for treatment of male impotence. Approved for treatment of Chronic Myelogenous Leukemia (CML) in 2001. Dr. Solomon Derese UPC 213 12  Nomenclature of Heterocyclic Compounds Dr. Solomon Derese UPC 213 13 The IUPAC rules allow three nomenclatures. I. The Hantzsch-Widman Nomenclature. II. Common Names III. The Replacement Nomenclature Dr. Solomon Derese UPC 213 14 I. Hantzsch-Widman Nomenclature n = 1,2,3, …… The Hantzsch-Widman nomenclature is based on the type (Z) of the heteroatom; the ring size (n) and nature of the ring, whether it is saturated or unsaturated. This system of nomenclature applies to monocyclic three-to-ten-membered ring heterocycles. Dr. Solomon Derese UPC 213 15 I. Type of the heteroatom The type of heteroatom is indicated by a prefix as shown below for common hetreroatoms: Hetreroatom Prefix O Oxa N Aza S Thia P Phospha Dr. Solomon Derese UPC 213 16 II. Ring size (n) The ring size is indicated by a suffix according to Table I below. Some of the syllables are derived from Latin numerals, namely ir from tri, et from tetra, ep from hepta, oc from octa, on from nona, ec from deca. Table I: Stems to indicate the ring size of heterocycles Ring size Suffix Ring size Suffix 3 ir 7 ep 4 et 8 oc 5 ol 9 on 6 Dr. Solomon Derese in UPC 21310 ec 17 The endings indicate the size and degree of unsaturation of the ring. Table II: Stems to indicate the ring size and degree of unsaturation of heterocycles Ring size Saturated Unsaturated Saturated (With Nitrogen) 3 -irane -irine -iridine 4 -etane -ete -etidine 5 -olane -ole -olidine 6 -inane -ine 7 -epane -epine 8 -ocane -ocine 9 -onane -onine 10 -ecane -ecine Dr. Solomon Derese UPC 213 18 According to this system heterocyles are named by combining appropriate prefix/prefixes with a stem from Table II. The letter “a” in the prefix is omitted where necessary. Each suffix consists of a ring size root and an ending intended to designate the degree of unsaturation in the ring. It is important to recognize that the saturated suffix applies only to completely saturated ring systems, and the unsaturated suffix applies to rings incorporating the maximum number of non- cumulated double bonds. Dr. Solomon Derese UPC 213 19 Systems having a lesser degree of unsaturation require an appropriate prefix, such as "dihydro"or "tetrahydro". Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the traditional "iridine", "etidine" & "olidine" suffix. Dr. Solomon Derese UPC 213 20  Examples Oxa+irane= Oxirane Thia+irane= Thiirane Aza+iridine= Aziridine Oxa+etane=Oxetane Thia+etane=Thietane Aza+etidine=Azetidine Oxa+olane= Oxolane Thia+olane= Thiolane Aza+olidine= Azolidine Dr. Solomon Derese UPC 213 21  Azinane Azine Pyridine Dr. Solomon Derese UPC 213 22 In case of substituents, the heteroatom is designated number 1, and the substituents around the chain are numbered so as to have the lowest number for the substituents. Dr. Solomon Derese UPC 213 23 The compound with the maximum number of noncumulative double bonds is regarded as the parent compound of the monocyclic systems of a given ring size. Dr. Solomon Derese UPC 213 24 Partial Unsaturation Use fully unsaturated name with dihydro, tetrahydro, etc 3 2 1 Azepine 2,3-Dihydroazepine 4,5-Dihydroazepine 2,5-Dihydroazepine Dr. Solomon Derese UPC 213 25 When numbering give priority to saturated atoms. 1-Ethyl-4-methyl-4,5-dihydroazepine 1-Ethyl-5-methyl-2,3,4,5-tetrahydroazepine Dr. Solomon Derese UPC 213 26 Revision Hetreroatom Prefix Type (Z) - Prefix O Oxa Size (n) - Suffix N Aza Nature of ring - Ending S Thia P Phospha Ring size Saturated Unsaturated Saturated (With Nitrogen) 3 -irane -irine -iridine 4 -etane -ete -etidine 5 -olane -ole -olidine 6 -inane -ine 7 -epane -epine 8 -ocane -ocine 9 -onane -onine 10 -ecane Dr. Solomon Derese -ecine UPC 213 27 Rings With More Than One Heteroatom Dr. Solomon Derese UPC 213 28 Two or more similar atoms contained in a ring are indicated by the prefixes ‘di-’, ‘tri’, etc. 1,3,5-Triazine If more than one hetero atom occur in the ring, then the heterocycle is named by combining the appropriate prefixes with the ending in Table I in order of their preference, O > S > N. Dr. Solomon Derese UPC 213 29  1,3-Thiazole Oxaziridine (Thiazole) 1,4-Oxazine 3-chloro-5-methyl-1,2,4-oxadiazole Dr. Solomon Derese UPC 213 30 Priority of heteroatoms for numbering purposes: Highest B C N O Lowest P S Se Dr. Solomon Derese UPC 213 31 The ring is numbered from the atom of preference in such a way so as to give the smallest possible number to the other hetero atoms in the ring. As a result the position of the substituent plays no part in determining how the ring is numbered in such compounds. 4-Methyl-1,3-thiazole Dr. Solomon Derese UPC 213 32 II. Common Names There are a large number of important ring systems which are named widely known with their non-systematic or common names. Dr. Solomon Derese UPC 213 33 Dr. Solomon Derese UPC 213 34  1,4-Dihydropyridine 2,3-Dihydropyridine Dr. Solomon Derese UPC 213 35 Identical systems connected by a single bond Such compounds are defined by the prefixes bi-, tert- , quater-, etc., according to the number of systems, and the bonding is indicated as follows: 1 1 2’ 2’ 2 4’ 2 3’’ 1’’ 1’ 2’’ 1’ 2,2' - Bipyridine 2,2': 4',3'' - Terthiophene Dr. Solomon Derese UPC 213 36  Naming Hetrocycles with fused rings When naming such compounds the side of the heterocyclic ring is labeled by the letters a, b, c, etc., starting from the atom numbered 1. Therefore side ‘a’ being between atoms 1 and 2, side ‘b’ between atoms 2 and 3, and so on as shown below for pyridine. c d b e a f Dr. Solomon Derese UPC 213 37 The name of the heterocyclic ring is chosen as the parent compound and the name of the fused ring is attached as a prefix. The prefix in such names has the ending ‘o’, i.e., benzo, naphtho and so on. b b c a a a b Benzo [b] furan Benzo [c] thiophene Benzo [b] pyridine Dr. Solomon Derese UPC 213 38  d Benzo [d] thiepine a c b Dr. Solomon Derese UPC 213 39 In a heterocyclic ring, other things being equal, numbering preferably commences at a saturated rather than at an unsaturated hetero atom. 1 2 1 2 3-Ethyl-5-methylpyrazole 1-Methylindazole Dr. Solomon Derese UPC 213 40  Handling the “Extra Hydrogen” Dr. Solomon Derese UPC 213 41 Heterocycles with maximum number of double bonds which can be arranged in more than one way. Examples Pyrans Double bonds Double bonds @ 2 and 4 @ 2 and 5 Double bonds Double bonds @ 2 and 4 @ 1 and 3 Pyrroles Double bonds @ 1 and 4 Therefore, should have different names. Dr. Solomon Derese UPC 213 42 This is a special problem resulting from isomerism in the position of the double bonds which is sometimes referred to as “extra-hydrogen” and this can be addressed by simply adding a prefix that indicates the number of the ring atom that possesses the hydrogen using italic capital ‘1H’ ‘2H’ ‘3H’, etc. The numerals indicate the position of these atoms having the extra hydrogen atom. 4 2 3 1 1 2 2H-Pyran 4H-Pyran The saturated position takes priority in numbering. Dr. Solomon Derese UPC 213 43  1H-Pyrrole 3H-Pyrrole 2H-Pyrrole (Pyrrole) 2 4 3 3 1 2 1 4 4-Methyl-2H-oxete 2-Methyl-2H-oxete Dr. Solomon Derese UPC 213 44 Dr. Solomon Derese UPC 213 45 III. The Replacement Nomenclature In replacement nomenclature, the heterocycle's name is composed of the carbocycle's name and a prefix that denotes the heteroatom. Thus, "aza", "oxa", and "thia" are prefixes for a nitrogen ring atom, an oxygen ring atom, and a sulfur ring atom, respectively. Notice that heterocyclic rings are numbered so that the heteroatom has the lowest possible number. Dr. Solomon Derese UPC 213 46 Dr. Solomon Derese UPC 213 47 Dr. Solomon Derese UPC 213 48  UPC 213 REACTIONS AND PROPERTIES OF AROMATIC HETEROCYLCES Dr. Solomon Derese  SIX MEMBERED AROMATIC HETEROCYCLES Pyridine is aromatic as there are six delocalized N.. electrons in the ring. Pyridine Six-membered heterocycles are more closely related to benzene as they are aromatic on the basis of their p-electron systems without the need for delocalization of heteroatom lone pairs. The empirical resonance energy for pyridine is about 28 Kcal/mol, only slightly lower than that for benzene. 50  Structure of Pyridine Pyridine has divalent negatively charged N, which is a stable condition for N. The positive charge is dispersed to carbons around the ring, specifically to C-2 and C-4. The net effect is to reduce the p-electron density in the ring relative to benzene, and as result pyridine is electron deficient compared to benzene. 51 As a result, unlike benzene pyridine is polar molecule due to the electronegative nitrogen.  Six membered heterocycles with an electronegative heteroatom are generally electron deficient compared to benzene. Such compounds are classified as p-deficient. Electron-withdrawing heteroatoms decrease the p-electron density at the carbon atoms and are thus p-deficient relative to benzene. 53  Structure of five membered heterocycles The five-membered aromatic heterocycle ring has a p-electron excess (six on five atoms), while in benzene, the p-electron density is one on each ring atom. Five membered heterocycles with an electronegative heteroatom are generally electron rich compared to benzene (six electrons for five carbons). Such compounds are classified as p-excessive. 54  The degree of aromatic character in a five membered ring is 36 kcal/mol determined by the ease with which the lone pair may be 29 kcal/mol released into the delocalized system. The ease with which the lone pair electron is released is directly 22 kcal/mol related to the electronegativity of the heteroatom. Thus the lower the electronegativity of the 16 kcal/mol heteroatom, the higher the aromaticity. 55 56  Aromatic Heterocycles p- Excessive p- Deficient This classification is not trivial; there is a vast difference between the properties of the two types of aromatic compounds. 57  Reactions of p-deficient heterocyclic aromatic compounds A hallmark of p-deficient heterocyclic systems is their low reactivity with electrophilic agents, slower than benzene. For example, pyridine is less reactive than benzene by a factor of 106 when subjected to conditions of nitration. The reactivity is on the order of that of nitrobenzene, which is well known to require much more drastic conditions than those for benzene itself. 58 For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in conc. sulfuric acid) at 130°C. Conversely pyridines are susceptible to nucleophilic attack. 59  Reactions of p-excessive heterocyclic aromatic compounds A significant feature of the p-excessive ring systems is that they undergo electrophilic aromatic reactions faster than benzene. The reactivity is greater than that of benzene and is in roughly the same range as found for benzenes bearing electron releasing groups such as in aniline. The greater electron density in these rings accounts for this higher reactivity. 60 These heterocycles undergo electrophilic aromatic substitution reactions much faster than benzene under similar conditions. The reasons for this are: I. The resonance energy of the heterocycles is less than that of benzene, i.e. less aromatic than benzene. II. The five-membered aromatic heterocycle ring has a p-electron excess (six on five atoms), while in benzene, the p-electron density is one on each ring atom. 61 Reaction with bromine requires no Lewis acid and leads to substitution at all four free positions. no Lewis acid 62 FIVE MEMBERED AROMATIC HETEROCYCLES 63 Electrophilic aromatic substitution reaction of five membered aromatic heterocycles X = O, S or NH a-substitution b-substitution The Substitution is regioselective to the a position; when these positions are occupied, the b-position is substituted. 64  WHY? The +ve charge is better resonance stabilized when the substitution is at the a-position than at b- position. A more stable intermediate carbocation having 3 resonance forms. only 2 resonance forms 65 Common reactions of pyrrole, furan, and thiophene The following reaction are common to the three five membered aromatic heterocycles. A. Electrophilic Aromatic Substitution Z = O, S, NH Electrophilic aromatic substitution reaction is easy and is preferred at a-position; also easy at b- position. 66 B. Substitution at a-position via a-lithiated Intermediates Z = O, S, NR C. Vilsmeier-Haack reaction Vilsmeier reaction (Vilsmeier‐Haack reaction) allows the formylation (addition of -CHO) of heterocyclic molecules. The formylating agent, chloroiminium ion, is formed in situ from N,N‐dimethylamide and POCl3. 67 Vilsmeier-Haack reaction Z = O, S, NH Example 68 Mechanism Chloroiminium ion 69 D. Mannich reaction The reaction of electron rich heterocycles with formaldehyde and primary/secondary amine forming an amino alkylated heterocylcic compound is called the Mannich reaction. Z = O, S, NH 70 Mechanism 71 Furans are volatile, fairly stable compounds with pleasant odours. Furan itself is slightly soluble in water. It is readily available, and its commercial importance is mainly due to its role as the precursor of the very widely used solvent tetrahydrofuran (THF). 72 Reactions of Furans By analogy with benzene, furan undergoes reactions with electrophilic reagents, often with substitution. However, it can also react by addition and/or ring-opening depending on reagent and reaction conditions. 73 Electrophilic Aromatic Substitution Reaction 74 Halogenation Furan can be halogenated at a-position. Bromination and iodination are easy to control as only one halogen atoms adds to furan. In the case of chlorination, di-substitution has been known to occur. 75 Acylation Acetyl groups in the presence of phosphoric acid (or a Lewis acid) add at a-position of furans. In general, position 2 (a-position) is more reactive than position 3. When position 2 is blocked, b-acylation can proceed smoothly. 76 Metalation n-Butyllithium in hexane metalates furan in the 2-position, while excess of reagent at higher temperature produces 2,5-dilithiofuran. 77 Addition reactions Furans yield the corresponding tetrahydrofurans by catalytic hydrogenation. In some addition reactions, furans behave as 1,3- dienes. For example, furan reacts with bromine in methanol in the presence of potassium acetate to give 2,5-dimethoxy-2,5-dihydrofuran by a 1,4- addition: 78 Ring-opening reactions Furans are protonated in the 2-position, and not on the O-atom, by BRÖNSTED acids: Concentrated acid Dilute acid 79  Thiophene prefers reactions with electrophilic reagents. Additions and ring-opening reactions are less important than with furan, and substitution reactions are dominant. Some additional reactions, such as oxidation and desulfurization, are due to the presence of sulfur and are thus confined to thiophenes. 80 Electrophilic substitutions Thiophene reacts more slowly than furan but faster than benzene. Substitution is regioselective in the 2- or in the 2,5-position. 81 Reactions with nucleophilic reagents 82 Oxidation Thiophenes are oxidized by peroxy acids to give thiophene 1,1 –dioxides: 83 Pyrrole reacts with sodium, sodium hydride or potassium in inert solvents, and with sodium amide in liquid ammonia, to give salt-like compounds: 84 Electrophilic substitution reactions on carbon Nitration 85 Halogenation 86  6-Membered Aromatic Heterocycles Containing one Heteroatom 87 Pyridines Pyridine is the simplest heterocycle of the azine type. It is derived from benzene by replacement of a CH group by a N-atom. 88 The structure of pyridine is completely analogous to that of benzene, being related by replacement of CH by N. The key differences are: I. The departure from perfectly regular hexagonal geometry caused by the presence of the hetero atom, in particular the shorter carbon-nitrogen bonds, II. The replacement of a hydrogen in the plane of the ring with an unshaired electron pair, likewise in the plane of the ring, located in an sp2 hybrid orbital, and not at all involved in the aromatic p-electron sextet; it is this nitrogen lone pair which is responsible for the basic properties of pyridines, and 89 III.A strong permanent dipole, traceable to the greater electronegativity of the nitrogen compared with carbon. 90 The following reactions can be predicted for pyridines on the basis of their electronic structure: I. The heteroatom make pyridines very unreactive to normal electrophilic aromatic substitution reactions. Conversely pyridines are susceptible to nucleophilic attack. Pyridines undergo electrophilic substitution reactions (SEAr) more reluctantly but nucleophilic substitution (SNAr) more readily than benzene. II. Electrophilic reagents attack preferably at the N- atom and at the b-C-atoms, while nucleophilic reagents prefer the a- and c-C-atoms. 91 Reactions of Pyridine Electrophilic Addition at Nitrogen In reactions which involve bond formation using the lone pair of electrons on the ring nitrogen, such as protonation and quaternisation, pyridines behave just like tertiary aliphatic or aromatic amines. 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. 92 Protonation at Nitrogen Pyridines form crystalline, frequently hygroscopic, salts with most protic acids. Nitration at Nitrogen This occurs readily by reaction of pyridines with nitronium salts, such as nitronium tetrafluoroborate. Protic nitrating agents such as nitric acid of course lead exclusively to N-protonation. 93 Acylation at nitrogen Acid chlorides and arylsulfonic acids react rapidly with pyridines generating 1-acyl- and 1- arylsulfonylpyridinium salts in solution. 94 Alkylation at nitrogen Alkyl halides and sulfates react readily with pyridines giving quaternary pyridinium salts. 95 Electrophilic substitution at Carbon atoms of the pyridine ring Electrophilic substitution of pyridines at a carbon is very difficult. Two factors seem to be responsible for this unreactivity: I. Pyridine ring is less nucleophilic than the benzene ring; nitrogen ring atom is more electronegative than carbon atoms and therefore it pulls electrons away from the carbon atoms inductively leaving a partial plus on the carbon atoms. 96 II. When pyridine compound is exposed to an acidic medium, it forms pyridinium salt. This increases resistance to electrophilic attack since the reaction will lead to doubly positive charged species. Less reactive than pyridine 97 When an electrophile attacks the pyridine ring, only position 3 is attacked. Why? Hint: draw resonance structures that result from electrophilic attack at various positions. The positive charge residing on an electronegative element with sextet configuration is unfavoured. 98 For example, 3-bromopyridine is formed when pyridine is reacted with bromine in the presence of oleum (sulfur trioxide in conc. sulfuric acid) at 130°C. 99  Mechanism of bromination of pyridine 100 Pyridine can be activated to electrophilic substitution by conversion to pyridine-N-oxides. A series of preparatively interesting reactions on pyridine can be carried out by means of pyridine N- oxides such as the introduction of certain functions into the ring and side-chain which cannot be achieved in the parent system by direct methods. 101 The activating oxygen atom can be removed by reacting the pyridine N-oxide with phosphorous trichloride. 102 In such reactions there is a balance between electron withdrawal, caused by the inductive effect of the oxygen atom, and electron release through resonance from the same atom in the opposite direction. Here, the resonance effect is more important, and electrophiles react at C-2(6) and C-4. 103 Thionyl chloride, for example, gives a mixture of 2- and 4-chloropyridine N-oxides in which the 4-isomer is predominant. 104 However, pyridine N-oxide reacts with acetic anhydride first to give 1-acetoxypyridinium acetate and then, on heating, to yield 2-acetoxypyridine through an addition-elimination process. 105 When a similar reaction is carried out upon the 2,3- dimethyl analogue, the acetoxy group rearranges from N-1 to the C-2 methyl group, at 1800C, to form 2-acetoxymethyl-3-methylpyridine. 106 107 108 Anion Chemistry of Pyridine The negative charge generated on the carbon goes to the electronegative nitrogen, which can better accommodate Resonance stabilized it. Works for 2(6)- and 4-alkylpyridines not for 3(5)-alkyl pyridines, why? 109 110 111 112 Nucleophilic substituition of pyridine a) X=H b) X=Good leaving group X=H, Substitution with “hydride” transfer Nu: NaNH2 - amination Nu: BuLi, PhLi etc - alkylation / arylation Nu: NaOH - “hydroxylation” 115 At high temperature the intermediate anion can aromatize by loss of a hydride ion, eventhough, it is a poor leaving group. 116 b) X=LG, The nucleophilic substitution is much more facile when good leaving group such as X: Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR, are employed. 117 118 -H: is a bad leaving group 119 120 Halogenopyridines can undergo metal-halogen exchange when treated with butyllithium. The lithium derivatives then behave in a similar manner to arylithiums and Grignard reagents and react with electrophiles such as aldehydes, ketones and nitriles. 121  UPC 213 Synthesis of Heterocycles Compounds :Nu Dr. Solomon Derese 122  UPC 213 Synthesis of Furan, Pyrrole and Thiophene Dr. Solomon Derese 123  UPC 213 Furans, pyrroles and thiophenes from 1,4-dicarbonyl compounds: Paal Knorr synthesis :Nu d+ d+ :Nu = RNH2, H2S Dr. Solomon Derese 124  UPC 213 Dr. Solomon Derese 125  UPC 213 Dr. Solomon Derese 126  UPC 213 Furans, pyrroles and thiophenes from 1,3-dicarbonyl (b-ketocarbonyl) compounds acidic hydrogens React with electrophiles Dr. Solomon Derese 127  UPC 213 Feist–Benary synthesis of furans The Feist-Benary synthesis is an organic reaction between a-haloketones and b- dicarbonyl compounds to give substituted furans in the presence of base. a-haloketones X = Cl, Br, I Dr. Solomon Derese 128  UPC 213 Dr. Solomon Derese 129 130  UPC 213 Knorr-pyrrole synthesis This involves the condensation of a-amino ketones with a b-diketone or a b-ketoester to give a substituted pyrrole in the presence of a base like pyridine. a-amino ketones Dr. Solomon Derese 131  UPC 213 Dr. Solomon Derese 132  UPC 213 Fiesselmann synthesis 1,3-Dicarbonyl compounds or b-chlorovinyl aldehydes react with thioglycolates or other thiols possessing a reactive methylene group to give thiophenes in the presence of pyridine. Dr. Solomon Derese 133  UPC 213 Dr. Solomon Derese 134  UPC 213 Synthesis of Pyridine :Nu = RNH2 Dr. Solomon Derese 135 I. Reaction between a 1,5-diketone and ammonia Ammonia reacts with 1,5-diketones to give unstable 1,4-dihydropyridine, which can be easily dehydrogenated (using nitrobenzene or nitric acid) to give pyridine. 1,4-dihydropyridine 136 II. The Guareschi synthesis Unsymmetrical pyridines can be synthesised from a reaction between a b-dicarbonyl compound and a b- enaminocarbonyl compound or nitrile. 137 138 139 III. The Hantzsch synthesis Symmetrical 1,4-dihydropyridines, which can be easily dehydrogenated (to form pyridines), are produced from the condensation of an aldehyde, ammonia, and two equivalents of a 1,3-dicarbonyl compounds (commonly a β-ketoester) which must have a central methylene. The product from the classical Hantzsch synthesis is necessarily a symmetrically substituted 1,4- dihydropyridine. Subsequent oxidation (or dehydrogenation) gives a symmetrical pyridine compound. 140 STEP I The reaction is believed to proceed via Knoevenagel Condensation. STEP II A second key intermediate is an ester enamine, which is produced by condensation of the second equivalent of the β-ketoester with ammonia: 141 STEP III Further condensation between these two fragments gives the dihydropyridine derivative: 142 143 MECHANISM 144 145 Nifedipine is in a group of drugs called calcium channel blockers. It works by relaxing the muscles of your heart and blood vessels. Nifedipine is used to treat hypertension (high blood pressure) and angina (chest pain). 146 147 OXAZOLE 148 IMIDAZOLES THIAZOLES 149 Diazepam (Valium) used for the treatment of anxiety disorders. Diazepam also is used for the treatment of agitation, tremors, delirium, seizures, and hallucinations resulting from alcohol withdrawal. It is used for the treatment of seizures and relief of muscle spasms in some neurological diseases 150 151 Antifungal drug 152 153 154 Clopirac Nonsteroidal Antiinflammatory Drug) 155 156