Synthesis and Characterization of New 1,3- Oxazepine, Diazepine, thiazepine Derivatives and Open Ring of Thio compounds

 

Dr. Nagham Mahmood Al-jamali

Ph.D., Assist. Professor, Chemistry Dept., Kufa Univ., Iraq.

*Corresponding Author E-mail: Dr.Nagham_mj@yahoo.com

 

ABSTRACT:

The scheme of this work involves synthesis of p-N,N-dimethylamino benzylideneareneamines (Schiff bases). Compounds (N2-N17) were synthesized by condensation of  p-N,N-dimethylaminobenzaldehyde with different primary aromatic amines in the presence of absolute ethanol with reflux  for (2) hrs to produce sixteen derivatives of Schiff bases. This work is divided to four different parts scheme(I):

First part:

To obtain oxazepine derivatives (N18-N33) and (N34-N49), Schiff  bases (N2-N17) were reacted with maleic anhydride in the presence of dry benzene with reflux  for (3) hrs to produce sixteen derivatives of oxazepine compounds (N18-N33) and also reacted with phthalic anhydride to produce other sixteen oxazepine compounds (N34-N49)which are 2-(p-N,N-dimethylaminobenzyl) -3-aryl -2,3-dihydro benz [1,2-e] [1,3] –oxazepine – 4,7- diones, the resulting colored crystalline solid was recrystallized form dry 1, 4-dioxan scheme (I).

Second part:

This part involves the synthesis of diazepine derivatives [N50-N54] . Oxazepine derivatives [N35, N38, N41, N46, N48] were reacted with various primary aromatic amines in dry benzene with reflux for (4-5)hrs to produce five derivatives of diazepine compounds of 1-(aryl)-2-(p-N,N-dimethyl amino benzyl) -3 - aryl - 1,2,3 - trihydro benzo [1,2,3] [1,3] – diazepine - 4,7 -diones [N50-N54] the resulting colored crystalline solid was recrystallized from ethanol scheme (I). 

Third part:

This part involves the thio derivatives of open ring [N55-N58] by the reaction of  oxazepine derivatives [N18, N19, N21, N31] were reacted with benzene thiol or with 2-mercapto benzene thiazol in dry benzene with reflux for (4-5) hrs to the four  derivatives of thio compounds of N-(p-N,N-dimethy (amino benzyl alcohol)- N-(4-benzo thiazol sulphide) -1.4 – done – 2- butane) –N-aryl amine [N55-N58].The resulting colored crystalline solid was recrystallized from ethanol.

Four part:

The attempt to synthesis thiazepine compounds by using oxazepine compounds was failed.

The Schiff  bases [N2-N17] , oxazepines [N18-N33] , oxazepines [N34-N49] , diazepines [N50-N54] , open chain thio derivatives [N55-N58] , have been characterized by melting points, C.H.N Analysis and spectroscopic methods (Uv-Vis, FT.IR, HN.M.R),  this work is summarized by the following scheme(I): 

 

KEYWORDS:

 

1.1- Schiff  Bases :       

In 1864 the German chemist H. Schiff described the formation of N-substituted imines so they are often called (Schiff base) (1,2) .Schiff bases. Contain an azomethine group () and the general formula of the schiff bases is    () (3,4) .

 

Schiff bases have several nomenclatures depending on the nature of the groups (R , R¹, R²) such as azomethines , imines , benzanils , anils , aldamines and ketimines. Alkyl primary amines (RNH2) or aryl primary amines (Ar-NH2) add to the carbonyl group of aldehydes or ketones to initially form carbinol amines , the carbinol amines lose water molecule to form N-substituted imine as the product (1-7) [1] scheme [1].

 

In general, the stability of the imine depends on the nature of the aldehydes and the primary amines . It can be concluded that schiff bases may be prepard for the following types of compounds [2-5] (3,8,9) scheme [2] :

 

1.2- Preparation Of Schiff Bases :

In general , schiff bases were prepared by condensation between equimolar of primary amines (aromatic, aliphatic or there derivatives) and carbonyl compounds (aldehydes, ketones or there derivatives) in absolute alcohol in presence drops of glacial acetic acid or concentrated hydrochloric acid or some time in presence of piperidine as a catalyst to produce [7,9](10) scheme [3] .

 

Condensation between substituent furan with methyl benzaldehyde to give the product [10] (10-12) scheme [4]

 

Some of schiff bases were prepared from different carbonyl compounds to produce compounds , such as vitamin A which can react with Macro protein molecular via azomethene bond to give Rohodopsin [11] (10) scheme [5] .

 

1.3- Reactions Of  Schiff Bases :

1.3.1- Reduction :

The imine can be reduced (hydrogenated) by hydrogen gas in the presence of a catalyst to give the corresponding amine [12](2,12) scheme [6] .

 

1.3.2- Hydrolysis Of Schiff Bases :

Hydrolysis of schiff bases is carried out in acidic medium , aliphatic schiff bases [13](13-15) is easily hydrolyzed scheme [7] , but aromatic Schiff 's base is rather slowly hydrolyzed (6,16) .         

 

1.3.3 – Condensation with Active methylene :

Base – catalyzed condensation with methyl ketones, as exemplified by the  condensation  of acetophenone with Schiff 's base (2) to produce [16] scheme [8] 

 

1.3.4 – Elimination Reaction :

Elimination reaction are found to occur much more readly in a pair of geometrical isomerizes in which the atom or groups to be eliminated are trans [17] to each than in the isomer in which they are cis [18](17-19) scheme [9].   

1.3.5- Tautomerism :

Schiff bases were derived form β-diketones having tautomeris effect    [20][20-23] scheme [10].     

 

1.3.6- Oxidation – Reduction :

The oxidation reaction between ninhydrine and amino acid produces a pigment that contains only the nitrogen atom of the original amino acid (21) scheme [11] .

 

1.3.7- Cycloaddition Reaction : 

For several years , the Dile-Alder reaction was the only widely useful example of the so-called cycloaddition reactions. The dimerazation of olefins, as well as the addition of carbenes and nitrenes to unsaturated centers has extended the series to include three- ,four- ,five- ,and six-memberd ring systems (22) :

 

1.3.7.1- Three-Memberd Rings :

Dichloro carbine added to N-benzylidene aniline to give the corresponding dichloroaziridine [25] (23) scheme [12] .

 

1.3.7.2 - Four-Memberd Ring :

Staudinger (24)  reported the formation of 1,3,3,4 – tetraphenyl-2- azetidinone [26] from the reaction of diphenyl ketene with N-benzylidineanilines scheme [13]:

 

1.3.7.3 - Five-Memberd Ring :

The reaction of diazomethane with p-nitro -N- (p-nitro benzylidene) aniline gave compound [27] via 1,3 –dipolar cycloaddition(22)  scheme [14]:

 

1.3.7.4 –Six – Memberd Ring :

The reaction of imino form of dimethyl aniline maleate with dienes give tetrahydropyridines [28](22) scheme [15] .

 

1.3.8 – DMSO Addition :

In 1986,V.D.Filimonov and L.V.Tomoshencho(7,25)studied the reaction of N-benzylidene aniline with DMSO in basic medium to give trans -2- phenyl vinyl methyl sulphide [29] scheme [16] .

 

1.3.9 – Azasugars :

Azasugars or imine sugars are analog of simple sugars such as glucose in which the ring oxygen of the ring has been replaced by an amino group .

 

Azasugars can modulate glucoproteine prosses by strongly interfering with glycohydrolysis as well as glyosyl transfers involved in a wide range of important biological processes .

Hassan synthesized azasugar derivatives [30](2)  .Scheme [17] .

 

1.3.10 – Formation of complexes :

Schiffs bases have been among ligands that are extensive used for preparing metal complexes. These ligands are described according to their donor set N,N- doner and N,N- donor schiff base(2). Bovenzeand G.A.pearse(2,26) synthesized coordination compound of tridented ligand [31] that  reacts with NiSO4 produced a complex of a single Ni atom [Ni (C7H9N5O2)2]+2 SO4 .

 

Some transition metals such as Co II , Ni II , Cu II , Pd II three compounds were square planer structure have been suggested for the complex (2,27-32) [32] .

 

1.4 – Importance of schif's  Bases :

Schiff bases have been among ligands that are extensive used for preparing metal complexes as a macrocyclic compounds(33-37) , biologically, schiff bases are important since they have biological activity(38-45)against bacteria , fungi and other medical compounds [33-39] (10-12) .

 

Some complexes  on biologically active Schiff bases compounds .

 

1.5 – Pericyclic Reaction :

Pericyclic reactions  involve bond changes in a circle of atoms . In Pericyclic reactions , bonds are made or broken in a concerted cyclic transition state (T.S) . This means that there are no intermediates formed in the course of the reaction (46) . Pericyclic reactions represent an important class of concerted ( single step ) process involving pi-systems ; a concert rearrangement of the electrons takes place which causes sigma and pi-bonds to simultaneously break and form , the fact that the reactions are concerted gives fine stereo chemical control of the product pericyclic reactivity can be understood in terms of frontier molecular orbital (FMO) theory , it can be predicted using the Woodward-Hoffman rules . The stereochemistry of any pericyclic reaction can be predicted by counting the total number of electron pairs (bond) involved in bond reorganization (46) .

 

1.6-Characteristic Properties of Pericyclic reaction :

Pericyclic reactions have certain Characteristic Properties , although as usual it is not difficult to find exceptions to all these rules (46-49) :

 

1- There is a relatively small solvent effect on the reaction rate , unless the reactions themselves happen to be charged for example carbonium or carbanion . Characteristic Properties  can be occur in the gas phase with no solvent . Quite recently , the use of water to accelerate pericyclic reactions (by perhaps a factor of 10 to 100) has been much investigated , but the acceleration is largely due to the formation of hydrogen bonds specific to the transition state (49) (T.S) .

 

2- There is no nucleophilic or electrophilic component , this means that in the arrow pushing sense , there is no beginning and ending for the arrows pushing can occur in rather a clockwise or anticlockwise direction .

 

3- Also many of pericycleic reaction could be catalysed either no catalyst is in need to promote the reactions . However , many transition metal complexes can catalyst pericyclic reactions by d-orbital participation (Lewis acids) . Also catalyst many of  pericyclic reactions , either directly or by changing the mechanism of the reaction so that it becomes a stepwise process . It is also possible to accelerate the reactions by the use of pressure for those reaction containers .

 

4. Pericyclic reactions normally show a very high stereospecificity.

 

5. Pericyclic reactions can be frequently promoted by light (denoted hγ in the text ) as well as heat (denoted  Δ in the text) . Normally the stereochemistry under the two sets of conditions is different , and it was originally thought invariable opposite. current thinking about the photochemical rout is more complex .

 

6. Unlike nucleophilic or electrophilic reaction , pericyclic reactions are unusual in that few enzymes which catalyst them are known .

 

1.7- Concerted Reaction : 

An important class of concerted  reactions are the pericyclic reactions , most of the reactions employed in this work are pericyclic reactions rather than classical organic reactions.  While the classical organic reactions involve several steps or rearrangement , with side reactions and relatively low yield , the pericyclic reaction is one step-process , take place through a single transition state (T.S) with relatively high yield and frequently no side reaction . There are many reactions in organic chemistry that give no evidence of involving intermediates when they are subjected to the usual probes employed for studying reaction mechanisms .

 

Highly polar transition states do not seem to be involved either , since the rates of such reactions are insensitive to solvent polarity , effect to detect free-radical intermediates by physical or chemical means have not been successful , and the reaction rates are neither increased by initiators nor decreased by free-radical inhibitors .

 

The lake of evidence of intermediates lead to the conclusion that the reactions are concerted process in which bond making and bond breaking both contribute to the structure at the transition state (22,46,50) .Concerted reaction include three classes : electrocyclic , cycloaddition and sigmataropic rearrangement . There are many unimolecular and bimolecular concerted reactions . A pericyclic reactions are characterized as a charge in bonding relationship which takes place as a continuous concerted reorganization of electrons , the word " concerted " specifics that there is a single transition state and thus no intermediate in the process .

 

To maintain continuous smooth electron flow , pericyclic reactions occur through cyclic transition states . Frequently , the cyclic transition state must correspond to an arrangement of the participitating orbitals that can maintain a bonding interaction between the reactive component throughout  the course of the reaction . Indeed as we shall see later these requirements make pericyclic reactions highly predictable , in terms of such feature as relative reactivity , stereo-specificity and regioselectivity (22) .

 

1.8- Classification of Pericyclic Reactions :

These reactions were very puzzling to chemists because they are generally not sensitive to any kind of catalyst or to any solvent , and what was even more puzzling was that some  pericyclic reactions take place only under thermal conditions , some only under photochemical conditions .Yet some could be successfully carried out under both thermal and photochemical conditions , pericyclic rearrangement classification is based on the migration of a sigma-bond such as a covalent bond directed along the line joining the centers of two atoms , in this classification , the reactions into three major categories(46-49) .

 

1.8.1- Electrocyclic Reactions :

Electrocyclic reactions involve the concerted formation of a σ-bond between the two ends of a linear conjugated π-system or the reverse reaction in which the σ-bond is broken to produce a linear conjugated , an electrocyclic reaction is a pericyclic process that involves the cyclization of a conjugated polyene  . One π-bond is broken , the  other π-bond is changed position then a new σ-bond is formed and  acyclic compound is resulted , for example a conjugated diene can be converted into a cyclobutene [40](46-49) scheme [18] .

 

It was reported that 1,3,5-hexane was cyclized to 1,3-cyclohexadiene [41] on heating, it can occur by either conrotatory or disrotatory paths , depending on the symmetry of the terminal lopes of the π-system . Conrotatory cyclization requires that lopes to  rotate in the same direction , whereas disrotatory cyclization requires that lopes is rotate in opposite direction(46-49,51) scheme [19] .  

 

1.8.2- cycloaddition Reaction :

The Diels –Alder reaction is one type of broader class of reactions that are known as pericyclic reaction , that takes place between adiene 4π-electrons and adienophile  2π-electrons to yield a cyclohexene [42] scheme [20] .

 

The total a count  of the product is 6(4n+2 , n=1), it must proceed via Hukel's rule and since the reaction is thermal . The Diels-Alder reaction results in a 1,4-addition because the carbon atoms of the carbon-carbon double bound of the dienophile add to the 1,4-carbon atoms of the conjugated diene to form a compound that contains a six-membered ring (cyclohexene) . Both new carbon-carbon single bond and the new double bond are formed as the three double bonds in the reactions break , so the reaction is concerted . The Diels-Alder reaction is very important synthetically because it forms a six-membered ring that contains two new carbon-carbon single bonds in one step.

 

Reaction rates are increased if the dienophile has electron-with drawing substituents cycloaddition . They encountered the Diels-Alder reaction, in which a conjugated diene and substituted alkene the dienophile react to form acyclohexene [43] scheme [21](46-49) .

 

Scheme [21]

 

1.8.3- Sigmatropic Rearrangements :

This reaction involved a migration group of its σ-bond within a π-bond framework-an ene or polyne the migration is accompanied by a shift in π-bond. For example (1,3-sigmatropic reaction )scheme [22] :

 

The third general kind of pericyclic reaction , are unimolecular process in which a σ-bond substituent atom or group migrates across a π-electron system from one position to another . a σ-bond is broken in the 1,3-diene [44] , the π-bonds move cyclic[45] , and, a new  σ-bond 1,3-diene [46] is formed as a product,  (46-49,52,53) for example (1,5-sigmatropic reaction) is scheme in [23] .

 

Both Cope [47] and Claisen rearrangements [48] are examples on sigmatropic rearrangements scheme [24] :

 

1.9-Oxazepine :

Oxazepam (serax) [49] is a new benzodiazepine derivative introduced in 1965 for use in the relief of the psychoneuroses characterized by anxity and tension(54) Oxazepam (serax) [49] is non-homologous seven member ring that contains two heteroatoms (Oxygen and Nitrogen)

 

Oxazepama (serax) marketed under brand names :

Alepam , Serax , Murelax , Serax-Sobril are the first dray of chemical series of compounds , the 3-hydroxy benzo diazepines , comprised of two aromatic ring is fused to the seven-membered ring and they contain a chloro-substituent or some other electronegative group(55-58) .

 

Oxazepam (serax) is 7-chloro-1,4-dihydro-3-hydroxy-5-phenyl-2H-1,4 benzodiazepine -2-one [50] of the following structural formula :

 

Oxazepam (serax) [50] is characterized by it's marked hydrophobicity and unsatisfactory wettability on contact with water , hydrolysis of oxazepine is very slow in water solution , even when alkali is added , it is difficult to decompose or decontaminate under practical conditions , at room temperature , the oxazepam is awhite solid substance , stable when heated , low solubility in water , has low vapor pressure , can be dissolved in several organic solvents(59,60) .

 

1.10 – Sythesis of 1,3- and 1.4- Oxazepine :

The compound 1-p-Nitrobenzoyl-2-vinylaziridine [51] undergoes thermal rearrangement in refluxing toluene to give 2-p-nitro phenyl -4,7-dihydro-1,3-oxazepine [52] which appears to be the first example of a dihydro-1,3-oxazepine . compound [51] also reacted with sodium iodide in acetone to give 2-p-nitrophenyl-5-vinyl-2-oxazoline [53](22,61) scheme [25] .

   

Cyclization of 5-chloro-3-hydroxyalkyl amino-6-nitro-3(2H)-pyridazinone [54] may occur in various ways (e.g., with the participation of C-5 or C-4 atom of pyridazinon ring) to form differently fused ring system scheme [26] . The ragiochemistry was found to be particularly dependent on the length of the side chain from the hydroxyl polyamine derivatives pyridoxine [55b,57b] oxazines , and from hydroxyl propylamine derivatives pyridazino [59b,61b] oxazepine and pyridazino [62b] oxazepine systems were formed(22) scheme [26] .

 

Erythro-1,2-diphenyl-2-phenyl amino ethanol [63] reacted with dimethyl acetylene dicarboxylate (DMAD) in benzene to yield cis-Michael adduct [64] , while the same reaction in methanol at room temperature afforded of Michael adduct and tetra hydro -1,4-oxazepine-7-one derivative [65] scheme [28] :

 

On the bases of the above observation scheme [29] as well as spectral data for [67] was deduced as 2,3,4,7-tetra hydro -5-methoxycarbonyl – 2,3,4-triphenyl -1,4-oxazepine -7-one [67] , and [68] as its hemiacetal(22,62) scheme [29]:

The reaction mechanism :

 

1.11 – Reaction Of 1,3 – Oxazepine :

The Lactone group (cyclic ester) can be converted into Lactame group (cyclic amide) by reaction with aromatic primary amines , this permits conversion of [1,3] –

oxazepine–4,7–dione ring in to [1,3]-diazepine-4,7-dione ring (22)   [70] scheme [31] :

 

Compound [71] was treated with pyrrolidine to give the open-chain anilide-pyrrolidine derivative of phthalic acid [72](63)  scheme [32] :

 

1.12 – Medical Important Of Oxazepine :

 Oxazepame is in a group of drugs called benzodiazepines , it is ametabolic by product of diazepam , it is used to relieve anxiety , nervousness , tension associated with anxiety disorders and to reduce the system associated with alcohol withdrawal(64)

 

Oxazepines (serax) is used antibiotics , enzyme inhibitors , pharmacological interest(65-69) , it has been much chemical(70-84) and biological studied(85-97) . .

 

1.13 – Diazepine :

Diazepam (valium) is a class of drugs used as relaxants , minor tranquilizers , hypnotics and muscle relaxant because it is often seen in fortensic and clinical cases . It introduced in 1969 under brand name valium [33](54,56.58).

 

Diazepam (valium) contain two nitrogen atoms in seven member(72) .

 

1.14-Synthesis of 1,3- and 1,4- diazepine :

4-Chloro-3-coumarincarbaldehyde [34] or 4-azido-3-coumarincarbaldehyde [37] are converted in to1,4-penzodiazepen [36]by nucleophilic substitution with diamines (72) scheme [33] .

 

Imidazole diesters [39] reacts with guanidine hydrochloride to give 1,3-diazepine derivatives [39] (22) scheme [34]

 

Reaction of quinazoline [40] with potassium tart-butoxide in tetrahydrofuran give mainly [41] , while , under approximately the same conditions , reaction of the  quinazolono [42] gives mainly [43](22) scheme [35] :

 

Substituted 2-chloromethyl-4-phenylquinazoline-3-oxides [48] undergo rearrangement to yield the corresponding-2-methylamino-5-phenyl-3H-1,4-benzodiazepine -4-oxides [48] , some of the benzodiazepine-4-oxides were converted into the corresponding benzodiazepines [49] by treatment with phosphorus dichloride . compound [45] were prepared as shown below from starting material o-amino benzophenone [45] which by heating with hydroxylamine hydrochloric in alcohol gave the oximes [46] .

 

The conversion of the oximes into the corresponding chloromethylquinazoline-3-oxides [47] was carried out by treatment with chloroacetyl chloride combined in same cases with the introduction of gaseous hydrogen chloride scheme [36](22) :

 

The reaction of 1- [(2-aminomethyl)phenyl] pyrrole hydrochloride [50] with carbonyl compounds give diazpines [51] in ring closer reaction (22) scheme [37] :

 

And the compound [51] was oxidized by manganese dioxide in toluene to the 4H-pyrrolo benzodiazepine [52] (22) scheme [38] :

 

1.15 – Reaction of 1,3-diazepine:

7-Chloro -2-methyl amino -5-phenyl -3H-1-4benzodiazepine -4- oxide [53] hydrochloride and its acetyl derivative , 7-chloro -2-(N-methyl-acetamido) -5-phenyl-3H-1,4-benzodiazepine- -4-oxide [54] , were hydrolyzed with dilute mineral acid at room temperature to give product [55] . treatment of [55] with an excess of alkali , split amide and an amine acid [57] were formed which may be converted into the lactam [55] with phosphorous dichloride or hydrogenation with Rany nickel as catalyst remove the N-oxide oxygen and gave the corresponding '' desoxylactam '' [56] which in turn may be deoxidized with hydrogen peroxide to compound [55] . Both the lactam [55] and the desoxylactam [56] may be hydrogenated in the presence of platinum catalyst . The lactam [55] may be substituted in position 1 to give [61] (22) scheme [39] .

 

Alkylation of [62] with sodium  borohydride in DMF , methyl iodide gave the corresponding 1-melthy compound [63] while the use of an excess of sodiumborohydride , ethyl iodide resulted in formation of the expected 1,3-dimethyl compound [64] (22) scheme [40] :

 

1.16 – Medical importancc ef Diaz pine :   

Diazepam (valium) is used to relive anxiety tension associated with anxiety disorder and muscle spasms as well as alcohol with drawl (93)   , and  other clinically  uses(94,97).

 

1.17 – Open Chain Thio Compounds :

These compounds contain in their structure a sulphur atom which reacts with other compounds to form open chain of thio compounds (65,68,71) .

 

Since these compounds have sulphur atom in there content which make them has many biological and pharmaceutical interest (65,68) . As a rest of high chemical activities of sulphur atom , many methods for preparation of different compounds have been developed . Example of thio compounds (10,65) [65-67]  scheme [41] :

 

1.18 – Synthesis Of Open Chain Thio Compounds :

Alkylation of 2-mercapto quinoline [68] gives thio derivatives (s-substitution) [69] (10) scheme [42] .

 

Alkylation of thio compound [70] with benzyl bromide to produce [71] (10) scheme [43] :

 

P-Nitro flouro benzene reacts with thiol compound [72] in ethanol with reflux for one hour to produce open chain thio compound (10) [73] scheme [44] :

 

Open chain thio compound [75] can be results from the reaction of alkyl bromide with thiol compound (50) [74] also scheme [45] :

 

1.19 – Reaction of open chain thio compounds :

The oxidation of the sulphide [76] with m-chloroperbenzoic acid (mCPBA) furnished the corresponding sulphoxide derivatives [77] (50) while the oxidation with hydrogen peroxide afforded the corresponding sulpher derivatives scheme [46] :

 

1.20 –Medical importance of Thio Compounds :

The activity of thio compounds due to the presence of sulphur atom in there structure , it has a wide spectrum of uses as a : selected HIV mutants [79] (10) , antibiotic [80] (10) , antitumer , dyes and in synthesis of polymers in thermal moldability , compound (11) [81] , scheme [47] :

 

1.21 – Thiazepine :

Many examples belonging to oxazepines , diazepines are documented ,but very little is known about thiazepine. 1,4 – Benzothiazepine derivatives are of considerable interest because of their biological activity as a muscle relaxants (65,68).

 

Thiazepine contains two hetroatoms (nitrogen and sulphur) in seven membered ring [82]

 

Thiazepine is one of hetrocyclic compounds which have pharmacological interest (65) .

 

1.22 – Synthesis of Thiazepine :

Many synthetic procedures where existed for the preparation of 1,4 – benzothiazepine [86] , most of these involve the reduction of a carbonyl group containing precursor such as 5-oxo-1,4-benzothiazepine [83] , 3-oxo-1,4-benzothiazepine [84] and condensing compound [85] (65) with BrCH2CH2Br                   scheme [48] :

 

1.23 – Medical Importance of Thiazepine :

Thiazepine is one of drugs which has biological interest due to their activity on the central nervous system , as enzyme inhibitors , anti-cancer , anxiolytic activity ,anticonvulsant, muscle relaxant (65)  and other uses (98) .

 

Aim of the work :

To synthesis new schiffs bases,oxazepines ,diazepine  and thaizepine derivatives which are expected to have a biological activity, they are derived from (amino acid, hetrocyclic amines and guanine from nucleic acid and substituent aromatic amines) and Synthesis of open chain thio compounds which have high molecular weight, they are derived from ( oxazepine, benzenethiol and 2-mercapto benzothiazole) .Also an attempt to synthesize of the thiazepine from oxizepine had been done .

 

Chapter  Two

1.2 – Chemicals and Instruments :

1. Melting points were recorded using : Electrothermal q300 , melting point ,   LTD , UK and are uncorrected.

 

2.  FT.IR spectra were recorded using Fourier transform Infrared SHIMADZU (8 300) (FT.IR) infrared spectrophotometer , KBr disc or thin film was performed by CO.S.Q.C IRAQ .

 

3.Uv-Vis spectra were recorded by: SHIMADZU (1700) double beam with computerized , Japan .

 

4. H-NMR were recorded on forruier transform Varian spectrometer , operating at 300 MHz with tetramethylsilane as internal standard in (C6D6) , measurements were made at chemistry department , AL-Al-Bayt University , Jordan .

 

5. Elemental analysis (C.H.N) were carried out by EA-017mth in center Lab. Institute of Earth and Environmental science , AL-albyat university J.H.K , Jordon .

 

6. All chemical used were supplied from Merck chemicals , BDH-chemical company and Fluke AG .

 

 

2.2 – Synthetic Methods :

2.2.1  Synthesis of p-N,N-dimethyl amine benzylidene arene amino (Schiff's base)s [N2-N17] .

 

General procedure (22,38,50) :

A mixture of equimolar amounts (0.05 mole , 6.30 ml) of p-N,N-dimethyl amino benzaldehyde and primary aromatic amine dissolved in (50 ml) of absolute ethanol with some drops of acetic acid was refluxed for (3 hrs) . The reaction mixture was then allowed to cool to room temperature and solid product was filtered and recrystallized from ethanol to give colored crystals , scheme [49] :

 

2.2.2- Synthesis of 2-(p-N.N-dimethyl amino benzyl)-3-aryl-2,3-dihydro [1,3]-oxazepine-4-7-diones .(Oxazepine derivatives) [N18-N33] .

 

General procedure (22,63) :

A mixture of equimolar amounts (0.02 mole) of schiff's bases [N2-N17] and maleic anhydride in dry benzene was refluxed for (4-5 hrs) , the solvent was removed and the resulting colored crystalline solid was recrystallized from dry 1,4-dioxane to give the title products , scheme [50] .

 

2.23- Synthesis of 2-(p-N.N-dimethyl amino benzyl)-3-aryl-2,3-dihydrobenz [1,2-e] [1,3]-oxazepine-4-7-diones. (Oxazepine derivatives) [N34-N49] .

General procedure (22,63) :

A mixture of equimolar amounts (0.02 mole) of schiff's bases [N2-N17] and phthalic anhydride in dry benzene was refluxed for (4-5 hrs) , the solvent was removed and the resulting colored crystalline solid was re-crystallized from dry 1,4-dioxane to give the title products , scheme [51] .

 

Chapter  Three

 

2.2.4 – Synthesis of 1–(aryl)-2-(p-N,Ndimethylamino benzyl)-3-aryl-1,2,3- trihydrobenzo [1,2-e] [1,3]-diazepine-4,7-diones. Diaz pine derivatives [N50-N54]

General procedure(22) :

A mixture of equimolar amounts (0.02 mole) of oxazepine derivatives [N35,N38,N41,N46,N48] with selected primary aromatic amines in (50 ml) of dry benzene was refluxed (4-5 hrs) , the solvent was (49,99) removed and the resulting colored crystalline solid was re-crystallized from ethanol to yield the title products , scheme [52] .

 

3.1 Synthesis and identification of p-N,N-dimethyl amino benzylidine arene amine [N2-N17]

                                                    Scheme [51]

 

2.2.5  Synthesis of N-(p-N,N dimethyl amino benzyl alcohol)-N-(4-benzothiazol sulphide)-1,4-dione-2-butene)-N-Aryl amine . Open chain thio derivatives [N55-N58] .

General procedure  (63) :

A mixture of equimolar amounts (0.02) mole) of oxazepine derivatives [N18,N19,N21,N31,] and 2- [N35,N38,N41,N46,N48] and 2-mercapto benzo thiazol or benzene thiol in (50ml) dry benzene was refluxed for (4-5 hrs) , the solvent was removed and the resulting colored crystalline solid was recrystallized from ethanol to give open chain (100) thio derivative of title products , scheme [53] :

 

 

2.2.6 synthesis of 2-(p-N,N-dimethyl amino benzyl)-3-aryl -2,3-dihydro[1,3]-thiazepine-4,7-diones. Thiazepine derivatives

General procedure : 

H2S gas was passed through a mixture of (0.04 mole) of any oxazepine compound of [N18,N19,N21,N31] in (50 ml) dry benzene, the mixture was refluxed for (4-5 hrs), the solvent was removed and the resulting crystalline solid was recrystallized from ethanol . Infrared spectra  gave no any change in the bands of product  compounds compared with reactant oxazepine compounds [N18,N19,N21,N31] , also melting points did not change.

 

That was an indication to the attempt is synthesis thiazepine compounds by this procedure failed only at this conditions.  

Compounds [N2-N17] were synthesized by condensation of equimolar quantity of p-N,N-dimethyl amino benzaldehyde [N1] with aromatic primary amino in the presence of absolute ethanol according to the reported procedure(22,38,63) scheme [55]

 

The synthesized compound were identified by their m.ps and FT.IR spectra are listed in table (3.1) . The FT.IR spectra , table (3.1) showed an appearance band at (1610-1650 cm-1) due to azomethine group (-CH=N-) (22,39,63) and at (1370-1373 cm-1) due to (-N(CH3)2 while the band at (3640 cm-1)is due to the stretching vibration of          (-OH) group of compounds [N2,N10] , also appearance two bands at (1340,1490            cm-1) (11,12,22,50) due to (C-NO2) group of compound [N5] .

 

3.2 Synthesis and characterization of 2-(P-N,N-dimethyl amino benzyl)-3-aryl-2,3-dihydro [1,3] – oxazepine - 4,7-diones. (N18-N33)

Schiff bases react with anhydrides(22,63,101) to give the corresponding addition products . Therefore , compound [N18-N33] were synthesized by reacting compound [N2-N17] with maleic anhydride in presence of dry benzene, scheme [56].

 

The synthesized compounds were identified by their m.p, FT.IR spectra , Uv-Vis spectra , some of them identified by HN.M.R and C.H.N analysis . The FT,IR spectra of compounds [N18-N33] were showed the disappearance of band at (1620 cm-1)(33,34) which is due to (C=N) Imines group and the appearance of band at (1660 cm-1) due to (C=O) Lactone/lactam(22) .

 

H-NMR spectrum , general figures of compounds [N20,N22,N23,N32,N33] , showed the following characteristics chemical Shifts (C6D6 as a solvent) were appeared : singlet signal at δ 2.18 – 2.38 of six protons for (-N(CH3)2) group, singlet signal (50) at δ 9.92-9.97 that could be attributed to the proton of oxazepine () group and doublet signal at δ (7.78-7.81)-(7.80-7.83) that could be attributed to the two protons of seven membered ring of oxazepine ( (, all signals showed in fig (2, 4, 6, 8, 10) . Moreover : to these general data , there are other data for each compounds as in the following : Other signal of compounds [N20,N22,N23,N32,N33] .

 

Compound [N20] showed : a doublets(50) leaning on each other at δ 6.34-6.37 that could be attributed to the aromatic four protons of (P-aceto amine    phenyl) . Fig (4) of compound [N22] showed : a doublet of doublets leaning on each other at δ 6.34-6.37 that could be attributed to the aromatic four protons of (2-pyridyl cycle) . Fig (6) of compound [N23] showed : a doublet at δ 6.34-6.37 that could be attributed to the two protons of thiazol ring (). Fig (8) of compounds [N32] , showed the doublet at δ 6.34-6.37 that could be attributed to the two protons of this ring () .     )  ) . Fig.(10) of compound [N33] , showed the doublet of doublets leaning on each other at δ 6.34-6.37 that could be attributed the three protons of this aromatic ring () .

 

Uv-Vis spectrum Table (3.3) of compounds [N18-N33] , showed the absorbance bands data were appeared at (λmax = 315 - 400 nm) (63), these compounds have chromophore group with oxochromic group due to hyperchromic effect such as conjugated system and carbonyl group in oxazepine compound with (-OH) group as oxochromic group of compound [N18] , (iodine) in compound [N19] , (-NH-CO-) group in compound [N20,N32]  ,(C=N) , (C-S) in compound [N22 , N23, N25] , (-N=C-N=) group in compounds [N24 ,N32 , N33 ] , (-NO2) group in compound [N21] , (COOH) groups in compounds [N26-N29] , for this reason , the bands shift(10) to the maximum wave length data for compounds [N18-N33] are listed in Table (3.3) .

 

It was found from (C.H.N)-Analyses, from that compared the experimental data for our compounds are in a good agreement data calculated. The data of analysis are listed in table (3.4) : Table (3.4) : C.H.N-analysis data of 1,3-oxazepine compounds:

 

Table (3.4) – C.H.N. – analysis data of 1,3-oxazepine compounds

N %

H %

C %

M.F

Comp. No.

8.28

8.07

5.32

5.11

Calc. 67.45

Found. 67.21

C19H18N2O4

N18

17.28

17.31

4.93

4.57

Calc. 62.96

Found. 62.71

C17H16N4O3

N24

11.26

11.04

5.09

4.84

Calc. 70.77

Found. 70.34

C22H19N3O3

N31

 

3.3 Synthesis and characterization of 2-(N,N-dimethyl amino benzyl)-3-aryl-2,3-dihydrobenz [1,2-e] [1.3]-oxazepine -4,7-diones [N34-N49]

The compounds [N34-N49] –oxazepine derivatives were obtained by refluxing equimolar amounts of imines [N2-N17] with phthalic anhydride in dry benzene.

 

The mechanism for the reaction(22,50) of phthalic anhydride or maleic anhydride with Schiff's bases an evidence supporting the 7-membred heterocyclic ring system for the product , will be outlined below : The reaction is initiated by attack the of the azomethine nitrogen at one of the two carbonyl groups of the anhydride , the mechanism involves the addition of one σ-bond () to one π-bond () to give 4-membered cyclic . Transition state (T.S) which opens into maleic anhydride or phthalic anhydride (5-membered cyclic ring) to give (7-membered cyclic ring)(22,50), scheme [58]:

 

These compounds were identified by m.p , FT.IR , H-NMR , Uv-Vis and C.H.N analysis .  The FT.IR showed the appearance of two bands(22,50,63) at (1720 cm-1) and (1650 cm-1) due to stretching(101-105) vibration of (C=O) Lactone and (C=O) Lactam , and the disappearance of band at (1610-1620 cm-1)(38,39) of imine (C=N) group and that is an evident to formation of this compound (106,107) .

 

H-NMR spectrum, general figures for the compounds [N36, N38, N39,N47,N49] , showed the following characteristics chemical shifts (C6D6 as a solvent) were appeared : singlet signal at δ 2.36 for the six protons of (-N(CH3)2) group , singlet signal at δ 9.96 that could be attributed to the proton of oxazepine (            ) group and mutilate leaning on each other at δ 7.79 –7.82 that could be attributed to the four protons (50)of  the aromatic structure () .

 

Moreover, to these general data , there are other data for each compounds as in the following : Fig (12) of compound [N36] were appeared : a doublet of doublets leaning on each other at δ 6.34-6.37 that could be attributed to the for proton of the aromatic structure () .  Fig (14) of compound [N37] were appeared : a doublet of doublets leaning on each other at δ 6.35-6.37 that could be attributed to the aromatic four protons of pyridyl ring () . Fig (16) of compound [N39] were appeared : a doublet signal at δ 6.35-6.38 for the  two protons of thiazol ring () . Fig (18) of compound [N47] were appeared : a doublet signal at δ 6.34-6.37 for the two protons of () of guanine ring and singlet signal at δ 2.63 for the one proton of (-NH) group of guanine ring and fig.(20) of compound [N49] were appeared : a doublet of doublet leaning on each other at δ 6.34-6.37 that could be attributed to the aromatic three(50) proton of pyrimidyl ring ().

 

Uv-Vis spectrum data of compounds [N34-N49] are listed in Table (3.6), most of them have chromospheres groups and oxochrom groups(106,107) due to bath chromic   shift , and they have electron transition (n→π* )(10,12,63) due to the hetro atoms (N,O,S) in these compounds beside of transition ( π→π*) of conjugated system.

 

It was found from (C.H.N )– analysis , from compared that the experimentally data, for our compounds are in a good agreement data calculated. This is other evidence for formatted compounds , the data of analysis are listed in Table (3.7).

 

3.4  Synthesis and characterization of 1-(aryl)-2-(p-N,N-dimethyl amino benzyl)-3-aryl-1,2,3-trihydrobenzo[1,2-e] [E1,3]-diazepine-4,7- dions . [N50-N54]

The compounds [N50-N54] – diazepine derivatives were obtained by refluxing equimolar amounts of oxazepine compounds [N35 , N38 , N41 , N46 ,  N48] with primary aromatic amines in dry benzene.

 

The diazepine compounds were identified by m.p , FT.IR and Uv-Vis spectra . The lacton group (cyclic ester) in oxazepine compounds can be converted into lactam group (cyclic amide) in diazepine compounds by reaction with aromatic primary amines (22,63) .

 

The FT.IR  showed the disappearance of the band at (1720 cm-1) is due to lactone in oxazepine ring, the appearance of the band at (1685 cm-1)is due to lactam in diazepine derivatives , other evidence disappearance band at (1232 cm-1) and that due to (C-O) lactone in oxazepine while the appearance of a band (1164 cm-1) is due to (C-N) of lactam in diazepine ring as a result of the conversion of oxazepine compounds to diazepine compounds (22,63 ,106,107).

 

Uv-Vis spectrum table (3.9) of compounds [N50-N54] , all of them have oxochrom group with chromophore group , this is explained (106,107) by the shift towards longer wavelength as compared with its corresponding of oxazepine compounds (10,22,63) , the maximum wave length data of compounds [N50-N­54] are listed in table (3.9) .

 

3.5 Synthesis and characterization of N- (p-N,N- dimthyl amino benzyl alcohol) -N- (4-benzo thiazol sulphide) -1,4-dione-2-butene)-N- Aryl amino .  [N55-N58]

The compounds [N55-N58] – thio derivatives were obtained by refluxing equimolar amounts of oxazepine compounds [N18 , N19 , N21 , N31] with thiol compound in dry benzene.

 

The open ring thio compounds were identified by there m.ps , FT.IR , Uv-Vis spectra and lassaigne's test .  The FT.IR showed the disappearance of bands at (1720 cm-1) is due to (C=O) of lactone , (1232 cm-1)is due to (C-O) of lactone in oxazepine and the appearance of band at (3440 cm-1) is due to (OH) group(63,100) as result of breaking of (C-O) bond of lactone and formation of open chain thio compounds .

The appearance of strong band at (1433 cm-1)(50) is due to () and other strong band at (675 cm-1)(10,50) is due to (C-S) are evidences for the formation of thio compounds , other data of functional groups(10,106-108) are showed in the table (3.10) . The compounds [N­­55-N58] were identified by lassaigne's test which gave black precipitate       of pbs .

 

Uv-Vis spectrum table (3.11) of compounds [N55-N58] , these compounds have high wave length due to the presence of oxochrom groups(106,107) (OH,S) in their structures with aromatic transition (π→π*)(10,63) , the maximum wave length data of compounds [N­­55-N58] are listed in Table (3.11) .

 

 

 

Table (3.2)– maximum wave length data of open chain thio derivative[ N55-N58]

λmax (nm­)

Ar

Comp.

No.

398

 

 

N55

385

 

 

N56

390

 

 

N57

370

 

 

N58

3.6 Synthesis of thiazepine

There appear to be very little work on the synthesis(thiazepine). In attempt to synthesize the thiazepine a solution of oxazepine in benzene was treated with (H2S) gas for(4-5)hrs. No reaction occurred when oxazipine was treated with (H2S) gas .

 

FT-IR showed no change in the bands of the starting material (oxazepine)compared with target compound (thiazepine) and no change in the melting point.

 

3.1 Synthesis and identification of p-N,N-dimethyl amino benzylidine arene amine [N2-N17]

Conclusion

In this research new compounds (oxazepine , diazepine and thio derivatives) were synthesized from sixteen derivatives of Schiff bases. The following conclusion could be drown:

 

1-       Schiff bases can be synthesized from p-N,N-dimethyl amino benzldehyde and different primary aromatic amines.

2-       1,3 –Oxazepine – 4,7- diones can be synthesized from p-N,N-dimethyl amino benzldehyde arene amines (Schiff bases).

3-       The diazepine derivatives can be synthesized from 1,3 oxazepine  – 4,7 –diones  .

4-       It is possible to synthesize open chain compounds of high molecular weight from  1,3 – oxazepine – 4,7 – diones. All these reactions showed the difference between the organic classical reactions and pericyclic reactions .

5-       The attempt is failed to synthesis thiazepine compounds by using oxazepine compounds.

 

Suggestions :

Suggestion for further work : on the bases of the experience gaind this work , we can suggest the following as future work : 

 

Table (3.11)– maximum wave length data of open chain thio derivative[ N55-N58]

 

λmax (nm­)

Ar

Comp.

No.

398

 

 

 

N55

385

 

 

 

N56

390

 

 

 

N57

370

 

 

 

N58

 

 

Figure (1) FT.IR spectrum of compound [N20]

 

 

Figure (2) H-NMR spectrum of compound [N20]

 

Figure (3) FT.IR spectrum of compound [N22]

 

Figure (4)-H-NMR spectrum of compound [N22]

 

Figure (5)- FT.IR spectrum of compound [N23]

 

Figure (6) H-NMR spectrum of compound [N23]

 

Figure (7) -FT.IR spectrum of compound [N32]

 

Figure (8)-H-NMR spectrum of compound [N32]

 

Figure (9) FT.IR spectrum of compound [N33]

 

Figure (10) H--NMR spectrum of compound [N33]

 

Figure (11) FT.IR spectrum of compound [N36]

 

Figure (12) H-NMR spectrum of compound [N36]

 

Figure (13) FT.IR spectrum of compound [N38]

 

Figure (14) H-NMR spectrum of compound [N38]

 

Figure (15) FT.IR spectrum of compound [N39]

 

Figure (16) H-NMR spectrum of compound [N39]

 

Figure (17) FT.IR spectrum of compound [N47]

 

Figure (18) H-NMR spectrum of compound [N47]

 

Figure (19) FT.IR spectrum of compound [N49]

 

Figure (20) H-NMR spectrum of compound [N49]

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Received on 31.10.2014         Modified on 11.11.2014

Accepted on 18.11.2014         © AJRC All right reserved

Asian J. Research Chem. 7(12): December, 2014; Page 1067-1104