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									                                  ‫مستخلص‬
    )‫احمذ عبذ االمير حسين. تحضير مشتقاث كيومارين جذيذة.(شهادة دكتوراه‬
              7002, ‫._الجامعت المستنصريت : كليت العلوم : كيمياء‬




      1-1 Coumarin compounds

  Coumarin was first isolated in 1820 by Vogel(1) from the seeds of Tonka
beans (coumarouna adorata). Coumarins belong to one of the most
widespread classes of natural compounds(1).Structurally coumarin is a fused
benzene ring with pyron ring (2) in two ways:




        O     O                                                O     O
  2H-Pyrone                                     Benzo-alfa-Pyrone
  2H-Pyran-2-one                                2H-1-Benzo-Pyran-2-one
  Alfa-Pyrone                                   Coumarin

       2                                               1

1- Benzo-α-pyron (coumarin) (1)
         O                                                  O




        O                                                  O
   4H-Pyrone                                   Benzo-gama-Pyrone
   4H-Pyran-4-one                              4H-1-Benzo-Pyran-4-one
   Gama-Pyrone                                 Chromone

         4                                             3

2- Benzo-γ-pyron (chromone) (2)




     Coumarin compounds are widely spread through the plant kingdom,
microorganism and animals both in the free state and as glycoside (3).



  H3CO                                          H3CO


    HO                O   O                       HO                    O   O

              O-Beta-D-Glucopyranoside                      OCH3

             Fraxin                                        Isoraxidin

              5                                               6




  Coumarins can be classified according to chemical structure into (4):
          R
                       O        O
       R=Alkyl, Hydroxyl, Chloro....

                    7

1- Coumarin substituted in benzene ring (7)




2- Coumarin substituted in pyrone ring (8).




          O                  OR   O

                        9
                         O    O
      R=Alkyl, Hydroxyl, Chloro....

                    8

3- Furo Coumarins (9)
          O             O      O

                 10


4- Pyrano Coumarins (10)




                       O     O

                  11

5- 5,6-BenzoCoumarin (11).




  Coumarin or benzo-α-pyrone is found in avariety of plants such as Tonka
beans lavender, sweet clover grass and licorice, but also occurs in food
plants such as straw, berries, apricots, cherries, and cinnamon(5).
Chemically(6) coumarin can occur either free or combined with the sugar
glucose to produce a coumarin glycoside. Medically "coumarin was banned
by the FAD as a food additive in 1940, due to studies showing liver toxicity.
There is also evidence that it may be carcinogenic.
  Some coumarins have been shown(7) to have blood–thinning, anti-
fungicidal, and anti-tumor activities. Warfarin(14) is the most commonly




             OH                               OH         OH




             O     O                          O
                                                   O O
        12                                          13



                            OH           O



                            O        O

                                14

                   Anti-coagulant compounds

used in oral anticoagulant medication.
 Hasnaa(8) found that 4-nitrowarfarin (15) has a special characteristic as
anti-coagulant, "without bleeding" due to nitro group.


                                 NO 2




                    OH
                                        O




                    O        O

                        17




  The isolated coumarins from plant so far investigated can be classified
into five groups according to chemical structure and their uses:

  Some of the first groups of coumarin had been found to show hypnotic


  Cl                                        H2N


                    O        O                              O       O
        6-Chlorocoumarin                          6-Aminocoumarin

               16                                      17
effect such as (16) and (17).




   7-Methoxycoumarin (9) " Herniarin " (18) that was isolated from
Matricaria in the north of Iraq was used as Antipyretics.




   H3CO               O         O

                 18
                 (9)
  Daphentin            (disubstituted coumarin) (19) that was isolated from
Daphnia Stifolia was used as anti-bacterial agent. Esculetin (20) was also
used as anti-bacterial substance. Scopoletin (21) isolated from Coronnilla



                                                HO


   HO                  O      O                 HO            O    O
           OH

            19                                           20

                           H3CO


                             HO             O        O



                                       21


Varial has wide applications in plant growth.




  Chinese workers found (10) that isofraxidin(6) used in Amnesia, Insomnia
and in sexual deficiency, are prepared from phenols.
  Kassier (11) and coworker synthesized 5-nitro isofraxidin and found out it



     H3CO


       HO              O         O
                OCH3

                 12


had anti-bacterial properties.




   Some coumarins (12) of 2nd group have insecticidal activity like Mammein
(22), Hymecromone (23), and Haloxon (24).
       CH3                        Ar                                            CH3


 H3C


             HO                   O        O             HO                     O     O

                   O

             22                                                        23
                       H3C        CH3                CH3




                                           O         O        O
                                       P
                                 O
                                      (OCH2CH2Cl)2

                                               24



                  (13,14)
  Coumarins                 of 3rd group like Bergapten (25), and Psoralene (26) .



             O


   OH                            O         O          O                               O
                                                                            O

                            25                                    26


Bergapten isolated from Citron Poaceae have been used in medicine.
  Compounds(15,16) of 4th group, Pyranocoumarin, Cunatilake isolate 12 of
coumarin derivatives from Rutaceae and found that they have a biological
activity as anti-carcinogen and showed also photo biological activity and




                                   O
              O              O

                      27


anti-proliferative effect.
                                                             (17)
 Coumarins of 5th group: Benzocoumarins, Fisher and Nier            found that
coumarin derivatives of poly aromatic hydrocarbon were carcinogenic.

   Perry (18) found out that 7-nitro-5,6-benzocoumarin (27) have anti



                                        O


                                    O


       O2N

                   28

tumor activity “applied on rats”.
1-2 Synthesis Of Coumarins.

  Coumarin has been synthesized in the laboratory since 1868 and used to
make perfums and flavorings. The most common methods of preparation
are outlined below:




1-2-1 From Salicylaldehyde (19)

  The Perkin reaction has been widely used, the required salicylaldehyde is
not always obtained and the yield of coumarin derivatives are generally low
although it is claimed that they are improved by the addition of iodine(20).
  Perkin condensation involves          coumarin derivatives by heating
salicylaldehyde with acetic anhydride and anhydrous sodium acetate at



            CHO                                                     CH=CH-COONa
                                     MeCOONa
                    + (MeCO)2O
                                     160-200C0
            OH                                                      OH




                                                                     O
                                                             O

                                                       1


160-200C˚ for 60 min.




  5,7-dihydroxycoumarin       (lemtlin)(28)      and       6-hydroxyl-5,7-dimethoxy
                                                   (21-23)
coumarin(29) (frascinol)      were obtained                     from 2,4,6-trihydroxy




          OH                                                      OH

                      O
                    CH
                                 (CH3CO2)2O

                                 CH3CO2Na
 HO               OH                               HO                       O       O

                                                                       28


             OCH3                                                    OCH3

    HO                    O                                HO
                        CH
                                  (CH3CO2)2O

                                  CH3CO2Na
 H3CO                 OH                           H3CO                         O       O

                                                                       29
benzaldehyde & 2,5-dihydroxy-4,6-dimethoxybenzaldehyde respectively.




  3-Phenoxycoumarin and 3-benzalcoumarin(24) was synthesized from the
reaction of salicylaldehyde with 2-Phenoxy (or 2-benzal) acetic acid in



  OHC          OH                          O
                                                                     R
                                    Ph-O-P-Cl
                                            2
                       RCH2CO2H
                                    NEt3 / heat
                                                                 O   O

                                                            30


presence of phenyldichlorophosphate




  Ahluwalia and coworkers(25) found that the reaction of salicylaldehyde
with N-(benzothiazolo-2-Yl thio) acetic acid hydrazide in presence of acetic
acid and PPA to gave 3-(benzothiazol-2-Yl thio) coumarin.
                              H2C       C    NHNH 2

                                  S     O
  R3                 CHO
                              N        S         1)CH3COOH

                          +                      2)PPA
                                                          R3
                                                                    S         N
   R2                OH

             R1                                                           S
     R1=H, R2=OMe, R3=H
     R1=Me, R2=OMe, R3=H                                       O          O
                                                   R2
                                                          R1
                                                               31




1-2-2 From Phenols

  The most important invaluable and widely used synthesis of coumarin
derivatives is through the Pechmann reaction.(26,27)            This involves the
condensation of phenols with β-ketoesters in the presence of concentrated



 R                                           R                  CO2CH2CH3
                   O   O          H2SO4
              + CH3CCH2COC2H5
                                      Heat
             OH
                                                          OH
                                                                    CH3



                                                      R
     R= H, CH3, OH                                                            O
                                                                    O
sulfuric acid to give substituted 4-methylcoumarin (32) .

         (28,29)
  Sonn             found that condensation of resorcinol with ethyl alfa-
cyanoacetate       in   presence   of    hydrochloric   acid       gave       4-hydroxy



                                                                   OH
                               CO2CH2CH3
                                              HCl
                         +   H2C
    HO                  OH     CN                 HO               O          O
                                                           33


umbelliferone (33).



                               (30-31)
  Pechmann and Duisbery                  suggested that the reaction proceeds
through the addition of hydrogen of the ring ortho to the hydroxyl group,
to the carbonyl group of the β-ketonic ester to give an intermediate
hydroxyester. Ring closure, takes place with the elimination of one
molecule each of water and ethanol to give the product. The effectiveness
of such condensation depends on the reactivity of o- position to the
hydroxyl group, when substituents like nitro or carbonyl group are present
in the aromatic ring the reaction may not take place at all. Morever phenol
derivatives may undergo Pechmann condensation with ethylacetate or its
corresponding compounds in presence of other reagents such as
phosphorous pentoxide, trifluroacetic acid, or aluminum chloride to give 4-

                                                               CH3

                               O          POCl3                           Ph
                          + CH3CCHPh
  HO                 OH       NC              HO               O          O
                                                           34
substituted coumarin derivatives.




  Koo(32) used polyphosphoric acid (PPA) in the synthesis of 7-hydroxy -4-



      OH                                                        CH3
                    O      O
                                          PPA
             +   CH3CCH2COCH2CH3

            OH                                  HO              O     O

                                                           23

methylcoumarin (23) from resorcinol.



                        (33)
  Ethylbenzoylacetate          was also used instead of ethylactoacetate. The
reaction of ethylbenzoylacetate with 2,4,6-trihydroxy acetophenone gives
6-acetyl-5,7-dihydroxy4-phenyl coumarin and 8-acetyl-5,7-dihydroxy-4-
phenyl coumarin.
                              (34)
  Soliman and Kapp                         proved that resorcinol derivatives orcinol
condensed      with        ethyl         β-aminocrotonate       to    give    5,7-hydroxy-4-



            OH                                                   OH       CH3
                               H3C           NH 2

                       + EtO                  Heat

   HO                 OH             O                 Me                 O       O
                                                                     35
            OH                                                   OH       CH3
                               H3C           NH 2

                       + EtO
  H3C                 OH             O                 Me                 O       O


methylcoumarin (35)




              (35)
  Al-Bayati          discovered that the reaction of ethyl β-methoxycrotonate
with phenol derivatives in presence of polyphosphoric acid gave 4-methyl




        OH                                                                    CH3
                                 H3C           OMe

                           EtO                   PPA
  R                   +                                     R

                                     O                                        O       O
coumarin derivatives.



                                            (36)
  Heating of β-methoxymethylmalonate               with phenol derivatives in
presence of CH3SO3H and CF3COOH gave coumarins substituted in



                                 H3C        OCH3
                                                           CH3SO3H
   HO                   +   H3CO                   OCH3
                                                           CF3COOH
             R                     O    O

                 CH3                                            CH3
                        COOCH3
                                   1)H3O+
  R                                                R
                                   2)-CO2
                 O      O                                       O        O
                                                        R=3,4-(OCH3)2
                                                        R=2,3-(CH3)2
                                                        R=2,3,5-(CH3)3

benzene and pyron ring.
 Michael (37) used the addition of m-alkoxyphenyl Lithium derivatives to the
diethylethoxyethylmalonate to give coumarin substituted in benzene ring.



  OR                                    OR
                                                        EtO2C    CO2Et
                      n-BuLi
                  +                                 +
                      Ether                                           H3O+
           OEt                                    Li     EtO     H

 R=H,CH3


                          OR                                     OR
                                           COOH
                                                        -CO2

                                                        Heat
                                    O         O                          O         O




           (39)
  Panta           prepared some coumarin derivatives by rearrangement of
allylarylether. The reaction of 2-methylphenol with triethylacrylate gave 8-


              OH
                               OEt
                                         Reflux
                  + CH2=CH     C OEt
                                         Torluene                           OEt Heat
              CH3             EtO
                                                                 O
                                                                      OEt
                                                           CH3


                        KOH

                                                        CO2H
              O    OEt                            OH                           O       O
               EtO
    CH3                                 CH3                           CH3

                                                                             37
methylcoumarin (37).




  Kanfmann and Kelly(40) in 1965 found that heating mixture of 1,3,5-
trihydroxybenzene with propynoic acid in presence of zinc chloride gave



          OH                                       OH


                                      ZnCl2
                +    HC   C   COOH

  HO                OH                        HO           O      O

                                                      32

5,7-dihydroxycoumarin (28).




1-2-3 From o-Hydroxy Carbonyl Compounds
   Claisen condensation of 2-acetoxybenzoylchloride yields substituted



             O               O                       O
                                        O
              CCl                                                 CO2Na
                                              OEt
                                                                  COCH3
             OCOCH3               NaOH               ONa
                                                              OH




                                                              O        O
                                                              OH

              CO2CH3              Na, 1.5h.

                                    240 C0
              OCOCH2-Et                                       O         O

                                                         38

coumarin (40-41).



                           (42)
   The condensation                of ethylcyanoacetate with 2-acetoxybenzoy
lchloride (Knoevengal reaction) yields 3-cyano-4-hydroxycoumarin (39).


                                                                   OH
                                    O
             COCl
                                                                            CN
                       +                 OEt
             OCOCH3           CN                                   O        O
                                                              39
  Reformatski (43) reaction of o-methoxyacetophenone with ethyl

α-bromopropionate followed by dehydration and demethylation leads to
3,4-dimethylcoumarin (40).

                                                                       OH       O
             COCH3                    O
                                                                                C
                +    H3C                           Zn                               OEt
                                           OEt                          CH3
             OCH3                                                          Me
                               Br
                                                                       OCH3


                         CH3          O                                Me

                                      C                                     CH3
                                          OEt      HI
                       CH3
                     OCH3                                              O    O

                                                                  40




                               (44)
  The reaction of                         methoxyphenylketones with corresponding



        R2     O                                                       R2    R1
                                      O
 R3            CR1                                           R3                      R
                     +                              POCl3
                          R3C              NEt 2
               OMe                                                             O     O
                                                            R, R1 = H, CH3, C2H5
                                                            R2, R3 = OH,CH3, OCH3

diethylactamide in presence of POCl3 gives the respective coumarin.

1-2-4 From active methylene compounds
     Azeotropic distillation of a mixture of ethyl α-alkyl (or aryl) malonate and
                                                                                             (45)
substituted phenols gives the corresponding 4-hydroxy-3-alkyl (or aryl)



                                                                           OH
                                R1                                                  R1

 R                                                    Heat   R
                    + O                    O
                OH                                                         O        O
                          OEt        OEt
                                                                      41

coumarin (41).




     While coumarin, unsubstituted in the pyran ring was obtained by
condensation of maleic acid and its derivatives, with resorcinol in presence


        OH


                                                H2SO4
                +    O                     O
               OH                               C6H5NO2          HO             O        O
                          OH         OH
                                                                           42

of nitrobenzene and concentrated sulfuric acid (46).



                                               (47)
     Dicoumarin (43) was obtained                      by condensation of pyrogallol with
malic acid in presence of concentrated sulphuric acid at 100-120 C0.
        OH                                                CH2COOH
                          O
             OH HO            OH H SO
                                  2  4
               +
             OH               OH Heat O         O
                                                     OH HO
                                                                           O   O
                          O
                                                          43




   Similarly, cyclocondensation (48) of substituted phenol with citric acid in
the presence of concentrated sulfuric acid gave 4- substituted coumarin



                                                          CH2CO2H


   R                                    H2SO4
                    +     Citric acid           R
                   OH                                     O        O

                                                     44

(44).




1-2-5 From Coumarin

   The oxidation of coumarin(49) by potassium persulfate in basic medium
gives hydroxy group in position –6- of coumarin–(6-hydroxy coumarin (45)).



                                                HO
                        + K2S2O8        KOH
             O      O                                          O       O
                                                          45
  Chauhan and Mathyr(50) found that the reaction of umbelliferone (41)
with equivalent weight of benzoylperoxide and chloroform gave daphintin (




                         Benzoylperoxide

  HO                O   O CHCl 3            HO             O        O
                                                   OH
           41                                           19


yield 43% ) (19).

  Daphintin (19) can be also obtained by refluxing the umbelliferone (41)
                                   (51)
with hexamethylenetetraamine               in presence of acetic acid (Duff




                              MeCOOH
   HO               O    O    (CH2)6(NH2)4 HO                  O        O
             22                                       CHO
                                                                H2O2




                                              HO                O       O
                                                      OH
                                                               21


reaction) then hydrogen peroxide to give daphintin (19).
   Fraxetin (46) can be synthesized(52) from umbelliferone ( 19) and then
the hydroxyl group is transfered to the benzyl by benzyl chloride and
oxidation at position –6- by potassium persulfate gave –6-hydroxy that is
converted to 6-methoxy by CH3-I and potassium carbonate to give fraxetin


                                     O

                            +      Cl-C-CH3
                                                          HO                   O       O
 HO              O         O
                                                                       C-CH3
                                                                   O               1)PhCH2Cl

                                                                                   2)KOH
  MeO                                 1)CH3I/ K2CO3                                K2S2O8
                                                          HO
                                      2)H2O2/ NaOH
                                      3)HCl
   HO                O         O                       PhCH2O                  O       O
          OH                                                           C-CH3
          46                                                       O

(46).

  Fraxinol (29) can be synthesized (53-54) from furanocoumarin by oxidation


          OCH3                                            OCH3
                                                   O
                                              H
                                Na2Cr2O7
                                H2SO4
   O                 O         O                  HO                       O
                                                                       O
            47                                                48


                                                       H3CO
                                                  HO
                         1)MeI/ K2CO3
                         2)H2O2/ H2SO4
                                              H3CO                     O       O
                                                               29
of 5-methoxyfuranocoumarin (47) by sodiumdicromate in presence of
concentrated sulfuric acid and then methylation of the hydroxy group at
(position–7-) by methyl iodide and sodium carbonate then the formyl group
in position –6- is changed to hydroxy group by hydrogen peroxide.




1-4-6 From Indan –1- ones

  The oxidation(55) of Indan–1-ones (49) by Baeyer-Villiger in presence of
30% hydrogen peroxide and acetic acid for 7-day at 50C0 gives coumarin



                R1                                                      R4
                             O
   R2           7                                                  R3
                                 1                                                        R
        6                                             H2O2
                                             R
                                     2
                                                     MeCO2H
            5                3                                                    O       O
   R3               4                                              R2
                R4                                                      R1
                        49


derivatives.

1-2-7 From Quinones (56)

  Dimethylcyclohexylaminomaleate reacts with p-benzoquinone in the
presence of Lewis acid, ZnCl2 to give 4-carbmethoxy–3-(cyclohexyl amino)–




                                                 O                           CO2CH 3
                    H                                                              H
                    N    CO2CH3                               HO
                                                                                   N
                                                       ZnCl 2
                                         +
                         CO2CH3                                              O        O
                                                 O                           50
6-hydroxy coumarin (50).




  The reaction (57) between γ-quinone and 2-aminodiethyl maleate in the
presence   of    borontrifluoride    gives       3-amino-4-carbethoxy-6-hydroxy
coumarin (53). When the reaction was carried out at –75 Cْ, it give 4-




                                                             CO2CH2CH3
                                         HO                          NH 2
                               BF3

                               Ether                         O       O
     O
           H2N       CO2Et                             52

            +
                     CO2Et                                       CO2CH2CH3
                                             HO                       OH
     O                                       0
                                BF3/ -75C
     51                         Ether
                                                                 O    O

                                                            53

carbethoxy-3,6-dihydroxycoumarin (53).

1-2-8 From Chromenes and Chromone (58-59)
  Chromenes and chromones were used in synthesis of coumarin
derivatives. Reflux of chromenes in 3M HCl, gave 41-85 % coumarin and
oxidation of chromones by m-CPBA gave hydroxychromones and small




        R1                                                        R1
  R2                                                        R2                             CH3
                                       Reflux/ HCl

 R3               O        N                                R3                 O           O
        R4                         O                              R4
                                                                          54

                  O                                    OH                      O
                                                                                           OH
                           m-CPBA
                                                             +
                  O                                    O     O                 O
             55                                   12                      56

amounts of 4-hydroxycoumarin(12).




1-2-9 Other Methods (60)

  Another important synthesis of 3- substituted coumarin involves
cyclization of acrylonitriles, using pyridine–HCl. Coumarin was synthesized
by cyclizing 2-(o-methoxyphenyl)–1- furyl acrylonitrile with pyridine –HCl.


              OCH3                                                                     O
                                       Pyridine
                               O
                                         HCl
              CH=C
                                                                      O            O
        57            CN                                         58
  Thermal rearrangement of α–aryloxymethylacrylic acid gave 3-methyl




  R2           HO2C           CH2        R2                       CH3
                                 Heat

  R1                 O                   R1                  O    O

           R                                        R
               59                                       60
                         R, R1, R2= CH3, OCH3, OH


coumarin(61).




1-3 Reactions of Coumarins

1-3-1 Sulphonation (62)

   The oxygen of the lactone ring, directs the sulphonation to 6-position
(para-director) in the coumarin. If this position was blocked, the
sulphonation will go to the 8- position (o-director)


                          HO3S                          HO3S
                      H2SO4                         H2SO4
                          0                          0
           O        O 100C                     O 140C                       O
                                         O                              O
                                                                 SO3H

       1                                                          61
   The presence of nitro group (63) at position 6 in coumarin, will deactivate
the aromatic ring, and the orientation of the sulphonation group will go to 3-
position.

                    CH3                                 CH3
  O2N                                O2N                      SO3H
                            ClSO3H
                                    0
                    O     O 130-140C                          O
                                                        O

             62                                    63

                                        (64)
   The orientation and substitution              in the sulphonation process depend
on the reactivity of substituted coumarin.
   Recently(64), 4,7-dimethylcoumarin–6-sulfonylchloride (64) was obtained,



                    CH3                                       CH3

                                        ClO2S
                             ClSO3H

  H3C               O      O Heat                                    O
                                           H3C                O

               64                                        65


by treating 4,7-dimethyl coumarin (65) with ClSO3H.




1-3-2 Nitration (65)
  Nitration of coumarin using concentrated nitric acid and concentrated
sulfuric acid (0C0) gave 6-nitrocoumarin (66) 93% and 8-nitrocoumarin (67).



                                              O2N
                                    H2SO4
                        CH3 O       HNO3                                        CH3
                    O                                                            O
                                                                          O
                                                    O2N                                 NO 2
           1                                                     66
                                    CH3COOH
                                4
                             SO        HNO3                      +
                            H2 OO3                                                      O
 HO                     O                           HO                          O
                               HN

           32                                                         NO 2      70
                                                                                    O
                                                                          O

                                                          NO 2             67



                                                            4              3
                                                       SO            O
                                                      H2          HN


  O2N                           NO 2        O2N


                                O                                               O
                        O                                             O

               68                                     NO 2            69

                                                          (66)
  Nitration of hymecromone (23) using                                 HNO3, in acetic acid gave 7-
hydroxy–4-methyl–3,6,8-trinitro-coumarin (70) in 74% yield.
   Nitration of 7-methoxy–4-methylcoumarin (71) gave 7-methoxy -4-
methyl-6–nitrocoumarin (67) (72) and 7-methoxy–4-methyl-3,6-dinitro
coumarin (73).
                           CH3                                                 CH3

                                                         O2N
                                     CH3COOH
                                         HNO3
  H3CO                     O         O                                                   O
                                                     H3CO                      O

                  71                                                      72
                                                                               CH3
                                                                           +
                                                           O2N                           NO 2


                                                                                         O
                                                     H3CO                      O
                                                                          73




1-3-3 Reaction with Alkali

  Coumarins as lactones are readily hydrolyzed by diluting hot solution of




                       NaOH                                 Acid
                           hot
                                                   CO2Na




                       O                                                             O       O
             O                                OH
         1                               74                                    1

sodium hydroxide to a yellow solution of sodium coumarinate (68) (74).

  7-methoxycoumarin(18) (Herniarine) was very(69) stable against alkali
    :




                                 O                                             O-
  H3CO                 O                             +                O
                                              H3CO
     :




                 20                                              75
because of the resonance that give phenoxide ion (75).




  When coumarin (1) is refluxed with alcoholic sodium ethoxide, the
lactone ring is readily opened to o-hydroxycinnamte (76) that gives with
acid o-hydroxycinamic acid (70) (77).

                                                    COOCH2CH3
                    Hot NaOEt
                                                           Hot H2O/ H+

             O     O                         OH
       1                                76
                                                                      COOH


                                                             OH
                                                      77
                                             Trans-o-hydroxy cinnamic acid




                                                                         (71)
  Hydrolysis of 4,6,7-trimethoxy-5-methyl-3-phenylcoumarin                      (7) yields
the        corresponding       2-(6-Hydroxy-3,4-dimethoxy-2-methyl-phenyl)-2-
methoxy-1-phenyl-ethanone (79).

                                                                  OCH3
                 CH3    OCH3                               CH3                  Ph
      H3CO                      ph           H3CO                 C      C
                                     NaOH
                                                                    H O
      H3CO              O       O            H3CO                 OH

                   78                                   79
1-3-4 Halogenation of Coumarin

  Bromination of coumarin (1) leads to the (72) formation of 3-bromo
coumarin (80), which can also obtain by means of NBS.


                                          Br

                                               Br Pyridine                    Br
                 Cs2/ Br2

             O   O                        O    O                          O   O

                                    NBS

     1                                                               83


                                                              (73)
  Similarly, 3-chlorocoumarin (81) can be obtained                   by chlorination of
coumarin (1) in 1,1,2,2-tetrachloroethan.

                                                             Cl
                         Cl2/ Br2

                         C2H2Cl4
             O       O                              O        O
         1                                     81




                     (74-75)
  The bromination              of 7-methoxy-4-methylcoumarin (71), using NBS
in CHCl3, gave 3-bromo-4-(bromomethyl)-7- methoxy coumarin.
1-3-5 Oxidation of Coumarins

1-3-5-1 Potassium Permanganate (76)

   Oxidation of coumarins with permanganate usually causes extensive
degradation to salicylic acid derivatives.


   H3CO                                      H3CO            COOH
                                    KMnO4

   H3CO                    O        O        H3CO            OH
               OCH3                                  OCH3
                               82                                 83


1-3-5-2 Nitric Acid (78)

   Oxidation of 5,7,8-trimethoxycoumrain (84) by 50% nitric acid in
presence of acetic acid gave quinone (85) that is reduced by sulphur dioxide
to 5,8-dihydroxy-7-methoxycoumrain (86).
          OCH3                               O                          OH
                               HNO3/ 50%
                                                            SO2
                               AcOH
H3CO             O         O          H3CO        O        O H3CO            O   O
          OCH3                               O                          OH
           85                                87                         86



1-3-5-3 Ozone (79)

  Ozonolysis of umbelliferone gave the corresponding substituted
salicyladehyde (87).


                                                                  CHO
                                      O3


    HO                 O          O          HO                   OH
                                                      88



1-4 Toxicity Of Coumarins(80-85)

   Coumarin is found in many plants , including lavender, woodruff, and
sweet clover; and also in strawberries, apricots, cherries, and cinnamon.
Coumarin smells like vanilla but what little flavor it has is bitter. This may
serve to repel some insects. It is found in high percentages in the tonka
bean ( dipteryx odorata, fabaceae ( pea) family ). Tonka bean extracted is
commonly used to adultereate vanilla in mexico.



  Additionally, it is a factor in some cases of livestock poisoning. Some
common molds break coumarin down into dicoumarol. Dicoumarol
interferes with the body’s ability to produce vitamin K. which is essential to
blood clotting. Thus, dicoumarol acts as an anticoagulant.

   When cattle eat sweet clover that has spoiled, the dicoumarol works to
thin their blood, leading ( in more severe cases ) to internal and/ or external
bleeding.

  Dicoumarol derivatives have been used as rat poisoning (namely,
warfarin ). Rodents that are in poisoned this way die from internal bleeding.



   Coumarin itself may or may not have anticoagulant properties.A further
derivative, warfarin sodium, is an anti-coagulant prescription drug, the use
of which must be carefully monitored by a physician, let the patient bleed
to death, But Kassier (8) found that 4-nitrowarfarin (17) has special
characteristic as anti-coagulant.
1-5 Schiff's Bases(86-88)

   Schiff's bases are compounds which contain an isomethine group (N=C ),
they are named after Schiff who prepared a number of these bases via
condensation of aliphatic and aromatic aldehyes and ketones with primary
amines. The general formula of these Schiffs bases (R-N=CRR-) and their
nomenclature depend on the nature of the groups R, R1, R.11. Schiff’s bases,
which are derived from ketones are known as ketemines, while those
derived from aldehydes known as aldimines.



1-5-1 Synthesis of Schiff’s bases(89-90)

   In general, Schiff’s bases are prepared by refluxing equimolar amounts of
the primary amines (aromatic or aliphatic or related derivatives) with
carbonyl compounds (aldehyde or ketones, aromatic or aliphatic
derivatives) in appropriate solvent (cyclohexane, benzene and
preferentially ethanol). Sometimes, the reaction is catalyzed by few drops
of glacial acetic or piperidine and refluxing for 2 hours.

  Ph
                  OHC                            Ph
            N
                                                          N             X
                NH 2 +         X CH3CH2OH/                         H
        S                        Ref. 2h. Pipredine           N    C
                                                      S
                                                              88


    It is concluded that (91-92) Schiff’s bases may be prepared from aromatic
aldehydes or heterocyclic aldehydes or ketones with aromatic amine such
as those bases derived from 2- carboxyl-5-nitrofuran, amino anti pyrine, 2-
amino-5-alkylthio-1,3,4- thiadiazole, and 3,4,5- amino, 1,2,4- triazoles as
illustrated respectively.
                                   SO2NHR                                    SO2NHR
                    +                                      H
                                                           C N
 O2N    O     CHO H2N                             O
                                          O2N
                                                      89




    Sciff’s bases which are known as hydrazone (93) have been synthesized
via the condensation of suitable acid hydrazides with aldehydes or ketones
in appropriate solvent as described.

                                                          O
                                                              CH
                        N N                                        Cl
  R             H
                N              SCH2CONHNH 2 + R       1
                         S
                                                                        Cl
                                        N N
                    R              H                               H
                                   N            SCH2CONHN          C
                                          S
                                                                              1
        R=H, 4-Cl, 4-CH3.          R1=2-OMe, 3-NO2, 4-NO2, 4-Cl.             R

                              91




1-5-2 Biological Activity(94-96)

   Schiff’s bases have been widely reported to be biologically versatile
compounds having antifungal, fungicidal, herbicidal and plant growth
regulating properties .
   The presence of imino linkage ( -N=C- ) in these compounds has been
regarded as being assential for the enhancement of antibacterial and
antimicrobaial (97) activities.



                             H
                             C N          SO2NHR
        O2N        O

                                     92




  In the medical area, some Schiff’s bases were reputed to be useful as
antidepressant, analgesic, and antimicrobial agents (98).

              10
          R
                  N CHR
   R9
                       R2 R4         R5
                                 N
     8                  1    3        6
    R                  R R           R
              7
          R
   R= aryl, heteroaryl, R1-4 alkyl or alkoxy,
    R4-6 = H, Me, R5= R6=H, R7-10 = halo, CF3.

                        93




  The following compound which also contains an imino group has been
shown to posses contraceptive action (99).
                                          H2
                                          C
                                     S
                             H
                       H2C   N                    3
                                                 R
                                     N
                                          O
       2                         1
    R                            R
                        N
                      R
                   1
        R=4-F ,R =F, sub.ph, R2=CHO ,R3=2-Cl, 2-NO2, 2-F.

                                     94




   Some hydrazones (100) have been synthesized with antimicrobial
properties and moderate activity against some candida species.

           N       N                                    1
                                                       R
   R                    SCH2CONHN         C
               N
                                  Me
  R=H, CH3, CH2CH3. R1=4-Cl, 4-OH, 4-NO2, 2-Cl, 2-OH, 2-NO2.


                                     95




1-6 Thiadiazoles



   The first 1,3,4-thiadiazole has been described by Fisher (101) in 1882 but
the true nature of the ring system has been demastrated first in 1890 by
Freund and Kuh.
   The pharmacutical interest in this kind of compounds started after the
discovery of sulfa drugs and new interesting drugs have been discovered,
the 1,3,4-thiadiazole compounds have found applications in
pharmaceutical, agricultural and other areas (102-120).

								
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