Carbonyl Addition Reactions: Part II

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Carbonyl Addition Reactions Part II
Chem 313Spring Semester 2009
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Addition of Complex Nucleophiles
Topic Sequence
1. Addition of 'simple' nucleophiles
- the reaction provides the 'simple' addition
product
2. Addition of 'complex' or 'functionalized'
nucleophiles
- the reaction proceeds via the addition product,
which reacts further depending upon the
functionality 'G' present in the nucleophile ?
alkenes, epoxides, ?,?-unsaturated ketones etc.
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Complex Nucleophiles. 1. Wittig Reagents
Wittig reagent (McMurry Ch. 19) i. Preparation
of phosphonium salt
methyltriphenylphosphonium bromide
triphenylphosphine
Reaction is SN2! 3 phosphine very
nucleophilic. - Compare with 3 amine (CH3)3N
CH3Br ? (CH3)4N Br-
ii. Deprotonation of phosphonium salt
pKa 22.4
triphenylphosphoniumyl methylide a 'zwitterion'
overall neutral
The 'ylide' is resonance hybrid
Å 1.66
methylidene triphenylphosphorane
dz
dz
sp2
sp2
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Wittig Reaction
ii. Deprotonation (cont.)
Other bases K -O-C(CH3)3 pKa HO-C(CH3)3
19 NaH - sodium hydride 'pKa' H2 35 Li
-NSi(CH3)32 lithium hexamethyldisilazide pKa
HN Si(CH3)32 30-35 Li -NCH(CH3)2 lithium
di-iso-propylamide pKa HN CH(CH3)2 2 37-40.
Reaction with carbonyl compounds The Wittig
Olefination Reaction
triphenylphosphine oxide
Other examples
Completely regioselective!- defines position of
double bond in the product!
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Wittig Reaction-Mechanism
Compare regioselectivity with other
alkene-forming reactions
The Wittig reaction (and related reactions) is
the most important reaction for making alkenes
from carbonyl compounds

• Mechanism
• addition of 'complex' nucleophile
• elimination via oxaphosphetan

betaine

• syn elimination of Ph3PO
• overall reaction exothermic
• (P-O bond dissociation energy 130-140 kcal mol-1)

oxaphosphetan
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Wittig Reaction- Mechanism and Stereoselectivity

• The ylide CH2-PPh3?CH2PPh3 which bears no EWG
  attached to C is
• termed an 'unstabilized ylide'.
• for unstabilized ylides, betaines may have very
  short lifetime, but equilibration
• with oxaphosphetan may occur.
• oxaphosphetans can be detected by 31P NMR

Stereoselectivity - consider
(Z)-
(E)

• The Wittig reaction is not completely
  stereoselective!
• unstabilized prochiral ylides with prochiral
  carbonyl compound gives
• the (Z)-alkene as the major product.
• - exact amount depend upon reaction conditions!

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Wittig Reaction Stereochemistry (cont.)
Topicity of addition of prochiral ylide with
prochiral carbonyl compound
i. ReP SiCO and SiP ReCO 'unlike addition'
'ul'
(Z)-
cis-oxaphosphetan
'unlike' or 'u' betaine
enantiomers
enantiomers
cis-oxaphosphetan
'unlike' or 'u' betaine
(Z)-

• interaction between dipoles in u-betaine
  stabilizes eclipsed conformer!
• u-betaine ? cis-oxapahosphetan ?(Z)-alkene

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Wittig Reaction-Stereochemistry (cont.)
Topicity of addition (cont.)
ii. SiP SiCO and ReP ReCO 'like addition'
'lk'
(E)-
trans-oxaphosphetan
'like' or 'l' betaine
enantiomers
enantiomers
trans-oxaphosphetan
'like' or 'l' betaine
(E)-

• interaction between dipoles in u-betaine
  stabilizes eclipsed conformer!
• l-betaine ? trans-oxaphosphetan ?(E)-alkene
• l-betaine should be more stable than u-betaine
  and trans-oxaphosphetan
• should be more stable than cis-oxaphosphetan
• however, (Z)-alkene is major product!
  preferential and irreversible formation
• of u-betaine!

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Wittig Reaction- Ylide Reactivity and
Stereochemistry
i. Unstabilized' ylides

• also others where R electron donating group
  (e.g. -OR', -NR'2
• R' alkyl group)
• react rapidly with aldehydes and ketones
• react rapidly with O2 generation and reaction
  must be carried out under N2!
• with prochiral carbonyl compound, (Z)-alkene is
  major product!

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Wittig Reaction Ylide Reactivity and
Stereochemistry (cont.)
ii. Stabilized' ylides ('relative' to
unstabilized ylides)

• react slowly with aldehydes, only react with
  ketones under extreme conditions!
• generally stable in air!
• with prochiral carbonyl compound, (E)-alkene is
  major product!

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Wittig Reaction Ylide Reactivity and
Stereochemistry (cont.)
ii. Stabilized ylides (cont.) Reaction with
prochiral carbonyl compound
(E)-
l-betaine
also ReP-ReCO addition ? enantiomeric betaine and
oxaphosphetan
u-betaine
(Z)-
also SiP-SiCO addition ? enantiomeric betaine and
oxaphosphetan

• The formation of the betaine and oxaphosphetan
  are reversible!
• Thermodynamic considerations apply l betaine
  more stable than u betaine!
• (E)-alkene is major product!

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Wittig Reaction - Examples
i.
(Z)
71 yield ZE ? 955

• Completely regioselective, highly
  stereoselective!
• selective for aldehyde 'chemoselective'!
• DMF 'dipolar aprotic solvent' strongly
  solvates Na,
• 'Salt free'-conditions enhances amount of
  (Z)-alkene!

Dipolar aprotic solvents
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Wittig Reaction Examples (cont.)
ii. Synthesis of prostaglandin F2? (Introduction!)
The hemiacetal provides the 'free' aldehyde under
the reaction conditions
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Wittig Reaction Examples (cont.)
iii. If ?,?-unsaturated aldehyde is used,
stereoselectivity is much poorer!
(E)
(Z)
75 yield ZE 13!
To enhance amount of (E)-isomer, conduct reaction
in a protic solvent, or use excess of 'salt'
(e.g. LiBr) in reaction mixture!
69 yield ZE 110!
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Wittig Reaction Examples (cont.)
iv. Synthesis of polyenes
?-carotene precursor to Vitamin A!

• (Z)-alkene also formed, but is unstable will
  isomerize rapidly in presence of light to the all
  (E)-alkene.
• Commercial preparation of ?-carotene!

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Wittig Reaction Examples (cont.)
v. Synthesis of polycyclic alkenes
40 yield
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Wittig Reaction - Difficulties

• Difficult to separate OPPh3 MW 278 from
  product alkene OPPh3 is not
• soluble in water.
• Wittig Reactions do not work well with ketones
  and stabilized ylides
• very difficult reaction to carry out!

• To overcome low reactivity of stabilized ylide?
• use a different phosphorus-based stabilizing
  group which has lower ability
• to stabilize negative charge than PPh3!

Phosphonate! note that the anion is not an
ylide!
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Horner Emmons Reaction
Preparation of Phosphonates
From ?-halo-esters and ketones and trimethyl or
triethyl phosphite

• Michaelis-Arbuzov Reaction - two steps
• formation of phosphonium salt
• SN2 reaction

Deprotonate phosphonate to generate nucleophilic
reagent
resonance-stabilized anion (Slide 17) not an
ylide!
also use diethyl ether, DMF, DMSO, HMPT as
solvents!
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Horner Emmons Reaction (cont.)
Reaction of Phosphonate anion with aldehydes and
ketones Horner-Emmons or Horner-Wadsworth-Emmons
Reaction
Addition intermediate not detectable
oxaphosphetan not detectable
dimethyl phosphite water soluble!
compare with Wittig reaction
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Horner Emmons Reaction - Examples
i. Pheremone of the dried-bean beetle
70 yield
(E)
ii. Prostaglandin analogue
(E)

• Completely regioselective, highly
  (E)-stereoselective, chemoselective for
• aldehyde!

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Horner Emmons Reaction Examples (cont.)
iii. Preparation of allylic alcohols
(E)
The ?,?-unsaturated ester is then reduced with
LiAlH4 or similar hydride donor
overall chain extension of aldehyde by addition
of 2 carbon units
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Carbonyl Addition Reactions Complex
Nucleophiles (cont.)
2. Addition of 'complex' or 'functionalized'
nucleophiles (cont.)
- the reaction proceeds via the addition product,
which reacts further depending upon the
functionality 'G' present in the nucleophile ?
alkenes, epoxides, ?,?-unsaturated ketones etc.
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Sulfur Ylides - Preparation

• dialkyl sulfides more nucleo-philic than dialkyl
  ethers!
• trialkylsulfonium salts stable
• trialkylsulfonium salts with three different
  alkyl groups are chiral, but racemize at 25 C!

Sulfonium iodides from diaryl sulfides are
relatively unstable they can be isolated, but
they slowly decompose. Best to replace iodide by
non-nucleophilic counterion

• treat iodide salt with AgBF4 or AgPF6
• BF4- and PF6- are 'non-nucleophilic' counterions

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Sulfur Ylides Preparation (cont.)
Substituted ylides
Deprotonation of sulfonium salts

• NaH/DMSO
• LDA/THF etc.
• also may be used
• ylide generated in situ

resonance hybrid

• ylide generated in situ
• more stable than
• sulfonium ylide

pKa 18.2
resonance hybrid
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Sulfur Ylides Preparation and Reactions
Deprotonation (cont.)

• ylide generated in situ

Reactions

• transfer of 'methylenegroup'
• -CH2-

betaine
betaine

• less reactive ylide addition reaction is
  reversible!

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Sulfur Ylides Reactions and Stereochemistry
i. Dimethylsulfonium methylide
'axial' epoxide 85
axial betaine
'equatorial' epoxide 15
equatorial betaine

• addition of ylide is irreversible
• conversion of betaine into epoxide is
  irreversible
• axial attack of ylide is stereoelectronically
  preferred
• kinetic preference for formation of axial betaine!

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Sulfur Ylides Reactions and Stereochemistry
(cont.)
ii. Dimethyloxosulfonium methylide
'axial epoxide' 0
axial betaine
'equatorial epoxide' 100
equatorial betaine

• Thermodynamic component
• less reactive ylide addition reaction leading to
  betaine is reversible!
• thermodynamic preference for formation of
  equatorial betaine
• Kinetic component
• more hindered ylide equatorial addition
  kinetically preferred!

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Sulfur Ylides Reactions (cont.)
Diphenylsulfonium cyclopropylide
betaine
Product can be rearranged in presence of Brønsted
acid

• epoxide is basic readily protonated.
• rearrangement 'driven' by reduction in ring
  strain in going from 3- to 4-membered ring!

Epoxides formed from sulfur ylides extremely
useful synthetic intermediates don't forget
their reactions!
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Carbonyl Addition Reactions Complex
Nucleophiles (cont.)
2. Addition of 'complex' or 'functionalized'
nucleophiles (cont.)
- the reaction proceeds via the addition product,
which reacts further depending upon the
functionality 'G' present in the nucleophile ?
alkenes, epoxides, ?-hydroxy and ?,?-unsaturated
aldehydes and ketones.
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The 'Classical' Aldol Reaction
'Condensation' of carbonyl compound with its
enolate
i. Generation of nucleophile
ii. Addition to carbonyl compound

• electrophilic component (neutral ketone) provides
  nucleophile!
• all reactions are reversible
• catalytic amount of base

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The 'Classical' Aldol Reaction (cont.)
iii. Under relatively vigorous reaction
conditions, aldol may dehydrate
- base-catalyzed elimination

• E1cb reaction reversible
• remove water to bring to completion

- acid-catalyzed elimination

• reversible remove water to bring to completion

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The 'Classical' Aldol Reaction 'Crossed' Aldols
Synthetically not useful when both carbonyl
partners are enolisable
Acetone and butanone ? three nucleophilic
enolates!
Acetone and butanone ? six regioisomers!
Regiochemical nightmare!
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The 'Classical' Aldol Reaction 'Crossed' Aldols
(cont.)
Synthetically useful cases i. electrophile has
no acidic ?-H atoms, and is more reactive than
other carbonyl partner which provides the
nucleophilic enolate

• nucleophile is acetone enolate (E)-alkene
  exclusively formed

ii. Intramolecular reactions

• ring closure is reversible base-catalyzed
  dehydration (E1cb, slide 31) is irreversible!
• also for six-membered rings

Read McMurry, Ch. 23 and Carey and Sundberg, Ch.
2, Part B, for other examples