Conjugate Addition Reactions

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Conjugate Addition Reactions
Chem 313Spring Semester 2009
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Conjugate Addition Reactions
Addition of 'simple' nucleophiles to carbonyl
compounds
Addition of 'simple' nucleophile to conjugated or
?,?-unsaturated carbonyl compounds two
possibilities -
i. carbonyl (or '1,2'-) addition
ii. conjugate (or '1,4'-) addition
Enolate
Note '1,2' and '1,4' should not be used! use
'carbonyl' or 'conjugate' addition
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Grignard and Alkyllithium Reagents
Regiochemistry of reactions with ?,?-unsaturated
carbonyl compounds
RMgBr and RLi i. cyclic ?,?-unsaturated ketones
Overwhelming preference for carbonyl addition! -
carbonyl activation by complexation!
M MgBr 95.0 5.0 M Li gt99.5 lt0.5
ii. Acyclic ?,?-unsaturated ketones RMgBr
sensitive to steric effects
100
100
RLi undergoes carbonyl addition!
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Grignard and Alkyllithium Reagents (cont.)
For conjugate addition replace Li or Mg by metal
ion less capable of forming complex with carbonyl
group! use Cu(I) at temperatures lt 0 C under
N2!
Overwhelming preference for conjugate addition!
no carbonyl activation by complexation!
M MgBr 1 99 M Li 1 99
Role of Cu(I)
CH3Cu precipitates as insoluble yellow precipitate
CH3Cu dissolves to form soluble dimethyl
'cuprate'
CH3Cu aggregate insoluble in ether or THF
detailed structure unknown (CH3)2CuMgX
soluble unstable above 0 C probably dimeric
(CH3)2CuMgX2
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Grignard and Alkyllithium Reagents (cont.)
Role of Cu(I) (cont.) for CH3Li -
(CH3)2CuLi soluble unstable above 0 C
probably dimeric (CH3)2CuLi 2

• 0.2 equivalents of Cu(I)X is added to solution
  of CH3MgX or CH3Li
• conjugate addition of (CH3)2CuMgX or (CH3)2CuLi
  much faster than carbonyl addition of CH3MgX or
  CH3Li!

• reactive species is (CH3)2CuMgX
• CH3Cu is unreactive!
• CH3Cu reacts with excess of CH3MgX to regenerate
  (CH3)2CuMgX!

Conjugate addition

• Works for all RMgX, RLi, except for R -C?C-R'
• For 2, 3 alkyl halides, lower temperatures must
  be used.

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Organocuprates
Preformed organocuprates required for
?,?-unsaturated carbonyl compounds containing
base-sensitive groups.
Generate organocuprate first, and then add
?,?-unsaturated carbonyl compound

• 'one' (CH3)3C- group is 'wasted' (CH3)3C-Cu is
  unreactive!
• Use 'mixed' alkyl cuprate RCuLM - where L is
  non-transferable ligand.

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Organocuprates (cont.)
Preformed, mixed organocuprates (cont.)
non-transferable ligand L
Commence with L attached to Cu(I)!
1. L -CN
soluble cuprates same reactivity as dialkyl
cuprates!
2. L -SAr
3. L -C?CR
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Reactions of Organocuprates
Extremely useful reagents
chemoselective! methyl ketone unaffected
chemoselective and regioselective! ester
unaffected attack at ?-carbon atom!
stereoselective generation of reactive enolate
enolate can be 'trapped' by electrophile!
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Reactions of Organocuprates Enolate Trapping
()
()
enolate generated in situ however, presence of
Cu(I) markedly affects reactivity of enolate!
generally less reactive!
()
alkylation of enolate must use reactive
alkylating agents - RCH2I, RCHCHCH2X,
RC?CCH2X X Br, I.
overall conjugate addition enolate trapping
'three-component' coupling!
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Reactions of Organocuprates Enolate Trapping
(cont.)
consider
PROSTAGLANDIN F2? Biosynthesized from C-20 fatty
acids in mammalian systems, highly active in
inducing biological effects, used clinically in
conjunction with other drugs for birth control.
PGF2?
strategy use 'three component coupling'!
R protecting group
Each step is stereoselective! asymmetric
induction from C-4 ? C-3 ? C-2 ? C-1
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Reactions of Organocuprates Synthesis of PGF2?
(cont.)
PGF2?
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Organocuprates Mechanism of Addition?

• Cu(I) shows little tendency to 'coordinate' to
  carbonyl
• Cu(I) complexes participate in electron transfer
  with enone???

proposed step 1
.........unpaired spin and negative charge
extensively delocalized!
radical anion!
or .......
anion radical!

• can be independently prepared, and examined by
  electron spin resonance (ESR) spectroscopy

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Organocuprates Mechanism of Addition? (cont.)
The radical anion ....
most important contributors

• maximum 'negative charge density' on O
• (most electronegative)
• maximum 'unpaired spin density' on C-?
• (measured by ESR spectroscopy)

proposed step 2
formal transfer of methyl ligand as .CH3
......... 'radical coupling' at point of highest
spin density!

• however, radical anions have never been detected
  by ESR spectroscopy in
• reactions of organocuprates with enones! thus
  above is a useful 'model'
• actual mechanism is unknown!

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Conjugate Addition Reactions Complex Nucleophiles
'simple'
Enolate
'complex'
Enolate
If group 'G' contains a latent electrophilic
site, then the nucleophilic enolate will undergo
intramolecular reaction with it.
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Sulfur Ylides

• Dimethyl-sulfonium methylide

carbonyl addition only!
ii. Dimethyloxosulfonium methylide

• less reactive ylide
• only conjugate addition product
• - carbonyl addition reaction is reversible!
• - smaller steric hindrance at C-?
• - conjugate addition is faster!

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Sulfur Ylides (cont.)
Functionalized dimethyloxosulfonium methylide
?,?-Unsaturated esters very good for conjugate
addition reactions!
()

• ?- carbon atom is 'sterically hindered' no
  attack by ylide!
• product structurally related to pyrethrins
  insecticides originally
• isolated from pyrethrum flowers!

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Why Synthesis? Natural Products (cont.)
2. commercially important natural products'
(cont.)
PYRETHRIN Part of a mixture of compounds
isolated from the dried chrysanthemum flowers
valuable insecticide for control of insects
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Enolates
i. Protic conditions methyl vinyl ketone (MVK)
Reaction are equilibria however, this is not the
end of the story!......
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Enolates and Robinson Annelation
Next Intramolecular aldol
40-50 overall

• Aldol product may undergo dehydration under
  vigorous conditions (slide 33, Carbonyl Addition
  Reactions, Part II)
• or aldol product may be isolated, and dehydrated
  under acidic conditions!

Overall reaction 'Robinson Annelation'
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Robinson Annelation (cont.)
Overall

• Widely used reaction actual conditions depend
  upon enolate -

However

• For cyclic ?-diketone, conjugate adduct shows no
  tendency to undergo intramolecular aldol reaction
  under conditions of conjugate addition!

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Robinson Annelation and Enamines
Cyclic ?-diketone (cont.)
To cyclize, treat product with amine base
catalyst under reflux

• reaction proceeds via intermediate enamine!

enamine
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Robinson Annelation and Enamines (cont.)

• Toluene (or benzene toxic) is used as solvent,
  as it forms azeotrope with water, which is
  removed.
• Catalytic amount of pyrrolidine is used.
• If an enantiomerically pure 2 amine is used,
  Robinson annelation becomes
• enantioselective.

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Enantioselective Robinson Annelation and Enamines
Use (S)-(or L-) proline enantiomerically pure
amino acids
973!
Step 1 formation of conjugate adduct (slide 17)
note its symmetry no chiral centres!
Step 2 formation of enamine (slide 20, 21)
enamine is chiral carbonyl groups are now
diastereotopic!
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Enantioselective Robinson Annelation and Enamines
(cont.)
Step 3 cyclization (slide 20, 21)
stereoselectivity is not understood!
Major product

• 2 moles of proline involved in cyclization step
• free carboxyl group is crucial methyl ester
  does not work!
• hydrogen bonding involving protonated proline N
  may be important.

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Enantioselective Robinson Annelation and Enamines
(cont.)
Step 3 previous slide is the intramolecular aldol
reaction catalyzed by proline! also works for
intermolecular aldol reaction!

• Only a catalytic amount of proline is required.
• 1 mole of proline shown to be involved in the
  catalytic step.
• free carboxyl group is crucial methyl ester
  does not work!
• other chiral, enantiomerically pure amino acids
  may be used.

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Enantioselective Intermolecular Aldol Reaction
(cont.)
This is a spectacular reaction! a catalytic
amount of the base which is chiral and
enantiomerically pure is used!
The use of proline and related chiral
enantiomerically pure catalysts is very popular
now! check K. Sakthivel, W. Notz, T. Bui, C. F.
Barbas, J. Am. Chem. Soc. 2001, 123, 5260-5267.
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Robinson Annelation Difficulties
i. Polymerization of MVK
or other nucleophile e.g. C2H5O-!
ii. formation of 'wrong' annelation product

• very common problem note that
• yields of Robinson annelation
• products are not very high!

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Robinson Annelation Use of MVK Precursor
i. Polymerization of MVK use a precursor of MVK
which provides MVK in the reaction mixture!
E1cb reaction!
'Mannich base methiodide' quaternary ammonium
salt
Preparation two steps
Mannich Reaction
1
source of formaldehyde (CH2On)
2
stable, crystalline
SN2 reaction 3 amine is converted into
quaternary ammonium salt
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Mannich Reaction Mechanism
i
amino-acetal 'aminal'
ii
iminium ion reactive electrophile
Crystalline salt! N,N-dimethylmethyleneammonium
iodide

• acid-catalysed enolisation
• B- conjugate base
• of acid e.g. HCl or CH3OH2 etc, in reaction
  mixture.

iii
acetone enol nucleophile
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Mannich Reaction Mechanism (cont.)
'Mannich base'
iv.

• addition of enol to 'carbonyl-like' iminium
  analogous to aldol reaction
• B- conjugate base of acid e.g. HCl or CH3OH2
  etc, in reaction mixture.

Mannich base protonated under the reaction
conditions
v

• Mannich base is isolated by neutralizing reaction
  mixture with OH-

Mannich base methiodide many examples of usage!
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Reactions of Enolates with Iminium Salts
Tropinone
Preparation of ?-methylene carbonyl compounds
Direct elimination of 2 amine can also take
place under certain conditions

• ?-methylene aldehyde is extremely reactive
  electrophile!

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Atropine
Atropa belladonna - exceedingly poisonous plant -
'deadly nightshade (Greek Atropos - one of the
Fates who held the shears to cut the thread of
human life)
Used in ancient and Medieval times

• Italian ladies used sap to dilate pupil of the
  eye - appearance considered to enhance beauty

Bella Donna 'beautiful lady (Italian)
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Atropine (cont.)
1831 atropine isolated by Mein
1880 Ladenburg synthesizes atropine from tropine
and tropic acid, and proves structure

• A classic drug which has assisted in
  understanding how modern drugs work in the body

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Robinson Annelation Difficulties (cont.)
Enolate regiochemistry can only use
'thermodynamic' enolate under 'classical'
conditions!
via thermodynamic enolate!
but not
Solution generate specific enolate under aprotic
conditions
and use MVK 'equivalent' which does not polymerize
G large 'removable' group
methyl ?-trimethylsilylvinyl ketone
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Aprotic Conjugate Addition of Enolates
Thus
the enolate is the final product in THF
Then add protic acid or base to remove
trimethylsilyl (TMS) group and complete
intramolecular aldol cyclization and dehydration!
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Aprotic Conjugate Addition of Enolates (cont.)
Other MVK 'equivalents' which do not polymerize
can be used.