Chapter 4 Formation of carbon-carbon bonds reaction of

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					     Chapter 4 Formation of carbon-carbon
       bonds: reaction of organometallic
                  compounds
Topics:
 Grignard reagents and electrophiles

 Other organometallic reagents and electrophiles

 Reactions of nucleophiles derived from alk-1-ynes

 Review

 Worked example
4.1       Grignard reagents and electrophiles

  4.1.1 Alkylation
  4.1.2     Reactions with carbonyl compounds
  4.1.3 Reactions with imine and cyano compounds
  4.1.4 Reactions with α,β-unsaturated carbonyl
           compounds

  4.1.5 Alkenyl and alkynyl Grignard reagents
  4.1.1 Alkylation



XMg       R          `R   Y             R   R`



XMg   R                            -+        H+
                 O        R CH2CH2 O MgX          R CH2CH3OH
For example

             MgI                     I
      n                         m                     n          m




                   MgBr
                          C2H5OSO2OC2 H5
                                                          C2H5




              ClCH2                        PhCH 2
  PhMgBr

                     Cl                          Cl


                          THF
    PhMgBr            O             PhCH2CH2OH
4.1.2 Reactions with carbonyl compounds



            R1               R1            R1
XMg   R             O       R     O-+MgX   R    OH
            R2               R2            R2
For example

                  HCHO
          MgCl
                               CH2OH




                          OH
                 CH3CHO
      MgBr



                          OH
              CH3COCH 3
      MgBr
          R1       R1            R1
XMg   R        O   R    O-+MgX              O
          Y        Y                 R

                                         RMgX


                                 R1
                                 R         OH
                                 R
For example

   2CH3MgI    PhCOCl                 Ph
                                   CH3    OH
  2CH 3MgI    (PhCO)2O              CH3

                     O                         OH

 2CH3MgI                 OC 2H 5



                       HCOOC2H5
              MgBr

                                               OH
 Synthesis of Alcohol by Grignard Reaction
                                              Mg                      CH2O
                                   RX                 RMgX                          RCH2OH
                                                                            O
                                                                                               primary

                                                                                   RCH2CH2OH




                                                                    R'C
                                                 '
                                   R''         R'




                                                          HCO2R'

                                                                       HO
                                 O           O2
                           R'C           R'
                                            C        R'

       R                                                                         R
                                                      O
HO      R"                                                                        CH OH
                           R
       R'                                                                       R'
                      HO    R       R'CH-CH2R             R
     ter                   R'
           tia                           OH               CH OH
                 ry
                                                          R
                                                                            ry
                                                                   se c onda
MgBr
             COOH


       CO2
4.1.4   Reactions with compounds containing C≡N


                                           O
                         CN                C

        MgBr
                N                 N
  4.1.4   Reactions with α,β-unsaturated carbonyl
          compounds

                                         O -MgX+                  OH
                   O             C                        C
XMg-R                                R                        R




                                     C      O-MgX +       C        O


                                                              H
                             R                        R
4.2    Other organometallic reagents and electrophiles


      4.2.1 Organolithium reagents
            more reactive and less bulkyl
      4.2.2 Organozinc and organocadmium
            reagents
            less reactive and used only for special
            purposes
      4.2.3 Organocopper (I) reagents
            less reactive and more selectivity
4.2.1 Organolithium reagents

  Preparation
   RBr + 2Li           RLi + LiBr
   RBr + R’Li          RLi + R’Br
                              (Generally R’ refers to n-BuLi)

  Organolithium reagents react similarly with Grignard
    reagents and more efficiently in certain cases. With α,β-
    unsaturated carbonyl compounds they show a greater
    preference for addition at the carbonyl carbon.
PhLi    PhCOO-Li+                 PhCOPh



CH3Li        PhCH=CHCOO-Li+                PhCH=CHCOCH3



        Li                                        CHO
                          O
H3CO           OCH3                        H3CO         OCH3

                      H       N

                              Ph
4.2.2 Organozinc and organocadmium reagents
   Organozinc reagents (Reformatsky reaction)

                                                                                 O-+ZnBr
      RCH(Br)CO2R1   +      Zn                 RCH(ZnBr)CO2R1       or   RHC C
                                                                                 OR1

                                                              R2COR3



                     HO              CO2R1         BrZn+-O          CO2R1
                          C      C             H+         C     C
                                     H                              H
                     R2R3        R           (Work-up) R2R3     R


  Note: Reactions with α,β-unsaturated carbonyl compounds
    give preferentially the 1,2-addition products.
 Organocadmium reagents

• Preparation

  2RMgX + CdCl2        R2Cd

• Used especially for the conversion of acyl chlorides into ketones

       R2Cd + 2R’COCl             2RCOR’

  e.g. [CH3(CH2)3]2Cd + ClCH2COCl       CH3(CH2)3COCH2Cl (51%)

       [(CH3)2CHCH2CH2]2Cd    +    ClCO(CH2)2CO2CH3



                (CH3)2CH(CH2)2CO(CH2)2CO2CH3 (73%)
4.2.3 Organocopper (I) reagents
 • Preparation
    RMgX + CuX         RCu + MgX2
    RLi     + CuX      RCu + LiX
    RLi     + RCu       R2CuLi
    2R-Li   + CuX      R2CuLi +      LiX
 • Ponits of synthetic importance:
     – Displacement of halogens is particularly facile.
     – Acyl halides are the only class of carbonyl compound to react with.
     – When reacting with α,β-unsaturated carbonyl compounds give 1,4-
       addition products.
     – Coupling reactions occur when heated.
4.3      Reactions of nucleophiles derived from alk-1-ynes

      4.3.1   Sodium, lithium and magnesium derivatives
                                               RC CNa
                                 Na+-NH2

                             RC CH
                                           RLi, ether
                         R'MgX                    RC CLi

                             RC CMgX

        They can undergo the usuall range of reactions with electrophiles:
              • Alkylation
              • Reaction with carbonyl compounds
4.3.2 Alkynylcopper(I) compounds

  • Preparation

              RC CH + CuCl       RC CCu + 2HCl



  • Ponits of synthetic importance:
     – Displacement of halogens from’unreactive’ positions.
     – Conversion of acyl halide into ketone
     – Coupling reactions giving conjugated diynes.
                           Me                           Synthetic equivalents
4.4 Review                Et      OH                     EtMgX + PhCOMe
                           Ph
                          synthons: Et                      or     Et-
                                    Me                             Me
                                                   OH                    +
                                                                             OH
                                         Ph                         Ph

  R-R’                     R-;        R’+
                                       R’-Y (Y = X (halides), OTs (sulfonates))
  RCH2CH2OH                R-;        +CH CH OH
                                           2   2
                                         O

  RCO2H                    R-;        +CO H
                                          2
                                       CO2

  R
      C
                                         +C
          C   O           R-;                 C        O
          H                                    H
                                         C
                                              C    O
Synthetic equivalents

  Nucleophilic -
                R           RMgX, RLi, R2Cd, RCu, R2CuLi
  Synthons
                R+          RCl, RBr, RI, ROSO2R1
                RC+=O       RCOCl, (RCO)2O, RCO2R1,RCN
                HC+=O       HCO2R1,
                HC+=O
  Electrophilic   |         CO2
                  OH
  Synthons
                C+H2OH      HCHO
                RC+HOH      RCHO
                R2C+OH      R2CO
                +CH CH OH
                    2 2       O
4.5 Worked example

                 1-phenyl-butan-2-ol
                                         Synthetic equivalent

                  PhCH2+    + CHCH2CH3   PhCH2+        PhCH2Br
                             OH          PhCH2-  PhCH2MgX
      OH                      +          +
                  PhCH2-    + CHCH2CH3   CHCH2CH3 CH3CH2CHO
                             OH          OH

                 PhCH2CH+     -
                            + CH2CH3
                                          -              EtMgX
                                          CH2CH3
                       OH                 +              EtBr
                                              CH2CH3
      OH         PhCH2CH- + +CH2CH3
                                          PhCH2CH+       PhCH2CHO
                       OH
                                                 OH


Two synthetic routes have therefor emerged:
PhCH2MgBr + CH3CH2CHO and PhCH2CHO + BrMgCH2CH3
Pentadecan-4-one
                   O




                   O




                   O
+               -

                    O


-               +

                    O


    O

            +       -



    O

        -       +
3-Phenyl-butyric acid methyl ester
                     O


                         O




                 O
                                              O
                     O
                                      -   +
                                                  O


                                              O

                              O
                                                  O
              CuLi   +
                         Cl       O
                                     O
                  O
MgBr
                                         O
                      OH
       CO2             CH3OH
                           H+




             Br

                                Br
O                      O


                             O   CH3-
    O


                        O


                             O


           methyl cinnmate

O
               O
    O
                                 Ph-

                     O
              O


                    O
        methyl crotonate
pent-3-yn-1-ol




                 OH
                                    Summary

 Grignard reagents, RMgX, are strongly nucleopholic, I.e.

 they act as synthetic equivalents of the synthon R-.

 They are alkylated by halogenoalkanes, they undergo addition to the carbonyl group

   of aldehydes and ketones, they react with acyl halides, anhydrides and esters giving

   first ketones and thence tertiary alcohols, with carbon dioxide giving carboxylic

   acids, and with tertiary amides, orthoesters and nitriles giving , after hydrolysis,

   carbonyl compounds (aldehydes or ketones).
                            Summary

 With α,β-unsaturated carbonyl compounds, nucleophilic addition to the

   carbonyl group and conjugate addition (at the β-carbon) are both observed,

   the former usually predominating. Grignard reagents are also strong bases

   and are protonated even by weak acids such as water, alcohols and alk-1-

   ynes.
 Organolithium reagents react similarly but are even stronger nucleophiles and
stronger bases. With α,β-unsaturated carbonyl compounds they show a greater

preference for addition at the carbonyl carbon.

 Organozinc and organocadmium reagents are less reactive nucleophiles than

Grignard reagents but are used nowadays only for certain specific purposed.

 Organocopper(I) reagents (Rcu or R2CuLi), although also synthetic

equivalents of the synthon R-, show a different pattern of reactivity: they readily

undergo alkylation, acylation and conjugate addition but do not undergo addition

to carbonyl groups.
 Deprotonation of alk-1-ynes (using a strong base such as sodamide or
a Grignard reagent) furnishes useful nucleophiles which undergo the
expected reactions, e.g. alkylation and reaction with carbonyl compounds.
Alkynyl-copper(I) reagents react smilarly to alkyl- and aryl-copper
reagents but they also undergo oxidative coupling to give conjugated
diynes.

 Some rules for the disconnection of target molecules, tabulated lists of
synthetic equivalents for various synthons and one worked example are
includeded at the end of the chapter.

				
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posted:5/24/2013
language:English
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