Nitrones In The Synthesis Of Organic Compounds Biology Essay

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In the past the use of nitrones in the synthesis of organic compounds and their applications in the synthesis of large variety of heterocyclic compounds and natural products is proved to be very useful21. With a range of dipolarophiles the nitrones undergo cycloaddition reactions to get monocyclic and polycyclic ring systems. Nitrones can be used for the stbilization of the free radicals in the reaction systems. in many journals and literatures already many methods have been mentioned for the synthesis of acyclic and monocyclic nitrones and still a continuous research is going on for the invention of new synthetic methods23,27.from the past literature it is evident that using oxidative and non-oxidative methods a great reasearch has been done for the invention of many new improved methods for the synthesis of acyclic and monocyclic nitrones21,23,27. But it is also evident that there are only few methods are there for the synthesis of bicyclic nitrones27. The main aim of this study is to investigate the many new methods for the synthesis of a range of bicyclic nitrones and also for the investigation of methods for the synthesis of potent natural product ,dioxyerthratidinone which is a potent acetylcholine antagonist.

1.1 Cycloaddition reactions

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The reaction in which two or more unsaturated molecules combine to form a cyclic compound with a net reduction in the bond multiplicity is called a cycloaddition reaction29. In normal reactions the addition usually occurs across double or triple bonds. But in cycloaddition reactions the cyclic product is formed by the introduction of two or more new σ-bonds. These cycloaddition reactions are very useful in the synthesis of organic compounds with mono or heterocyclic ring systems. The most important cycloaddition reactions which are present are (1) Diels-Alder reaction and (2) 1,3-dipolar cycloaddition reaction. In Diels-Alder reactions commonly a six membered cabocyclic ring is produced from a conjugated diene and dienophile30,31 , while in 1,3-dipolar cycloaddition reactions a five membered ring is produced using 1,3-dipoles and dipolarophiles. After this a few years later Gresham and Steadman stated that a formaldehyde can be used as a dienophile for the synthesis of six membered heterocyclic ring system, this report gave rise to a concept called Hetero-Diels-Alder reaction. The classification of cycloaddition reactions can be done according to the formation of the ring size this representation can be done as [ a+b] where a and b are the atoms of contribution by the reactant species towards the formation of the ring system. Since in Diels-alder reactions the contribution of atoms by the reactant species is to synthesise a six membered ring system , hence they are classified as [4+2] cycloaddition reactions . and similarly in 1,3-dipolar cycloaddition reactions the contribution of atoms by the reactant species is to synthesise a five membered ring system hence they are classified as [3+2] cycloaddition reactions. The another way of classification of cycloaddition reactions is done by the concept the number of reactant electrons tha take part in the formation of the ring system. In this way both the Diels-alder and 1,3-dipolar cycloaddition reactions are considered to be as [π4s + π2s] or [4+2] cycloadditions. Thus in 1,3-dipolar cycloaddition reactions 4π electrons from dipoles and 2π electrons from dipolarophiles are involved in the formation of the ring system.

Examples of cycloaddition reactions :

2-Diisopropylborylaminopyridine undergoes cycloaddition with diphenylcarbodiimide and malononitrile, while 2-dibutylborylaminopyridine undergoes the analogous reaction with phenyl isocyanide.

[1-(N2N-Diphenylamidino)pyridon-2-iminato]diisopropylboron (IV) undergoes thermal isomerization to [N1-(pyrid-2-yl)-N2,N3-diphenylguanidinato]diisopropylboron (V).

Alkylation reactions

In IUPAC literature the definition of the alkylation is given as substitution of an alkyl group with the hydrogen of another molecule or it may be defined as the transfer of the alkyl group from one molecule to the another molecule1,2 . And the transferred or the substituted alkyl group may be a free radicle, a carbocation, a carbanion or a carbene.

The agents which are used for the alkylation are called alkylating agents2. The classification of the alkylating agents is done on the bases of the alkyl group they are substituting or transferring to perform a reaction3. They are classified as (a) Nucleophilic alkylating agents

(b) Electrophilic alkylating agents

(c) carbene alkylating agents

(a) Nucleophilic alkylating agents :They provide or deliver alkyl anions known as carbanions. These compounds can be easily added to a carbonyl group which is electron deficient. These compounds can be used for the displacement of halides substituents on the carbon atom3. The examples of most commonly used nucleophilic alkylating agents are organosodium, organolithium, organocopper and organomagnesium (grignards reagent)3.

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(b) Electrophilic alkylating agents : They provide or deliver alkyl cations to perform reactions. Alkyl halides are the best example of electrophilic alkylating agents.

(c) Carbene alkylating agents : They provide or deliver carbenes for alkylation. The highly reactive alkyl groups are carbenes. They are used for attacking the unactivated C-H bonds2,3.

In cancer chemotherapy alkylation of DNA of cancer cells is done to damage the DNA of cancer cells. Alkylation is of main use for refining the oil in the petrolium industry.

Michael additions or Michael reactions

Originally these reactions were discovered and defined by Michael arthur in the year 18873. According to the michael it is that to an α,β-unsaturated carbonyl compound an enolate of a ketone or an aldehyde is added at the position of the β-carbon12,13. Later on kohler defined this reaction in a different way that a doubly stabilised carbon nucleophile is added the to an α,β-unsaturated carbonyl compound at the position of β carbon in a 1,4-addition way5. Beta-ketoesters, malonates, and beta-cyanoesters are some of the best examples of the nucleophiles present.

Some of the best examples of the michael addition reactions are the reactions between diethyl malonate and diethyl fumarate5,

2-nitropropane and methyl acrylate3,

Nitropropane and methyl vinyl ketone5,

Ethyl phenyl cyano acetate and acrylonitrile4,

Mesityl oxide and diethyl malonate3,

Diethylmalonate and methyl crotonate3.

Typical reaction mechanism of michael addition

In the above schematic diagram the compound 1 is a nucleophile in which the R is a alkoxy residue. Deprotonation of the compound 1 leads to the formation of a carbanion which is the compound 2, electron withdrawing groups are stabilising this compoun. 2a, 2b and 2c are the three resonance structures of the compound 2. Out of which two of them have enolate ions. In a conjugate addition reaction this nucleophile reacts with an electrophilic alkene 3 to form a compound 4. Proton is abstracted from the protonated base by an enolate 4 to form a compound 5 is the final step of tthis reaction.

Asymmetric michael addition

This method consists of chiral phase transfer catalysis, consists of chiral quaternary ammonium salts which causes activation of enamine or iminium with chiral secondary amines, which are the derivatives of proline.

The diagrram below represents the reaction between the cyclohexanone and nitrostyrene in which the base proline is derivatized which in conjunction works with p-Toulenesulfonic acid the syn and anti addition is favoured with 99% enatiomeric excess.

A good example of Michael reaction is the synthesis of warfarin from 4-hydroxycoumarin and Benzylideneacetone . Several asymmetric versions of this reaction exist by the usage of chiral catalysts. 18,19

In the mukaiyama michael-addition reaction the catalyst used is titanium tetrachloride and the nucleophile is the silyl ether19.

The concept of 1,3-dipole and dipolarophile cycloaddition reactions

1,3-dipolar cycloaddition reactions are also known as Huisgen cycloadditions or huisgen reactions33. It is the name given after the german chemist Rolf huisgen for his contributions in chemistry. Huisgen reaction is considered to be the member of large class of cycloadditions33,34,36. It is the main path for the organic synthesis of heterocyclic rings. Huisgen reaction can be considered as the reaction between the 1,3-dipole and dipolarophile for the formation of a five membered ring. In organic chemistry 1,3-dipolar cycloaddition reaction is considered to be the most important for the construction of 5-membered heterocyclic ring37,38. 1,3-dipolar reaction is a concerted reaction which means both the bond making and the bond breaking occurs simultaneously. Stereospecific creation of new chiral centres in organic molecules is benefitted by the 1,3-dipolar cycloadditions. Depending upon the structure of the dipole in a single step upto four continuous chiral centres can be formed in 1,3-dipole cycloaddition. When 1,2-disubstituted alkene is involved in cocerted reaction with 1,3-cycloaddition , two chiral centres are formed on the alkene due to the syn attack on the double bond . This is well represented by the 1,3-dipole reaction types such as allyl anion type reactions and allenyl anion or propargyl type reactions.

1,3-dipoles

1,3-dipoles are the three atoms π electron systems in which the four electrons are delocalised over three atoms.these consists of the elements from the 4 , 5 and 6 groups of the periodic table. The central atom in the 1,3-dipoles is either the nitrogen or oxygen. Some of the examples of the 1,3-dipoles are azides,ozone, diazo compounds, nitro compounds and some oxides like nitrones , nitrous oxide, nitrile oxides, carbonyl oxides and azoxide compounds. Some imines like carbonyl imines, nitrilimines, and azomithine imines. Some ylides like carbonyl ylide, nitrile ylide and azomethine ylides.

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1,3-dipolar cycloaddition reactions have only been explored for five types of dipoles . Nitrones are the main subject of study in this field. Nitrones can be readily obtained from the compounds such as aldehydes, amines, imines and oximes and this is the main cause of this reason. Cyclic nitrones are less stable when compared to acyclic nitrones which can be stored easily under ambient conditions.The preparation of Azomethine ylides is done by in situ since they are very unstable . Many methods are in use for the synthesis of Azomethine ylides, they areabstracting proton from imine derivatives of alpha amino acids, aziridines subjected to photolysis or thermolysis and imonium salts subjected to dehydrohalogenation. Azomethine ylides are found to be of large use for the synthesis of nitrones. among the 1,3-dipoles Carbonyl ylides are less common for their use in synthesis . though the access to carbonyl ylides via rhodium carbenes made a enormous development in this area. Since past three years metal catalysed asymmetric reactions are appearing.for the synthesis of five membered heterocyclic rings Nitrile oxides are in close competition with nitrones . since they are readily available from aldoximes or primary nitro compounds , due to high reactivity and rapid dimerization most nitrile oxides must be prepared in situ43,44 . the catalytic control of this reaction may be one of reason for the high reactivity of nitrile oxides.

Dipolarophile

It is considered to be the unsaturated system in this the second reactant that undergoes cycloaddition reaction with 1,3-dipoles. Alkenes ,alkynes and their enormous derivatives may react as dipolarophiles44.

Stuart Warren (1987). Organic synthesis The Disconnection Approach. Great Britan: John Wiley & Sons. 93-102

Stereiselectivity

The mechanism chosen or elected to perform a reaction either to produce a more stable product or to follow a most encouraging kinetic pathway which will be of less energy consumption is called a stereoselective reaction and the term used to describe this phenomenon is called as stereoselectivity47.

The reaction which is used to produce a specific stereochemical compound is called a stereospecific reaction47 , and the term used to describe this reaction is called stereospecificity. This explains the stability of the resultant product and this is performed by considering that each stereoisomer of the product will be different from that of the stereoisomer of the starting material. There may be enantiomers or diastereomers of the resultant products47.

An example of stereoselectivity:

The formation of two cis and trans alcohols by the reduction of the ketone.

Regioselectivity

Regioselectivity is the phenomenon where a reaction takes place by breakage of bond or by the formation of bond other than the normal possible way. And the reaction is called regioselective reaction.

Based upon the selectivity of the reaction to proceed the compounds can be termed as high or low regioselective. If the discrimination is 100% the reaction is said to be completely regioselective and it is said to be partial if the product obtained at different reacting sites is different44.

Example:

Choosing an unsymmetrical ketone for Alkylation and a nucleophiles is added to an unsaturated carbonyl compounds to get either Michel addition or direction addition.