RESEARCH OF HETERO CYCLIC CHEMISTRY........

HETEROCYCLIC CHEMISTRY





,4,5,&6 MEMBERED RINGS 3



















Hantzsch-Widman Nomenclature

• Type of heteroatom

The type of heteroatom is indicated by a prefix according to Table 1. The sequence in this table also indicates the preferred order of prefixes (principle of deer easing priority).





• Ring size

The ring size is indicated by a suffix according to Table 2. 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.







A ) The stemirine may be used for rings containing only N.



b) The traditi ional stems 'irine1 'etidine' and 'olidine' are oreferred for saturated heteromonocycles having three, four or five ring members, respectively.



C)The stem for six-membered rings depends on the least preferred heteroatom in the ring, that immediately

preceding the stem. To detemine the correct stem for a structure, the set below containing this least-

preferred heteroatom is selected.

6A: O, S, Se, Te, Bi, Hg; 6B: N, Si, Ge, N, Pb; 6C: B, P, As, Sb

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. The naming is carried out by combining one or more prefixes from Table 1 with a suffix from Table 2. If two vowels succeed one another, the letter a is omitted from the prefix, e.g. azirine (not azairine)



.



Note that trivial names are permitted for some systems, e.g. pyrrole, pyridine. Permitted trivial names can be found in the latest IUPAC Blue Book pp 166-172; if a trivial name is permitted then it should be used. Partly or completely saturated rings are denoted by the suffixes according to Table 2. If no ending is

specified the prefixes dihydro-, tetrahydro-, etc. should be used.







• Monocyclic systems, one heteroatom

The numbering of such systems starts at the heteroatom.

• Monocyclic systems, two or more identical heteroatoms

The prefixes di-, tri-, tetra-, etc., are used for two or more heteroatoms of the same kind. When indicat-ing the relative positions of the heteroatoms, the principle of the lowest possible numbering is used, i.e.the numbering of the system has to be carried out in such a way that the heteroatoms are given the low-est possible set of locants:







In such a numerical sequence, the earlier numbers take precedence, e.g. 1,2,5 is lower than 1,3,4. For heteroatoms of different kinds, prefixes are used in the order in which they appear in Table 1, e.g.thiazole, not azathiole; dithiazine, not azadithiine

Theheteroatom highest in Table 1 is allocated the 1-position in the ring. The remaining heteroatoms are assigned the smallest possible set of number lo-

cants:



Although in the first example the systematic name is 1,3-thiazole, the locants are generally omitted because, except for isothiazole (1,2-thiazole), no other structural isomers exist. Similar rules apply to oxazole (1,3-oxazole) and isoxazole (1,2-oxazole).

• Identical systems connected by a single bond Such compounds are defined by the prefixes bi-, tert-, quater-, etc., according to the number of sys-tems, and the bonding is indicated as follows:







• Bicyclic systems with one benzene ring

Systems in which at least two neighbouring atoms are common to two or more rings are known as fused systems. For several bicyclic benzo-fused heterocycles, trivial names are permitted, e.g.:









If this is not the case, and only the heterocycle has a trivial name, then the systematic name is formulated from the prefix benzo and the trivial name of the heterocyclic component as follows:





The system is dissected into its components. The heterocyclic component is regarded as the base component. The bonds between the ring atoms are denoted according to the successive numbers of the ring atoms by the letters a, b, c, etc. The letter b in brackets between benzo and the name of the base component denotes the atoms of the base component which are common to both rings. The letter must be as early as possible alphabetically and hence benzo[c/]furan is incorrect.

It is generally accepted that the numbering of the whole system in the case of bi- and also polycyclic systems should be done independently of the numbering of the components, and as follows:

The ring system is projected onto rectangular coordinates in such a way that

— as many rings as possible lie in a horizontal row

— a maximum number of rings are in the upper right quadrant.

The system thus oriented is then numbered in a clockwise direction commencing with that atom whichis not engaged in the ring fusion and is furthest to the left

— in the uppermost ring or

— in the ring furthest to the right in the upper row.

C-Atoms which belong to more than one ring are omitted. Heteroatoms in such positions are, however,included. If there are several possible orientations in the coordinate system, the one in which the heteroatoms bear the lowest locants is valid:















If the base component does not have a trivial name, the entire system is numbered as explained aboveand the resulting positions of the heteroatoms are placed before the prefix benzo:



• Bi- and polycyclic systems -with two or more heterocyclesFirst the base component is established. To this end the criteria in the order set out below are applied,one by one, to arrive at a decision. The base component is

— a nitrogen-containing component

— a component with a heteroatom, other than nitrogen, which is as high as possible in Table 1

— a component with as many rings as possible (e.g. bicyclic condensed systems or polycyclic systems which have trivial names)

— the component with the largest ring

— the component with most heteroatoms

— the component with the largest number of heteroatoms of different kinds

— the component with the greatest number of heteroatoms which are highest in Table

— the component with heteroatoms which have the lowest locant numbers.

Two isomers are given as an example:







First, the system is dissected into its components. The base component cannot be established until the fifth criterion has been reached: pyrimidine. The bonds between the ring atoms are marked by consecutive lettering according to the serial numbering of the base component. In contrast to the example on p9, the fused component must also be numbered, always observing the principle of assignment to the lowest possible locants. The name of the fused component, by the replacement of the terminal V with 'o', is put before the name of the base component. The atoms common to both rings are described by numbers and letters in square brackets, wherein the sequence of the numbers must correspond to the

direction of the lettering of the base component. Finally the whole system is numbered.

• Indicated hydrogen

In some cases, heterocyclic systems occur as one or more structural isomers which differ only in the position of an H-atom. These isomers are designated by indicating the number corresponding to the position of the hydrogen atom in front of the name, followed by an italic capital H. Such a prominent H-atom is called an indicated hydrogen and must be assigned the lowest possible locant.





The name pyrrole implies the 1 -position for the H-atom.

Heterocyclic compounds in which a C-atom of the ring is part of a carbonyl group are named with the aid of indicated hydrogen as follows:





Three membered rings



?-Amino alcohols, which are conveniently made from oxiranes with ammonia or amines, react with thionyl chloride to give chloroamines, which can be cyclized to aziridines by alkali hydroxide:'

























* Oxirane synthesis



1) Cyclodehydrohalogenation of ß-halo alcohols



Bases deprotonate /?-halo alcohols to give the corresponding conjugate bases. This is followed by anintramolecular displacement of the halogen atom as the rate-determining step.



(2) Epoxidation ofalkenes



Peroxy acids react with alkenes to give oxiranes. hi the PRILESCHAJEW reaction, peroxybenzoic acid, wchloroperoxybenzoic acid or monoperoxyphthalic acid is used. In weakly polar solvents, the reaction

occurs in a concerted manner [5]:







(3) Darzens reaction (glycidic ester synthesis)



The reaction of a-halo esters with carbonyl compounds in the presence of sodium ethoxide leads to 2(ethoxycarbonyl)oxiranes (DARZENS 1904). They are known as glycidic esters. In the first step, ta-halo ester is deprotonated by the base to the corresponding carbanion. This ncleophile





adds to crbonyl compound in a rate-determining step. Finally, the halogen atom is intramolecularly substuted, e.g.:





(4) Corey synthesis



In this synthesis, S-ylide nucleophiles derived from trialkylsulfonium or trialkylsulfoxonium halides are made to react with carbonyl compound corey 962 [1], e.g.:











Thiirane synthesis

Ammonia, or primary or secondary amines, react with thiiranes to give amino thioles :



: alkenes and sulfur monoxide

























































































Five-membered Rings :



Synthesis of pyrrole:



Numerous routes to pyrroles rely on cyclization of suitable nitrogen-containing precursors incorporating all the necessary carbon atoms. For example, a set of -amino-,-enals 5 can be annulated to the products 6 upon exposure to acidic reaction conditions without touching the t-butoxycarbonyl (BOC) protecting group:



A synthesis of 2H-pyrroles has been reported, relying on reductive annulation of nitroketones:





The nitroketone 12, which was prepared by Michael addition of ethyl nitroacetate to the appropriate enone, was treated with formamidinesulfinic acid and triethylamine, yielding the pyrrole-2-carboxylate:







The azaallylic anion generated from the substrate 15 underwent alkylation to provide the intermediate 16, which could be cyclized to the 1-pyrrolines 17. Treatment of the latter with methoxide eventually gave the pyrrole:





It has been established that the azadienes 26 may be converted to the precursors 27, which will cyclize to the pyrroles 28 under thermal conditions. Subsequent hydrolysis in the presence of hydrochloric acid gives access to the substituted -acylpyrroles 29:











Synthesis of furan:



The widely applicable acid-catalyzed cyclization of 1,4-dicarbonyl compounds and their surrogates, known as the Paal–Knorr furan synthesis, is frequently used in the synthesis of furan-containing compounds:



2-Butene-1,4-diones and 2-butyne-1,4-diones can also serve as starting materials in furan syntheses according to the Paal–Knorr method. 2,5-Diaryl- and 2,3,5-triaryl- furans are obtained in high yield in the presence of Pd/C and H₂SO₄ with formic acid as hydrogen source and poly(ethylene glycol)-200 as a solvent under microwave irradiation:





α , β-Unsaturated hydroxyketones can be liberated by acetal cleavage to yield 2,3,4-substituted furans. This route has been followed for the synthesis of compounds that serve as dimethylidenechromane-4-one equivalents:







With a strong base (KOBut, potassium hexamethyldisilazide (KHMDS), or KH), trimethyl silyl (TMS)-substituted alkynones yield annulated 2-methylene furans in moderate to good yields:







From cyclopropenylketones, either 2,3,4- or 2,3,5-trisubstituted furans are available with high regioselectivities, depending on the choice of the catalyst <2003JA12386>. Pd(II)-catalysis leads to the formation of the 2,3,5-isomers, whereas with CuI as a catalyst 2,3,4-isomers are obtained:













Synthesis of Thiophene:



Intramolecular addition of thiols 2 derived from the acetates 1 affords thieno[3,4-c]cepham sulfones 3 having properties as a human leukocyte inhibitor:







Lithiation of propargyl amine 12 and treatment with methyl isothiocyanate afford the thiolate 13, which cyclizes in the presence of KOBut and is methylated by iodomethane to produce 2,5-bis(N,N-dimethylamino)thiophene 14:





The cyclization of the Pummerer rearrangement product 30 derived from o-methylsulfinyl-difluorostyrene 29 leads to 2-fluorobenzothiophene 31:







Treatment of unsaturated diketones 36 with sulfuration reagents affords a mixture of thiophenes 37 and 38:







Dihydrobenzothiophene 84 is prepared from anisole derivative 83 via intramolecular cyclization using phenyliodin(III) bis(trifluoroacetate) and BF₃.Et₂O followed by treatment with aq MeNH_2:

















Reactions of pyrrole:



Reaction of unsubstituted pyrrole with acyl and sulfonyl chlorides in ionic liquids, [Bmim][PF₄ ] or [Bmim][PF₆] leads to N-substituted pyrroles in excellent yields:





Compared to C–C bond forming reaction, the C–N bond formation is still immature. Moreover, new amination methodologies will have a direct impact on pharmaceutical and fine chemical industries for the synthesis of a variety of commercially interesting compounds. Since the pyrrolyl anion exhibits ambident behavior as a nucleophile, alkylation can occur at carbon as well as at nitrogen:



Solutions of 4H-furo- and 4H-thieno[3,2-b]pyrrole derivatives 89 in dioxane were alkylated with chloroacetone or bromoacetophenone under phase-transfer conditions , in the presence of potassium carbonate and 18-crown-6, to afford the keto esters 90 in good yields (60–85%(:











The catalytic system involving But3P as ligand allows for arylation of azoles such as indole and pyrrole to provide N-aryl azoles 182 in high yields:







The key starting material for the synthesis of linear polypyrrolepeptide conjugates (novel sequence-specific DNA binders), 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid, was obtained in ca. 40% yield by nitration of corresponding pyrrole:













Reactions of furan:



Interesting intra- and intermolecular transformations involving oxonium ions formed by protonation of furan rings were shown to lead to elaborated ring systems





A Lewis acid-promoted intramolecular conjugate addition of a furan to a dienone was used to generate the seven-membered ring of the fused tricyclic framework of sesquiterpene echinofuran







Electron-rich furans were found to condense with aryl aldehydes under mild AuCl3 -catalyzed conditions, forming Triheteroarylmethanes









A regioselective oxidation of 3-substituted furans (except 3-carboxylate) to -substituted -butenolides was achieved by using N-bromosuccinimide (NBS), followed by elimination of the more acidic C-2 proton of the 2,5 -diethoxy intermediate under acidic hydrolytic conditions





substituents at the 3-position of the furan moiety are essential for achieving high diastereoselectivity in the alkylation step











Reactions of thiophene:



As part of a program on replacing AlCl3 with ecologically acceptable catalysts, the acylation of thiophene with 4 -fluorobenzoyl chloride in the presence of commercial acid-treated clays has been investigated. Complete conversion could be achieved, leading to almost complete formation of the 2-acylthiophene with only traces of the 3-isomer





Trifluoroperacetic acid in MeCN in the absence of water is an effective reagent for the oxidation of thiophenes bearing electron-withdrawing groups (EWGs) to the corresponding thiophene 1,1-dioxides







Treatment of 3-chloro-2-phenylbenzo[b]thiophene with butyllithium, followed by quenching with NH4Cl, gave a 71% yield of the diphenylacetylene





3,4-Bis(2-methoxyphenyl)-2,5-dimethylthiophene 62 reacts with methyl acrylate in the presence of BF ?Et O to give the pentasubstituted benzene 63 in 65% yield







The Suzuki coupling of thiopheneboronic acids with a range of aryl bromides has been carried out efficiently by the use of [Pd(C3 H5 )Cl2] in the presence of cis,cis,cis-1,2,3,4-tetrakis(diphenylphosphinomethyl) cyclopentane





















[b]Six-membered Rings :



Synthesis of pyridine:



The cyclization of enamines under acidic and basic conditions gives the 2-chloro and 2-amino derivatives:





In an interesting reaction, furo- and thieno[2,3-b]pyridine derivatives have been synthesized via a facile Smiles rearrangement under basic conditions followed by a cyclization forming the pyridine ring in modest yields:







Pyridines have been formed by the cyclization of azadienes, themselves obtained by a conjugate addition between 24 and alkyne diesters:





The insertion of a nitrogen-containing fragment is a traditional strategy for the synthesis of pyridines. Reported examples include the amination of acetylenic ketones:



The application of Diels–Alder methodology to pyridine formation can take different approaches. The heteroatom can be sourced from the diene or the dienophile and by varying its position in the starting materials can lead to strategies for different substitution patterns in the pyridine product. While such approaches are well documented, recent reports have both extended the range of derivatives available and incorporated new technology to assist in the optimization of reactions. An N-1-diene-1-aza-1,3-butadiene was employed in a Diels–Alder reaction to synthesize the key intermediate, a tetrasubstituted pyridine, in the total synthesis of the pyridine-base natural product, piericidin:











Synthesis of pyran:



Numerous syntheses of 2H-pyrans feature the preparation of an acyclic dienone precursor that readily undergoes electrocyclic ring closure. In this manner, 2H-pyrans can be prepared directly from cis-2,4-dienols using a variety of oxidizing reagents. The epoxyquinoid-fused 2H-pyrans 2 are formed in high yield upon oxidation of their corre-

sponding cis-2,4-dienols:









The palladium-catalyzed cyclization of (E)-3-alkynyl-3-trifluoro- methyl allylic alcohols proceeds via a favourable 6-endo-dig cyclization due to the electron withdrawing properties of the trifluoromethyl group to afford 4-trifluoro- methyl-2H-pyrans:









Dimethyl acetylenedicarboxylate (DMAD) reacts with a-chloro carbonyl compounds to form 2H-pyrans as the major products and furans:







The majority of syntheses of 4H-pyrans derive from the ring closure of 1,5-dicarbonyl compounds:









5-Hexyn-1-ol reacts with tosyl iodide to form the (E)-iodovinyl sulfone 185, which can undergo 6-exo-dig cyclization upon treatment with KN(TMS)₂ followed by elimination of HI to afford the 3,4-dihydropyran:















Synthesis of thiopyran::



In the presence of morpholine and malononitrile, the initial reaction of cyclohex-3-enal with cyanothioacetamide is followed by a condensation with the dinitrile. Cyclization follows through attack of the thiol on a nitrile function and a penta-substituted 4H-thiopyran is formed:







Thionation of the 1,5-diketone 413 with P4S10 affords the 4,4-dicyanothiopyran:







Highly substituted 4-dimethylamino-4H-thiopyrans result from a cycloaddition–cycloreversion–cycloaddition sequence commencing with the heterodiyne 417 and dimethyl acetylenedicarboxylate (DMAD):







The reaction of 4-dimethylamino-2-phenylthiabuta-1,3,-diene with methyl acrylate affords the endo product at room temperature or below along with smaller amounts of the separable trans-4,5-disubstituted dihydrothiopyran. However, at 80 C the exo adduct alone is formed together with a thiopyran arising from the loss of dimethylamine:







Only insertion into the S–C(2) bond of 4-amino-2,5-dihydrothiophene-3-carbonitriles is observed on reaction with a-diazocarbonyl compounds in the presence of rhodium(II) acetate. The ring expansion is regioselective and leads to the 4-cyano-3,6-dihydro-2H-thiopyrans; there is no evidence for the 5-cyano isomer:















Reactions of pyridine:



The iodination of pyridine, quinoline, and isoquinoline via -metalation using lithium di-tert-butyltetramethylpi-peridinozincate (TMP-zincate) proceeds smoothly at room temperature using iodine as the electrophile. The chemoselective deprotonative zincation generated 2-iodopyridine:









Pyridine undergoes nitration at least 1022 times slower than benzene:







Interestingly, 3-nitropyridine can be sulfonated with Na₂SO₃ to give 2,5-disubstituted pyridine:







Sulfonylation of 2-aminopyridine occurs at the 5-position under fairly harsh (140 C) conditions of sulfur trioxide in sulfuric acid. Subsequent C-3 bromination under mild conditions







A novel route to unsymmetrical trans-2-allyl-6-alkyl(akyl)-1,2,3,6-tetrahydropyridines 127 was developed using the known 1,2-addition of RLi to pyridine followed by an allylboration of an intermediate imine formed on addition of methanol













Reactions of pyran:



The photochemical reaction of 2,6-bis-(trimethylsilyl)-4H-pyran 148 with various ketoesters results in functionalization at the 4-position in moderate to good yields (61–73%):







Treatment of 4-methoxy-2H-pyran-2-one with a haloether in the presence of TiCl4 provided 3-formyl-4-methoxy-2H-pyran-2-one, which is a useful synthon in natural products synthesis:







A novel and unusual oxidative rearrangement of 6-methoxypyran-2-ones to form highly functionalized ,-buteno-lides has been reported:









A variety of carbanion-based nucleophiles that allow ring transformation of pyran-2-ones into a diverse array of benzene frameworks have recently been studied and reviewed:







A number of leaving groups at position C-4 of pyran-2-ones such 6-aryl-3-cyano-4-methylthio-2H-pyran-2-one 222 are able to permit substitution reactions with nucleophiles:























Reactions of thiopyran:



Initial facile halogenation at the 3- and 5-positions of 2,4,4,6-tetraaryl-4H-thiopyrans can be followed by further reactions in the presence of an excess of halogen. Thus, chlorine induces a rearrangement to a bridged benzothiepine:







The enantioselective aldol reaction of tetrahydrothiopyran-4-one with aldehydes is efficiently catalyzed by proline. In aqueous DMF, aromatic aldehydes give high yields of the anti adduct:













2,6-Diamino-4-(cyclohex-3-enyl)-4H-thiopyran-3,5-dicarbonitrile undergoes a ‘ring opening–ring closing’ sequence with base, here forming the pyridine-2-thione:





Two products also result from reaction of the organolithium derived from 300 with benzaldehyde:







2-Substituted 3,6-dihydro-2H-thiopyrans 323 are oxidized to a mixture of the cis and trans 1-oxides by MCPBA, with the latter the major product:












Reference



Comprehensive Heterocyclic Chemistry III, 13-Volume Set, Volume 1-13: A Review of the Literature 1995-2007 (Advances in Heterocyclic Chemistry)
by: Alan Katritzky, Christopher A. Ramsden, Eric F.V. Scriven, Richard J.K. Taylor.

اجمعين يا غسوقة يا وردة المنتدى................................

الله يوفقني ومعايا الي ابالي....................

شكرا على المرور منورة.....................