Heterocyclic Chemistry
Heterocyclic Chemistry
6-Membered rings with two heteroatoms
Diazines
pyrimidine
1
Prepared by:
Erfan narimani
Heterocyclic Chemistry
Introduction
Replacing a CH group in the pyridine ring with a nitrogen atom can give rise to three compounds having the molecular formula C4H4N2 known as diazines :
2
Introduction
Pyrimidine was first isolated by Gabriel and Colman in 1893.
Pyrimidine is the trivial name for 1,3-diazine, m-diazone: two meta oriental CH units in benzene have been replaced by nitrogen atom.
Pyrimidine has:
one axis of symmetry about the 2-5 axis
three different pairs of bond lengths and four different bond angels
three different chemical shifts in 1H and 13CNMR spectra(Brown et al., 1994)
Heterocyclic Chemistry
3
Introduction
Pyrimidine is the most important member of all the diazines
Pyrimidine itself is not found in nature but substituted Pyrimidines and compounds containing the Pyrimidine ring are widely distributed in nature Derivatives of barbituric acid,widely used in medicines, for eg., veronal, Pentothiol, Luminol are used as hyphotics while is used as anesthetic. Purines, Uric acid, alkoxan, barbuturic acid and a mixture of amtimalarial and antibacterial also contain the Pyrimidine ring
Substances containing un-fused Pyrimidine rings occur in free stage as in Uracil, Thymine, Orotic acid, Cytosine, the glycosides, Vitamin B(thiamine), and various others.
Heterocyclic Chemistry
4
Heterocyclic Chemistry
Introduction
The main biological importance of diazines is that they are main components of nucleic acids ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) the molecules that carry the genetic information in the cells.
The classical structural definition is that a nucleoside is a pyrimidine or purine N-glycoside of D-ribofuranose or 2-deoxy-D-ribofuranose.
Informal use has extended this definition to apply to purine or pyrimidine N-glycosides of almost any carbohydrate.
The purine or pyrimidine part of a nucleoside is referred to as a purine or pyrimidine base.
5
Heterocyclic Chemistry
Pyrimidines that present in DNA are: guanine,cytosine,adenine,thymine (G-C-A-T)
Pyrimidines that present in RNA are:
guanine,cytosine,adenine,uracil (G-C-A-U)
Bioactive diazines: (a) Pyrimidines
6
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring.
Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature.
Purines and pyrimidines make up the two groups of nitrogenous bases, including the two groups of nucleotide bases.
Two of the four deoxyribonucleotides and two of the four ribonucleotides, the respective building-blocks of DNA and RNA, are purines.
Heterocyclic Chemistry
7
Two of the four bases in nucleic acids, adenine (2) and guanine (3), are purines.
Other notable purines are hypoxanthine (4), xanthine (5), theobromine (6), caffeine (7), uric acid (8) and isoguanine(9).
The name 'purine' (purum uricum) was coined by the German chemist Emil Fischer in 1884.
Heterocyclic Chemistry
8
Heterocyclic Chemistry
9
Uracil
Uracil one of the four nucleobases in the nucleic acid of RNA that are represented by the letters A,G, C and U. In DNA, the uracil nucleobase is replaced by thymine.
Methylation of uracil produces thymine.
5-Fluorouracil is an anticancer drug. this drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping thegrowth of cancerous cells.
Heterocyclic Chemistry
10
Thymine
Thymine is also known as 5-methyluracil,a pyrimidinenucleobase.
Thymine (T, Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the lettersG–C–A–T.
As the name suggests, thymine may be derived by methylation of uracil at the 5th carbon.
In RNA,thymine is replaced with uracil in most cases.
Heterocyclic Chemistry
11
Cytosine
Cytosine (C) is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA).
It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an amine group at position 4 and a keto group at position 2).
Cytosine recently found use in quantum computation.
Heterocyclic Chemistry
12
Alloxan
Alloxan is an oxygenated pyrimidine derivative. It is present as alloxan hydrate in aqueous solution.
Alloxan is a toxic glucose analogue, which selectively destroys insulin-producing cells in the pancreas (that is beta cells).
The original preparation for alloxan was by oxidation of uric acid by nitric acid.
Heterocyclic Chemistry
13
Thiamine
Thiamine or thiamin or vitamin B1 named as the "thio-vitamine" ("sulfur-containing vitamin") is a water-soluble vitamin of the B complex.
The best-characterized form is thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids.
Heterocyclic Chemistry
14
Orotic acid
Orotic acid is a heterocyclic compound and an acid; it is also known as pyrimidinecarboxylic acid.
Historically itwas believed to be part of the Vitamin B complex and was called vitamin B13, but it is now known that it is not avitamin.
Heterocyclic Chemistry
15
Heterocyclic Chemistry
Sodium thiopental
Thiopental,5-ethyl-5-(1-methylbutyl)2-thiobarbituric acid, is synthesized by the alkylation of ethylmalonic ester with 2-bromopentane in the presence of sodium ethoxide.
heterocyclization with thiourea, using sodium ethoxide as a base.
16
Barbital
Barbital (as known in the United States)
barbitone (as known elsewhere)
marketed under the brand names Veronal for the pure acid
The chemical names for barbitone are diethylmalonyl urea or diethylbarbituric acid
commercially available barbiturate
It was used as a sleeping aid (hypnotic) from 1903 until the mid-1950s
Heterocyclic Chemistry
17
Theobromine
Theobromine (theobromide also known as xantheose,is a bitter alkaloid of the cacao plant.
It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola (or cola) nut.
Theobromine found in cocoa and chocolate.
In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), a diuretic (urination aid), and heart stimulant.
Heterocyclic Chemistry
18
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names.
It is naturally found in tea, although in trace amounts (~1 mg/L)significantly less than therapeutic doses.
It is found also in cocoa beans.
Heterocyclic Chemistry
19
Xanthine
Xanthine is a purine base found in most human body tissues and fluids and in other organisms.
A number of stimulants are derived from xanthine, including caffeine and theobromine.
Heterocyclic Chemistry
20
tautomerism
When a hydroxyl,thiol or amino group is present at the 2, 4 or 6 position then they are tautomeric with oxo,thioxo and imino forms. This Pyrimidines are of considerable biological important because of their relation to the nucleic acids viz., Uracil, Thymine, Cytosine.
Heterocyclic Chemistry
21
Heterocyclic Chemistry
22
Hydroxy-oxo-tautomerism
Physiochemical technique show that 2- and 4-hydroxy pyrimidine are predominantly in the oxo forms.
Heterocyclic Chemistry
(Pozharski and Dalnikovskaya 1981)
23
II) Thiol-thioxo-tautomerism
Pyrimidines with a thiol group in an electrophilic position exist predominantly in thione form as shown in structure (2b) and (3b Z = S), in the pyrimidines series 2-thiolpyrimidines exist almost exclusively in the thione form.
Heterocyclic Chemistry
(Pozharski and Dalnikovskaya 1981)
24
III) Amino-imino-tautomerism
All spectroscopic and pKa of amino pyrimidines show the amino form an over whelming extent (Brown et al., 1994).
Heterocyclic Chemistry
25
SYNTHESIS OF PYRIMIDINE
substituted pyrimidine compounds are generally prepared by five types of ring synthesis (I, II, III, IV and V).
Heterocyclic Chemistry
(Elderfield 1966)
26
Heterocyclic Chemistry
Synthesis from C-C-C-N and C-N Fragment
Synthesis of Pyrimidine from N-C-C and C-N-C Fragment
Synthesis of Pyrimidine from C-C-C and N-C-N Fragment
Synthesis of Pyrimidine from N-C-N-C and C-C Fragment
Synthesis from N-C-C-C-N and C- fragment
synthesises
27
Type (I): Synthesis from N-C-C-C-N and C- fragment
Heating of acetyl acetone and benzaldehyde in presence of two equivalent of ammonium acetate yielded the pyrimidine derivatives via the intermediate .
Heterocyclic Chemistry
(Lweis and Rosenbach 1981)
28
The reaction of 1,3-diaminopropane with formaldehyde yielded perhydropyrimidine,and with diethylcarbonate yielded the 2-oxo derivative and with carboxylic acid and give tetrahydropyrimidine .
Heterocyclic Chemistry
(Bischoff et al., 1901; Fischer and Koch 1986 and Grath 1988)
29
Cyclocondensation of enaminonitrile with CS2 in the presence of sodium methoxide gave pyrimidinethione derivative.
Heterocyclic Chemistry
(Briel et al., 1992)
30
Cyanocrotonamide derivatives condensed with diethoxyalkyl-amine to yield the pyrimidine derivative.
Heterocyclic Chemistry
(Gronik and Kaimanakava 1983)
31
The reaction of malonodiamide with an ester such as malonic ester yielded the 4,6-dihydroxypyrimidine derivative.
Heterocyclic Chemistry
(Remfry 1911)
32
The reaction of β-aminocrotonamide with succinic anhydride yielded β-succinamido-crotonamide, which inturn undergoes cyclization in basic medium to give 3,4-dihydro-6-methyl-4-oxo-2-pyrimidinyl-propanoic acid.
Heterocyclic Chemistry
(Hiromichi and Kato 1983)
33
Type (II): Synthesis of Pyrimidine from N-C-N-C and C-C Fragment:
Reaction of 1,3-dicarbonyl compound with N-Cyano-guanidine in the presence of Ni(OAc)2 gave the pyrimidine derivatives a,b.
Heterocyclic Chemistry
(Dorokhov et al., 1991)
34
Reaction of 1,3-diaza derivative with keten derivative afforded pyrimidine derivatives.
Heterocyclic Chemistry
(Mazumdar and Mahajan 1991)
35
Cycloaddition between diazadiene and alkynes derivatives afforded pyrimidine derivative.
Heterocyclic Chemistry
(Guzman et al., 1992)
36
Reversed polarization as in the 2-trimethylsilyloxy and 2-trimethylsilylthio-1,3-diene allow percyclic reaction with acyclic enamines from pyrrolidines or morpholine pyrimidinones and pyrimidinethione are formed in high yields in dichloromethane.
Heterocyclic Chemistry
(Sain et al., 1991)
37
Type (III): Synthesis of Pyrimidine from C-C-C and N-C-N Fragment:
the first synthesis of pyrimidine nucleus is achieved from the condensation of urea with malonic acid in the presence of phosphoryl chloride, it was named barbituric acid.
Heterocyclic Chemistry
(Grimoux 1879)
38
Condensation of benzamidine with ethylacetoacetate in alkaline solution yielded 4-hydroxy-6-methyl-2-phenyl-pyrimidine.
Heterocyclic Chemistry
(Pinner 1884)
39
The enamino ester condensed with amidine derivatives to yield ethyl pyrimidine-5-carboxylate derivative.
Heterocyclic Chemistry
(Breaux and Zwikelmaier 1981)
40
The reaction of ethylcyanoacetate derivatives a,b with S-alkyl isothiourea derivatives yielded pyrimidine derivatives.
Heterocyclic Chemistry
(Melik-Ogandznyan et al., 1975)
41
The reaction of bromopyruvate esters with urea yielded the 71-89% of the corresponding uracil derivatives.
Heterocyclic Chemistry
(Andreichikov and Plakhina 1987)
42
The reaction of diethylmalonate derivative with urea gave the pyrimidine derivative.
Heterocyclic Chemistry
(Macquarrie and Imwinkelried 1995)
43
The ketoester reacted with guanidine derivative to yield2-ureido-6-triflouromethyl-3,4dihydropyrimidine-4-one.
Heterocyclic Chemistry
(Alferd and Fenning 1981)
44
The guanidine derivatives reacted with the ketoesters to yield the corresponding pyrimidine derivatives.
Heterocyclic Chemistry
(Kramer et al., 1971 and Aroyan, A.A., and Kramer 1971)
45
The reaction of diaminoguanidine with β-ketoester yielded 3-amino-2-hydrazino-6-phenyl-3,4-dihydro-4-pyrimidin-one.
Heterocyclic Chemistry
(Hlavka et al., 1984)
46
type(IV): Synthesis from C-C-C-N and C-N Fragment
Benzoylacetonitrile reacted with two moles of trichloroacetonitrile to give 2,4-bis-trichloromethyl-5-cyano-6-phenylpyrimidine.
Heterocyclic Chemistry
(El-Nagdi et al., 1979)
47
The reaction of enaminoester and phenylisocyanate in refluxing DMF yielded the corresponding pyrimidine.
Heterocyclic Chemistry
(Choji et al., 1983)
48
Heterocyclic Chemistry
Reaction of aroyl isothiocyanate with cyanothio-acetamide yielded the pyrimidinethione derivatives a-c.
(Assy and Moustafa 1995)
49
Heterocyclic Chemistry
Cyclocondensation of aminoethylene derivative with isocyanat derivative gave pyrimidine derivative.
(Gordeev et al., 1990)
50
Heterocyclic Chemistry
Cyanamide reacts with 4-aminopent-3-en-2-one and substituted derivatives in aqueous solution to form the 2-aminopyrimidine in high yield.
(Alherola et al., 1987)
51
Heterocyclic Chemistry
Heating ethyl 2-amino-4-methyl-5-phenylthiophene-3-carboxylate with potassium thiocyanate in dioxane in presence of conc. HCl flowed by cyclization with acetic acid yield compound .
(Abdel-Raouf 1994)
52
Type (V): Synthesis of Pyrimidine from N-C-C and C-N-C Fragment
Regioselective heterocyclization of the isocyanate derivatives with aminocrotonate afforded tetrhydropyrimidine-4-ones.
(Vouk and Pirozhenko 1994)
Heterocyclic Chemistry
53
The reaction of N-acetylacetamidrazones with N-[bis (methylthio)methylene] cyanamide at room temp. in the presence of potassium carbonate in dimethyl sulphoxide afforded ethyl-4-acylhydr-azino-2-amino-6-methylthio-5-pyrimidine carboxylate.
(Cocco et al., 1992)
Heterocyclic Chemistry
54
Aminocrotonates reacted with two moles of aldehyde derivative in the presence of ammonium acetate to give benzoate salts of pyrimidine derivative.
(O’Callaghan and McMurry 1990)
Heterocyclic Chemistry
55
Benzensulphonylacetamide reacts with methyl N-cyano-formimidate to yield 2-amion-5-benzenesulphonyl-4(3H)-pyimi-dinone.
(Pére et al., 1985)
Heterocyclic Chemistry
56
Type (VI): Synthesis from N-C-C-C-N-C Fragment
Hofman type degradation of appropriate diamides afforded pyrimidine presumably via the initial formation of an isocyanate intermediate.
(Barluenga et al., 1984)
Heterocyclic Chemistry
57
Addition of HCl to N-cyano group whereby the nitrogen becomes nucleophilic and add to the appropriately positioned C-cyano group with formation of the 2,6-diamino-2-chloro-pyrimidine.
(Barluenga et al.,1984)
Heterocyclic Chemistry
58
Intramolecular cycloaddition of amino group to the activated double bond in the thiourea derivative 258 yielded perhydropyrimidine 259
(Elghandour et al., 1988)
Heterocyclic Chemistry
59
Cyclization of 1,3-diacetamidopropane using hydrogen chloride as cyclizating agent yielded 3-acetyl-2-methyl-4,5,6-tetrahydro-pyrimidine.
(Hofmann 1992)
Heterocyclic Chemistry
60
Synthesis of Pyrimidine from Ring Transformation
I- Ring transformation of pyran into pyrimidine
The reaction of pyran with benzamidine in the presence of acetic acid and ammonium acetate gave the pyrazolpyrimidine ketone.
(Fritz and Guenther 1979)
Heterocyclic Chemistry
61
Rearrangement of 1-benazyl and benzhydrazyl-3,5,-dimethylpyrazole a,b in the presence sodium hydroxide at 150-155oC followed by hydrolysis gave pyrimidine derivatives a,b.
(Bogachev and Tetrov 1980)
Heterocyclic Chemistry
62
Hydrogenation of the 1,2,4-oxadiazole derivatives a-c followed by cyclization gave the pyrimidine derivatives a-c.
(Rucia et al., 1974)
Heterocyclic Chemistry
63
II-Ring transformation of azetes into pyrimidines:
Kinetically stabilized azetes 275 and acceptor substituted nitriles undergo [4 + 2] cyclo addition to give pyrimidine 276 via the initial formation of Dewar pyrimidine.
(Hees et al., 1990)
Heterocyclic Chemistry
64
III- Ring transformation of 1,3-oxazine and oxazole into pyrimidine:
Aminolysis of 6-chloro-1,3-oxazine-2,4-diones with primary aliphatic amines such as methyl amine gave 1,3-dimethylbarbituric acid.
(Yogo 1981)
Heterocyclic Chemistry
65
The reaction of 1,3-oxazine with dimethyl amine caused transformation to pyrimidine derivative .
(Perronnet et al., 1981)
Heterocyclic Chemistry
66
Heating of oxazole derivative 285 with aq. ammonia give O-protected pyrimidine derivative 286.
(Conner and Kostlan 1994)
Heterocyclic Chemistry
67
IV- Ring transformation of 1,3-thiazine into pyrimidine
5-Aryl or alkylsulphonyl 1,3-thiazine on treatment with β-iminonitriles or sulfones in presence of sodium 1,1-dimethyl peroxide in tetrahydrofurane gave 2,5,6-trisubstituted pyrimidine derivatives .
(Otatsuo and Motomu 1982)
Heterocyclic Chemistry
68
V- Ring transformation of isoxazole into pyrimidine
Oxoisoxazole derivative underwent ring cleavage followed by condensation upon treating with isothiourea derivative, give pyrimidine carboxamide derivative.
(Bossio et al., 1993)
Heterocyclic Chemistry
69
Heterocyclic Chemistry
Reaction of Pyrimidine derivatives
Pyrimidine is Л-deficient because of electronegative N-atom consequently the electron densities at the 2-, 4- and 6- positions are depleted, and these positions become strongly electrophilic and are here in referred to as the electrophilic position. The electron density at the 5-position is only slightly depleted the ring therefor retains benzenoid properties at this position this is indicated by the canonical forms for the pyrimidine ring.
70
Heterocyclic Chemistry
Electrophilic Substitution Reaction
Electrophilic reagents almost invariably attack the pyrimidine ring at the position C-5, which is the carbon atom least, depleted in the electronic charge.
For example pyrimidine-bearing electron releasing group can be halogenated, nitrated, nitrosated and diazocoupled at position C-5.
Electrophilic Substitution Reaction primidine included:
Formylation
Halogenation
Nitration
Nitrosation
71
Electrophilic Substitution Reaction
1- Formylation:
6-Amino-1,3-dimethyluracils are readily formylated by dimethylform-amide (DMF), POCl3 acylated by acid chlorides or converted into thiocarbamoyl derivatives by isothiocyanates.
(Hirota et al., 1984; Wamhoff et al., 1992 and Tominaga et al., 1979)
Heterocyclic Chemistry
72
Electrophilic Substitution Reaction
2- Halogenation:
The reaction of cytosine with bromine in acetic acid yielded 5-bromocytosine as a major product.
(Taguchi and Wang 1979)
Heterocyclic Chemistry
73
Electrophilic Substitution Reaction
3- Nitration:
The nitration of 2-hydroxypyrimidine using potassium nitrate and sulfuric acid yielded the corresponding 5-nitropyrimidine.
(Wempen et al., 1969)
Heterocyclic Chemistry
74
Electrophilic Substitution Reaction
4- Nitrosation:
Treatment of 2-phenyl-4-hydroxy-6-morpholinopyrimi-dine with sodium nitrate in sulfuric acid yielded the 5-nitrosopyrimidine derivatives.
(Yoned et al., 1971)
Heterocyclic Chemistry
75
Heterocyclic Chemistry
Nucleophilic Substitution Reaction
The 2-, 4- and 6-positions are activated for nucleophilic attack due to the presence of adjacent electron attracting nitrogen atom.
Nucleophilic Substitution reaction included:
Alkylation
Aminolysis
Ammonolysis
Cyanation
Hydrazinolysis
Hydrolysis
Reaction with sulphur nucleophile
Reaction with oxygen nucleophile
76
Nucleophilic Substitution Reaction
1- Alkylation
(i)-reaction with methyl iodide
Alkylation of nitropyrimidine derivatives with methyl iodide in presence of aqueous potassium hydroxide yielded 5-methyl-2-acetonyl-4,6-dimethoxypyrimidine.
(Longsted and Ludwikow 1982)
Heterocyclic Chemistry
77
Nucleophilic Substitution Reaction
(ii)- Reaction with Grignard Reagent
5-Cyano-2-methylthiopyrimidine alkylated by Grignard reagent R-Mg+X to give the dihydro derivative.
(Boarland and Meomie 1951)
Heterocyclic Chemistry
78
Nucleophilic Substitution Reaction
2-Aminolysis
Treatment of 2-methylsulfonyl-4,6-dimethylpyrimidine with cyclohexylamine or butylamine give the corresponding amino-pyrimidines a,b.
(Johanson et al., 1937)
Heterocyclic Chemistry
79
Nucleophilic Substitution Reaction
3- Ammonolysis
Treatment of 2,4,6-trichloro-5-methylthiopyrimidine with 28% ammonium hydroxide in ethanol in a sealed tube at 100 oC for 6 hours yielded the 2,6-diaminopyrimidine.
(Jaeyer 1981)
Heterocyclic Chemistry
80
Nucleophilic Substitution Reaction
4- Cyanation
When 2-methylsulphonylpyrimidine was treated with potassium cyanide 2-cyanopyrimidine was obtained.
(Daria et al., 1972)
Heterocyclic Chemistry
81
Nucleophilic Substitution Reaction
5-Hydrazinolysis
Treatment of 6-chloropyrimidine derivative with hydrazine hydrate derivative yielded the corresponding pyrimidopyridazine derivative.
(El-Bahaie et al., 1990)
Heterocyclic Chemistry
82
Nucleophilic Substitution Reaction
6-Hydrolysis
Selective hydrolysis of 2-amino-4,6-dichloropyrimidine-5-carboxyaldehyde yielded 2-amino-4-chloro-3,6-dihydro-6-oxo-pyrimidine-5-carboyaldehyde.
(El-Bahaie et al., 1991)
Heterocyclic Chemistry
83
Acidolysis of the 4-chloropyrimidine using 98% formic acid or acetic acid yielded the hydroxy derivative.
(El-Bahaie et al., 1991)
Heterocyclic Chemistry
84
Nucleophilic Substitution Reaction
7- Desulphurization
Desulphurization of 6-amino-5-cyano-4-(4-alkylbenzyl)-2-thio-pyrimidine derivative was achieved by the action of H2O2 to give hydroxypyrimidine derivative.
(Daboun and El-Reedy 1983)
Heterocyclic Chemistry
85
Nucleophilic Substitution Reaction
8- Reaction with oxygen nucleophile
4-Chloropyrimidine react with 2,4-dinitrophenoxide and/ or sodium ethoxide in refluxing ethanol to give the corresponding ether.
(El-Bahaie et al., 1991)
Heterocyclic Chemistry
86
Nucleophilic Substitution Reaction
9- Reaction with sulphur nucleophile
Treatment of 2-chloropyrimidine with sodium hydrogen sulfide and/ or thiourea in methanol yielded 2-mercaptopyrimidine.
(Roblin and Clapp 1950)
Heterocyclic Chemistry
87
Similarly when was treated with thiourea in refluxing methanol the corresponding mercaptopyrimidine was obtained
(El-Bahaie et al., 1991)
Heterocyclic Chemistry
88
Heterocyclic Chemistry
89
Thanks an ocean