1. reaction is the transformation of one or more compounds into

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					Chem 6311                                                       Synthesis Warren CH 23-25                               page 1

1. Two group disconnections IV: 1,2 difunctional groups
   1.1. problem of unnatural synthon, alternatives to epoxide/alkene
    X                      Y                               X                              Y
                                                                                                           Y
                                                                         = ?                   =     H
   R1                                                     R1                                                R2
                          R2                                                              R2

   1.2. acyl anion equivalents: acetylide
         1.2.1. addition to carbonyl: analysis
         OH
                                                          O              R
                          R

              O

         1.2.2. synthesis
                                                                     O             OH                              OH    O
                        NaNH 2, NH3                                                                      HgO
   HC         CH                               HC         CNa
                                                                                                         H+, H2O


         1.2.3. use alkyne starting material: analysis ????
                  O                                             O
                                                                                                MeO
   MeO                                              MeO                                                             OMe
                                                                                  OMe




                                               HO
                                                                             OH


         1.2.4. synthesis
                                                Me2SO4                                         HgO
         HO                                                    MeO
                                       OH       NaOH                                    OMe    H+, H2O

                                   O                                                O
                                                          TsOH
                  MeO                                                MeO
                                                OMe

   1.3. use of nitriles
         1.3.1. based on cyanohydrin and Strecker synthesis
         1.3.2. reduce acid to alcohol or aldehyde
                                       N
              O          NaCN                   OH        NaOH       HO 2C        OH
                                           C
                               +                          H2O
                           H
Chem 6311                                                             Synthesis Warren CH 23-25                                             page 2

                                           N
                O               HCN                  NH 2      NaOH            O2 C        NH 3
                                               C
                            (NH4)2CO3                          H2O

           1.3.3. Analysis: Grignard, Hydrolysis, cyanohydrin, FC
                        OH
                                                          OH                          OH                  O
                                      OH
                                                                                                                       KCN                           O
                                                               CO2H                         CN           Ar                        Cl
                                                     Ar                         Ar
                                                                                                                                               Cl
Cl

      1.4. alkenes are 1,2 difunctional
           1.4.1. Wittig is best method to form alkenes
           1.4.2. alkyl ylid prefers cis, activated ylid prefers trans
                                                                                      R2            R1            R2          R1
                                                                    RCO3H
                    O                                                                                                        Nu
                                                                                              O                   HO
                                               R2              R1                           R2            R1
           R1               H                                          Br2

                                 R2
                                                                                            Br          Br
           Ph3P                                                           OsO4
                                                                                             R2              R1


                                                                                            HO           OH

           1.4.3. addition reactions transform to 1,2 addition products
           1.4.4. analysis
                                                                                                                                                     O
                                                                                                         Br             O                   HO
      HO            OH                                                                                             H

                                                                                                  Ar1                         Ar2                          Ar2
Ar1                             Ar2            Ar1                            Ar2

           1.4.5. acids are converted to aldehydes by bulky hydride
        O                                                             O                                                                      O
HO                              MeOH, H+                                               NaAlH2(OCH2CH2OH)2                               H
                                                          MeO

                  Ar2           or CH2N2                                                                                                             Ar2
                                                                               Ar2
           1.4.6. addition to  substituted ester yields 1,2 function: analysis

       OH                                                                                                                                        EtO2C
Ph                                                   EtO2C                N                        EtO2C
                        N                                                                                              Br
                                                                                                                             HN
Ph


           1.4.7. 1,2 dicarbonyls can be made by SeO2 oxidation of ketones
Chem 6311                                       Synthesis Warren CH 23-25                         page 3

             O                                            O
                              R2     SeO2
                                                                    R2
       R1                                       R1
                                                              O
      1.4.8. Analysis of Metaproterenol: reagents?
                                                                         O
      HO
                                                              Ar                                      O
                                OH
                                                                         CHO
                                                                                             Ar

                                     NH
       HO
                                                              H2N
      1.4.9. synthesis, protect ArOH, oxidation by SeO2, aldehyde more reactive carbonyl with
            amine, imine and carbonyl are reduced, remove methyls with HBr
MeO                O          MeO                             MeO

                         Cl                      O    SeO2                         O
                                                                                                     NaBH4
                                                                                       H2N
                 AlCl3
                                                                                   CHO
MeO                           MeO                             MeO


MeO                                                  HO
                    OH                                                   OH
                                          HBr

                          NH                                                  NH
MeO                                                  HO
      1.4.10. analysis
            1.4.10.1. Wittig does not react with esters
Chem 6311                                                  Synthesis Warren CH 23-25                          page 4

              CO2Me O                                                         CO2Me                   O

                                                                                       Ph3P
MeO2C                          O                                  MeO2C            O                      O

                                                     CO2Me
                                                                                         O
                                       MeO2C
                                                                              Cl
                                                                                                O

                                                                                   O
2
    O                              O                                     Cl                     HO
                                                                                         Cl
        1.5. Analysis: work back to starting material that has 1,2 substitution!
                  OH
                                                     EtO2C                             HO 2C
        Ph
                  Ph                                                                            OH
                        OH                                     OH

             1.5.1. protect alcohol during Grignard addition
             1.5.2. see List of 1,2 substituted reagents page 174
2. Useful radical reactions
        2.1. non radical methods of formation of allylic functional groups via allylic alcohols
             2.1.1. condensation of carbonyls followed by reductions
                   O                                    O                               O                              OH
O                                      HO



             2.1.2. formation of benzylic functional groups via benzylic alcohol
             2.1.3. Freidel-Crafts followed by reduction
                   O                        O                       HO
ArH +
             Cl                                                          Ar
                                                Ar
        2.2. benzylic bromination, chain reaction
             2.2.1. photolysis of bromine forms bromine radicals that abstract at weak CH bond
                                                     CH3                                CH2                        CH2Br
                  CH3
                         h, Br2                                                                Br2
                                                       + Br                             + HBr                          + Br
Chem 6311                                         Synthesis Warren CH 23-25                       page 5

   2.3. Allylic bromination, use N-bromosuccinimide (NBS)
           2.3.1. can’t use Br2 directly, it adds to C=C
           2.3.2. N-bromosuccinimide slowly forms Br radicals and Br2
                                                                                             Br            O
       O

                                                                               Br2
           NBr             Br       +                                  + HBr                       +           N



    O                                                                                                      O

           2.3.3. analysis: bromination of starting material
                 2.3.3.1. Use NBS for bromination
                 2.3.3.2. don’t use NaSH to make thiol
   NO 2                         O2N




   S                                         HS
                                                                  Br

           2.3.4. analysis; NBS or Br2 work fine

  Br
                       O                                                       O




                                O                                                    O
                                                  Br
   2.4. Allylic oxidation can be effected by weaker oxidizing reagent
           2.4.1. SeO2 or CrO3
           2.4.2. better than bromination, FGI to OH, then oxidation
                  O

                                                                                                       + PhMgBr


                                                         Ph       OH                     O
   Ph                                   Ph

   2.5. Pinacol formation
           2.5.1. strongly reducing metal used to convert two carbonyls to diol
           2.5.2. magnesium works best
Chem 6311                                    Synthesis Warren CH 23-25                          page 6

                                            Mg                              Mg
  O            O                    O             O                     O                          OH        OH
                          Mg                                                     O       H+


                                                                                          H2O

          2.5.3. analysis- use pinacol synthesis to make this target
              2.5.3.1. have to start from carbonyl, and then convert to diol
              2.5.3.2. look for diol precursor to product
                                                                    OAc




                AcO
      2.6. skip 202-204
      2.7. Functional group additions
          2.7.1. sometimes there are no functional groups available
          2.7.2. add group so that you can do a disconnection
          2.7.3. analysis: add double bond so we can change to OH for C-C connection


                                                                                         BrMg
                                                      OH
                                                                                     O

          2.7.4. analysis: what kind of reactions occur at each step?
              2.7.4.1. What are the reagents? Alternative?
                                                                O
                                                                                                             O

                               Ar                          Ar

                                             OH                                                          O
                                                                            OH
MeO                                                                                  MeO
                                        O                               O
                   O                                                                                         O

          2.7.5. raspberry ketone analysis
                               O                                    O
                                                                                                CHO          O



MeO                                  MeO                                     MeO
Chem 6311                                                     Synthesis Warren CH 23-25                                         page 7

       2.7.6. analysis: hint- add two double bonds
                     O




3. 1,4 difunctional compounds
   3.1. -halocarbonyls: analysis
      O                                               O
                                                                  Br


                         CO2Et                                             CO2Et



       3.1.1. synthesis by two methods
                                     O                                 O
                 O                               Br
      O

                 N                                        CO2Et                                                    O
                                     N                                 N          Br
                 H


                                                                                                                                CO2Et
                                                                                             CO2Et




                                                                                                                       O
      O                                                           O
                                                                                                  1. OH-/H2O
                                Br
                CO2Et                                                        CO2Et
                                                                                                  2. HC/heat                     CO2Et
                                                                                           COEt
                                         CO2Et                                                    3. HCl/EtOH


   3.2. use of epoxide?
                CO2Et



                                                                                                         O

                                                                                                                           Br
                OH          ,
   3.3. Michael Addition with cyanide and nitroalkanes
       3.3.1. analysis: more stable double bond is formed
       3.3.2. both  and  carbons of nitro alkane are nucleophilic
                                                      O                       O                         NO 2
            O        NO 2
                =
                                                                                       O                       O
Chem 6311                                       Synthesis Warren CH 23-25                        page 8

      3.3.3. synthesis
                                H
                                N                          O                        O
                                     NO 2

                    NO 2                          TiCl3                 EtONa
                O                                                   O
                                            O     H2O




   3.4. FGI with alkynes
      3.4.1. carbonyl addition at either end of triple bond, remove triple bond
            OH
                                            OH
                                R2                             R2               O
                                                                                            R2
       R1
                                     R1                   OH
                           OH                                             R1
                                                                                        O

      3.4.2. analysis, use alkyne

       R               O
            O

				
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