The above lecture slides prepared for UG and PG students.

1. D R . V. S I VAM U R U G A N
P R O F E S S O R I N C H E M I S T RY
PAC H A I YA P PA’ S C O L L E G E , C H E N N AI –
6 0 0 0 3 0
S I VAAT N U S @ G M A I L . C O M
FORMATION C-C BOND
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4. 1.1 Main-group chemistry
1.1.1 Alkylation of enolates and enamines
1.1.2 Conjugate addition reactions of enolates and enamines
1.1.3 The aldol reaction
1.1.4 Asymmetric methodology with enolates and enamines
1.1.5 Organolithium reagents
1.1.6 Organomagnesium reagents
1.1.7 Organozinc reagents
1.1.8 Allylic organometallics of boron, silicon and tin
1.2 Transition-metal chemistry
1.2.1 Organocopper reagents
1.2.2 Organochromium chemistry
1.2.3 Organocobalt chemistry
1.2.4 Organopalladium chemistry
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5. 1.1.1 ALKYLATION OF ENOLATES AND
ENAMINES
Carbonyl groups increase the acidity of the proton(s)
adjacent (α-) to the carbonyl group.
The acidity of the C-H bonds in these compounds is
caused by a combination of the inductive electron-
withdrawing effect of the unsaturated groups and the
resonance stabilization of the anion formed by removal
of a proton
Order of electron withdrawing capacity:
NO2>COR>SO2R>CO2R>CN>C6H5
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6. FORMATION OF ENOLATE
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7. • It is these enolate anions that are involved in many reactions
of carbonyl compounds, such as the aldol condensation, and
in bimolecular nucleophilic displacements
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8. TABLE 1.1. APPROXIMATE ACIDITIES OF SOME ACTIVATED
COMPOUNDS AND COMMON REAGENTS
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9. • In the presence of a protic acid, ketones may be
converted largely into the enol form, implicated in many
acid-catalysed reactions of carbonyl compounds.
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10. ALKYLATION ON ENOLATE
• Alkylation of enolate anions is achieved readily with alkyl halides or
other alkylating agents.
• Both primary and secondary alkyl, allyl or benzyl halides may be
used successfully
• tertiary halides poor yields of alkylated product often result because
of competing elimination.
• Advantageous - proceed by way of the toluene-p-sulfonate,
methanesulfonate or trifluoromethanesulfonate rather than a halide.
• The sulfonates are excellent alkylating agents and can usually be
obtained from the alcohol in a pure condition more readily than
corresponding halides
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11. With secondary and tertiary allylic halides or sulfonates, reaction of an enolate
anion may give mixtures of products formed by competing attack at the α- andγ-
positions
Dialkylation also becomes a more serious problem with the more acidic
cyanoacetic esters and in alkylations with very reactive electrophiles such as allyl
or benzyl halides or sulfonates
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12. REACTION WITH ARYL/ALKENYL
COMPOUNDS
Benzyne
Reactive intermediate
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13. INTERMOLECULAR ALKYLATION OF
AN ESTER
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15. CONTROLLING POLYALKYLATED
CYCLOHEXANONE
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16. 2 AND 9-ALKYLATED TRANS-
DECALONE
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17. STORK-ENAMINE REACTION
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18. 1.1.2 CONJUGATE ADDITION REACTIONS
OF ENOLATES AND ENAMINES
Addition to α,β-unsaturated carbonyl or nitrile compounds to the enolates –
Micheal addition
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19. ADDITION OF PHENYL VINYL
SULFOXIDE
• The electron-withdrawing group is commonly an ester or ketone, but can
be an amide, nitrile, nitro, sulfone, sulfoxide, phosphonate or other
suitable group capable of stabilizing the intermediate anion.
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20. HINDERED ACCEPTOR
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21. REGEOSELECTIVE ADDTION
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22. REACTION WITH ENDOCYCLIC ENAMINES
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23. STEREO CONTROLLED ADDITION
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24. SILYL ENOL ETHERS STABILISED
ENOLATES
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25. TRIBUTYLTIN ENOLATE
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26. INTRAMOLECULAR CONJUGATE
MICHEAL ADDITION
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28. ROBINSON ANNULATION
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29. 1.1.3 THE ALDOL REACTION
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30. REACTION WITH METAL ENOLATES
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31. REACTION WITH BORON ENOLATES
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32. CLAISEN CONDENSATION - SELF-
CONDENSATION PRODUCT
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34. STEREOSELECTIVE ALDOL REACTIONS
• the syn or the anti (traditionally erythro and threo) aldol product can be
prepared. This is often termed a diastereoselective reaction
• suitable chiral auxiliaries or catalysts, high selectivities for one enantiomer of
the syn or the anti diastereomer can be obtained -enantioselective reactions
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35. REACTION WITH CIS AND TRANS
ENOLATE
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36. ZIMMERMAN–TRAXLER MODEL
chair-like six membered cyclic transition state in which the ligated metal atom is
bonded to the oxygen atoms of the aldehyde and the enolate
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37. 1.1.5 ORGANOLITHIUM REAGENTS
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38. ALKYLATION TO CARBONYL
COMPOUND
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39. PROSTAGLANDIN F2 BY COREYα
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40. CONVERSION OF ACID TO KETONE
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42. SIMMONS–SMITH-TYPE
Reaction of dimethylsulfoxonium methylide with the enone
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43. UMPOLUNG TYPE REACTION
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45. 1.1.6 ORGANOMAGNESIUM REAGENTS
• Organomagnesium reagents are commonly referred to
as Grignard reagents.
• Typically, a Grignard reagent is formed by reaction of an
alkyl halide (RX) in ethereal solvent with magnesium to
give the species RMgX.
• The ethereal solvent co-ordinates to the magnesium
atom and the Grignard reagents are in equilibrium with
the dialkylmagnesium species R2Mg and MgX2 (Schlenk
equilibrium).
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46. REACTION WITH GRIGNARD REAGENT
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47. ASYMMETRIC GRIGNARD REAGENTS
• Asymmetric induction occurs in the addition of a Grignard reagent to an
aldehyde or ketone bearing a chiral auxiliary.
• An example is the use of the 8-phenylmenthol ester 138, in which Grignard
addition to the aldehyde occurs from the front face opposite the bulky
substituent on the auxiliary and with the conformation of the carbonyl groups
cis to one another
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48. REACTION WITH UNSTATURATED
CARBONYL
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49. CONJUGATE REACTION WITH IMIDE
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50. 1.1.7 ORGANOZINC REAGENTS
Organozinc compounds are less nucleophilic and less basic
than the corresponding organolithium or organomagnesium
reagents.
They can therefore effect chemoselective carbon–carbon
bond formation in the presence of otherwise reactive
functional groups.
The most common method for the formation of an organozinc
reagent involves the insertion of zinc metal into the carbon–
iodine bond of an alkyl iodide.
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51. REFORMATSKY REACTION
• Reformatsky reaction, in which an organozinc
species is generated from an α- bromoester.
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52. CYCLISATION TO LACTONE
 Insertion of zinc into allyl bromides occurs readily, for example to give the allyl
zinc reagent 145.
 Addition to an aldehyde occurs by attack through the γ-carbon atom to give a
homoallylic alcohol.
 With substrate 145, bearing a β–ester group, the product homoallylic alcohol
cyclizes spontaneously to give the lactone 146.
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53.  In the presence of a Lewis acid, alkyl zinc halides react with aromatic aldehydes
to give secondary alcohols.
 However, alkyl zinc reagents are less reactive than their allyl derivatives and
reaction with aliphatic aldehydes is very sluggish.29-12-2018 53

54. NEGISHI CROSS-COUPLING REACTION
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55. REACTION WITH DIETHYL ZINC
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56. 1.1.8 ALLYLIC ORGANOMETALLICS OF
BORON, SILICON AND TIN
A useful reaction in organic synthesis is the addition of an allylic
organometallic reagent to a carbonyl group.
A number of different metals can be employed, although those of
boron, silicon and tin have found the most use.
The carbon–carbon bond-forming step is often stereoselective and
generates the versatile homoallylic alcohol unit
Oxidative cleavage of the product alkene to the aldehyde (or other
carbonyl derivative) provides the -hydroxy-carbonyl compound and
offers an alternative stereoselective approach to the aldol-type
product.
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58. ORGANO BORON REAGENT
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59. ORGANO TIN/SILYL REAGENTS
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60. STEREO CONTROLLED REACTION
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61. 1.2 TRANSITION-METAL CHEMISTRY
The use of transition metals to promote the formation of
carbon–carbon bonds has grown tremendously in recent
years.
This section describes some of the important
transformations using the metals copper, chromium,
cobalt and palladium.
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62. 1.2.1 ORGANOCOPPER REAGENTS
• There are various types of stoichiometric organocopper
reagent, the most common being R2CuLi, RCu(CN)Li or
R2Cu(CN)Li2.
• For example, a lithium dialkylcuprate species, R2CuLi, often
referred to as a Gilman reagent, is most conveniently
prepared by reaction of two equivalents of an organolithium
compound with copper(I) iodide in diethyl ether
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63. REACTION WITH GILMAN REAGENTS
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64. SYNTHESIS OF CIS-DECALONE, 168
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65. ASYMMETRIC CONJUGATE ADDITION
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67. THE E-ALKENE IS FORMED FROM THE E-ALKENYL HALIDE.
LIKEWISE, THE Z-ALKENE IS FORMED SELECTIVELY FROM THE
Z-ALKENYL HALIDE.
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68. 1.2.2 ORGANOCHROMIUM CHEMISTRY
• Arylchromium complexes can be prepared easily, simply
by heating the arene with chromium hexacarbonyl,
Cr(CO)6 or by ligand exchange with
(naphthalene)chromium tricarbonyl complex.
• The desired arylchromium complex is generated, bearing
the arene (η6 species) and three carbon monoxide
ligands on the chromium(0) atom (18 electron complex)
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70. REACTION WITH ORGANO CHROMIUM
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73. 1.2.3 ORGANOCOBALT CHEMISTRY
• The most common use of cobalt in organic synthesis is
as its alkyne complex.
• Addition of dicobalt octacarbonyl [Co2(CO)8] to an alkyne
generates the stable organocobalt complex 184 that
exists as a tetrahedral cluster
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74. PAUSON–KHAND REACTION
• The reaction combines the alkyne, alkene and carbon
monoxide, in what is formally a [2+2+1] cyclo addition
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75. ANTITUMOR SESQUITERPENE
CORIOLIN (186)
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76. 1.2.4 ORGANOPALLADIUM CHEMISTRY
Organopalladium species tolerate many different functional groups
and promote a variety of carbon–carbon (and other) bond-forming
reactions with extremely high chemo- and regioselectivity.
Oxidative addition of palladium(0) species into unsaturated halides
or triflates provides a popular method for the formation of the -bound
organopalladium(II)species.
Organopalladium species generated by oxidative addition react with
organometallic species or with compounds containing a π-bond,
such as alkynes or alkenes.
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77. It is important to use an unsaturated (e.g. aryl or alkenyl) halide or
triflate, as β-hydride elimination of alkyl palladium species can take
place readily.
Oxidative addition of palladium(0) into alkenyl halides (or triflates)
occurs stereospecifically with retention of configuration.
The palladium is typically derived from
tetrakis(triphenylphosphine)palladium(0), [Pd(PPh3)4], or
tris(dibenzylideneacetone) dipalladium(0), [Pd2(dba)3], or by in situ
reduction of a palladium(II) species such as [Pd(OAc)2] or
[Pd(PPh3)2Cl2].
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78. STILLE REACTION – ORGANO
STANNANE
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79. MACROCYCLIZATION - ZEARALENONE
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80. MECHANISM
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81. INSERTION OF CO
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82. SUZUKI REACTION – ORGANO BORON
REAGENT
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83. INTERMEDIATE OF PROSTAGLANDIN E1
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85. SONOGASHIRA CROSS-COUPLING
REACTIONS
Crosscouplings of two alkynes (Glaser reaction)
provides diynes.
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86. HECK REACTION
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87. MECHANISM
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88. INTRAMOLECULAR CYCLISATION
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