Alcohol deoxygenation and C-C bond formations

1. An Old Dog with New Tricks:
Enjoin Wolff–Kishner Reduction for
Alcohol Deoxygenation and C–C Bond Formations
Presented By:
Stephin Baby
Dept. Of Medicinal Chemistry
MC/2019/21

2. THE PRESENTATION INCLUDES:
Introduction
1
History and
emergence of
Wolff-Kishner
reduction
2 Transitions in
Development3
Evolution and
exploration of
Wolff-Kishner
reduction
4 Conclusion
5 Reference
6
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3. INTRODUCTION
The Wolff-Kishner reduction
Nikolai Matveevich Kizhner (1867 – 1935) and Ludwig Wolff (1856 – 1919)
Carbonyl deoxygenation,subsequently developed two unprecedented new types of
chemical transformations:
a) alcohol deoxygenation
b) C–C bond formations
 Grignard-type reaction
 Conjugate addition
 Olefination
 Diverse cross-coupling reactions.
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3

4. HISTORY AND EMERGENCE
Kizhner, Professor of Organic Chemistry at the Imperial Tomsk Technological Institute, in
Siberia(1912).Published his report in the Zhurnal Russkogo Fiziko-Khimicheskogo
Obshchestva [Journal of the Russian Physical-Chemical Society]
Wolff, working at the Chemical Institute of Jena University, published a variant of the
same reaction in Justus Liebigs Annalen der Chemie(1912)
The reaction became known as the Wolff reduction until January 10, 1913, when Wolff
acknowledged Kizhner’s priority for the discovery.
In the first disclosure, Kizhner reported the Four deoxygenations.
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5. Fig 2: Kizhner’s base-promoted
decomposition of saturated ketone
hydrazones
Nikolai Matveevich Kizhner
( Ки ж не р , Н ик о лай Ма
т веевич ) 1867 – 1935
Ludwig Wolff (1854-1919).
Image of Kizhner © 2017 Matthew Bergs. All rights reserved. Image of Wolff © 2017 Sierra Lomo.
2/21/2020 5

6. Fig 2: Wolff’s first report of a semicarbazone decomposition
 The first reaction reported by Wolff was the conversion of the quinone
monosemicarbazone into the phenol
 Ironically, the paper was entitled, “Method for replacing the oxygen atom of ketones and
aldehydes by hydrogen. [First paper.]” No second paper appeared.
 Wolff describes that the inspiration for his discovery was an observation by Johannes
Thiele and his student, Willy Barlow.
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7.  Wolff modified his procedure after obtained sufficient evidence for the involvement of a hydrazone intermediate
Fig 3: Wolff’s decomposition of semicarbazones by base.
Kishners
exploration
Wolff exploration
Camphor(28%) Benzophenone(90%)
Fenchone(28%) Acetophenone(80%)
α-ionone p-Anisaldehyde(66%)
β-ionone Vanillin(67%)
pseudoionone dibenzyl ketone
Furfural(70%) P-aminoacetophenone
carone Micheler’s ketone
Menthone(89%) 2-Hexanone
isothujone
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7

8. Ketone +
NH2NH2.H2O
(Ethanol-Reflux)
Dried over fused
K2CO3
The purified hydrazone
was then added dropwise
to hot, powdered KOH
160
100%
200%
150%
1911
1912
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9. Scope and Limitation of the reaction
Scope
 The synthesis of the
corticosteroids and sex hormones
 Systematic synthesis of
pyrroles(Hans fischer 1929)
 Structure elucidations of the
pentacyclic triterpenes(Leopold
Ruzicka 1939)
 Wharton reaction
 Eschenmoser-Tanabe
fragmentation
 C-C bond formations
Grignard-type reactions
Conjugate additions
 Transition-metal-catalyzed cross
coupling reactions
Suzuki coupling
Kumada–Corriu coupling
Stille coupling
Hiyama coupling
Negishi coupling
Sonogashira coupling.
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10. • Azine formation
• Hydrazone hydrolysis to
alcohols(Eisenlohr and Polenske)
• Required higher temperature for
the reduction proceed to
completion(180 deg.cel)
• Relatively low yields(Fenchone
and camphor)
• Decomposition of the hydrazones
to the alkene
• Time taken for completion of
reaction is more
• Dehalogenation in heterocyclic
compounds
Limitation.
Scope and Limitation of the reaction
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11. 1
1
Russian Federation
Hamburg
Niedersachsen
Bremen
Hessen
BayernSaarland
BerlinBrandenburg
Sachsen
Sachsen-Anhalt
Schle
swig-
Holst
ein
Meckl
enbur
g-
Vorpo
mmer
n
Nordrhein-Westfalen
Thüringen
Rheinland-Pfalz
Baden-Württemberg
Germany
Settling the question of priority
Very dear Colleague!
The publication of your
work, which was
completely unknown to
me, surprised
me very much. I very
much regret that I have
not referred to your
undertakings,and that
in the meantime I have
examined the
My mistake for
which I apologize
to you, is that I
usually read only
original papers
and I do not
understand
Russian. First of
all, in my second
paper, I will, of
course, make up
for it and
mention your
experiments.
2/21/2020 11

12. Mechanistic investigations
THE IONIC MECHANISM
Azo tautomer of the hydrazone
Reacts with hydroxide anion to
give its conjugate base
Loses molecular nitrogen to give the
carbanion
Protonated by the water molecule
Alkane
H. Harry
Szmant(1952)
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13. Fig 4: The mechanism and reaction
energy profile for the base-promoted
decomposition of cyclohexanone
hydrazone.
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14. Free-radical mechanism
 Nitrogen gas & alkane
 Azo compound
intermediate
 React with a radical to generate
a new carbon radical
Fig 5: A putative free radical mechanism for the Wolff-Kishner reduction2/21/2020 14

15. Which one of the two, predominates???.............
Free radical
Ionic mechanism
Azo tautomer
 Free radicals undergo coupling
instead of hydrogen atom
abstraction when the concentration
of hydrazine is low
 N-alkylhydrazone as substrate
 Hydrogen atom abstraction from
hydrazine when the concentration
of hydrazine is high
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16. Modern adaptations of the Wolff-Kishner reduction
Challenge 1
Strongly basic conditions and high
temperatures of the reaction.
Challenge 2
steric hindrance
high concentration of hydrazine
Challenge 3
Hydrolysis by water and subsequent
formation Azo derivatives
Removal of water(distillation) from the reaction
medium and use of anhydrous
01
02
03
Challenges Variation of reaction from primary observation
Relatively unencumbered ketones
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17. The Huang-Minlon modification
The first major advance in this reaction was discovered by Professor Huang-
Minlon (or Huang Ming-Long, 1898–1979)
Solvent Base Reaction time
estimated
Ketone to
Hydrazine
ratio
Yield
Soffer and
coworkers(1945)
Diethylene (b.p. 244 °C)
or triethylene
glycol (b.p. 285 °C)
triethanolamine (bp. 335
°C)
Conjugate base of
the solvent as the
base
“
Longer time is
required
“
Usually 1:10
Lower ratio
Good
Poor yield
Whitmore and his
students(1945)
High boiling alcohols
(Acid catalyst)
“ Short time was
required
1:2 Good
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18. Fig:6 The first Huang-Minlon modification of the Wolff-Kishner reduction
Outcome
Ease of use and its generally higher yields
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19. Bergmann and Orchin(1949)
Bartlett and
Knox(1939)
Sargent(1957)
Gates(1950)Rapoport(1960)
Zhilkibaev(2007)
Determination of the stereochemistry of the
Rauwolfia indole alkaloid, rauwolscine
Pelletier(1954)
3-Ethylacridine has been obtained by reduction of 3-
acetylacridine,reduction of 3-acetyl-9,10 dihydroacridine
thienyl ketones, as well
aldehydes
The reduction of the keto-
lactam to the lactam
Fieser(1948)
Stenhagen(1949)
Non-conjugated unsaturated linear keto-
esters and keto-amides to the straight-chain
carboxylic acid derivatives.
Cason(1949)
G.M. Badger(1948)
Branched-chain ketoacids(β,β-
Dialkyl-γ-ketoesters)
synthesis of the geometric
isomers of hexahydrochrysene
from the diketones
Preparation of the bornane-1-
carboxylic acid by reduction of the
2-bornanone-1-carboxylic acid
Synthesis of cyclobutane
from cyclobutanone
structural and stereochemical studies of the
diterpenes of Agathis australis
Fluorene-1-carboxylic acid from
reduction of the keto-acid
Enzell and Thomas(1965)
Roberts and Sauer(1949) Buu-Ho(1953)
Reduction of the geissoschizine
aldehyde to the methyl compound
His proofs of structure and
stereochemistry(veratrine)
The reduction of 3-aryl-2-azabicyclo[4.4.0]-decan-5-
ones gave good yields of the perhydroisoquinolines
Chatterjee and Prakash(1954)
Long-chain linear keto-acids to
the straight-chain carboxylic acids
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20. Nucleophile
used
Solvent Base Yield and Reaction
time
Temperat
ure
Outcome
Moffett and
Hunter
(1951)
anhydrous
hydrazine
Anhydrous
alcohol(methanol)
Anhydrous
alkoxide bases
Na-methoxide
11-ketosteroids-
63-82%
12h
200oC Reduction of
streically hindered
11-ketosteroids
The Barton
modification
(1955)
Anhydrous
hydrazine
Anhydrous
diethylene glycol
Sodium
alkoxide
(conjugate
base)
Hindered
diterpene dione -
69-70%
18-24h
180-
240oC
Reduction of
streically hindered
diterpene dione
The Nagata
modification
(1964)
Hydrazine
dihydrochloride
(Acid catalyzed)
Glycols(Diethylene
glycol or triethylene
glycol)
KOH 3-epi-11-oxo-
ticogenin &
Hindered imines-
90%
200oC Hindered carbonyls
and masked
carbonyl groups,
such as imines
Henbest
modification
(1963)
Hydrazine
semicarbazide
toluene
“
Potassium
tert-butoxide
“
piperidinylpinacolo
ne -83%
4-cholestene –Low
yield
Higher yield
<120oC
“
Lower
temperatures
reductive
elimination of α-
aminoketones
Further modifications………
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21. Nucleophile
used
Solvent Base Yield and Reaction
time
Temperat
ure
Outcome
The Cram
modification
(1962)
Hydrazine dimethyl sulfoxide
Potassium
tert-butoxide
Diphenyl ketone-
90%
Cyclohexanone-
80%
RT Reduction at room
temperature
Fig 7:The generation of an alkyldiazene by reduction of a hydrazone carrying a leaving group.
What about not using a base at all ?........
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22. Diazene
P-toluenesulfonylhydrazone
• A complex metal hydride(reducing
agent & Base)
• Protic solvents
• NaBH4 or LiAlH4
• Milder Reaction conditions
• Yield is good
• Two steps
• Carried out under conditions of
low pH
• Mixed DMF-sulfolane solvent
• Higher temperatures
• Sodium
cyanoborohydride(Reducing
agent)
• DMF can act as the
deprotonating base
• Higher yields & Single step
Caglioti Modification Hutchins Modification
The Caglioti & Hutchins modification(1964-1967)
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23. Synthetic Toolbox
Natural products and & Lead compounds
Desired biological Properties
Largely unexploited
Fossil-based
C feedstocks
‘Un-functionalized’
 Selective
Functionalisation
To build up complexity
biomass-based
feedstocks
‘Overfunctionalized’
 Selective
Defunctionalisation
by maintaining
complexity
Synthetic Mainstream
2/21/2020 23

24. Classical Alcohol Deoxygenation
Barton-McCombie deoxygenation
THIOXOESTER
(thiocarbonate,xanthate)
 Barton–McCombie deoxygenation(1975)
 Ionic SN2 Based Pathway
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25. Unsolved Challenge >>>>
Direct Deoxygentation with High selectivity and efficiency ????.......
One Step Deoxygenation Historical Pathway
I. Benzylic alcohol
II. Allylic alcohol
III. 1,2-dihydroxy compounds
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26. One step Methodolgy
 Total Synthesis of
Sesquiterpene(Sesquicarene)
 Pyridine-SO3 Complex in THF
 Sulfate monoester-
intermediate(LiAlH4)0-3oC
 C12H12Ti(Benzene titanium)
 Deoxygenation and C-C bond
formation
 THF is used(quench free
radical)
 Allyl alcohol(Trans/cis)
 Hydroalumination(Allyl
alcohol&Ethers
 LiAlH4 in Zr
compounds(Cp2ZrCl2,ZrCl2)
 Also done by Ti compounds
 Tungsten Cmplex
Activate C-O bond
WH2Cl2(PMe3)4
 Deoxygenate non-
allylic alcohols
 Β-cyclodextrin promoted
 No cis product
 Terminal olefins will be
formed(RT)
E.J Corey(1969)
Henry ledon (1979)
Fumie sato(1980)
Jong-Tae Lee (1990)
Thomas J.crevies(1997)
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27. ‘Borrowing hydrogen’ strategy
Alcohol deoxygenation inspired by the ‘borrowing hydrogen’ strategy
2/21/2020 27

28. Catalysts used:
Iridium(Ir)
Ruthenium(Ru)
Manganese(Mn)
Substrate scope:
 Primary alcohol(Secondary cyclicalcohols >>>>> Steric Hindrance)
 Benzylic alcohol>>>ortho-methoxybenzyl alcohol(Low yield)>>>>>Strong
chelation
 Allylic alcohol>>> carbon–carbon double bond (C=C) and the hydroxy group
were simultaneously reduced2/21/2020 28

29. A: Initial formation of the active species
B: Alcohol generated complex
C: β-H elimination
D: Regeneration of catalyst
Proposed Mechanism
2/21/2020 29

30. NH2NH2.H2O
NH2NH2.H2O
2/21/2020 30

31. Short Summary
 Efficient mainly with benzylic &
allylic alcohol
 Harsh conditions
 Highly concentrated
solution(10M)>>Scale up
 Stoichiometric innocuous
byproducts
 Practical reaction
conditions
 Synthetically benign
 Single step with High
selectivity on 1o alcohols
 Great functional group
tolerance
 Excellent chemoselectivity
 Great regioselectivity
 Iridium- and Ruthenium-
catalyzed deoxygenation
methods is that these are
precious metals
 Functional-group tolerant
 Selective in both primary and
Benzylic alcohol2/21/2020 31

32. C-C Bond Formation
Grignard-Type Reactions
Represented examples for the Ru-catalyzed addition of hydrazone to aldehydes and ketones.
 Ru-Catalyzed Addition of Hydrazones with
Aldehydes and Ketone
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33.  Presynthesize the Hydrazones
 Umpolung Carbanion
 Metal free surrogates
 Good chemoselectivity
 Good functional group tolerance
 Minor influence of the substituent
 Relatively complex substrate
is also tolerated
Characteristics
2/21/2020 33

34. Proposed mechanism for the ruthenium-catalyzed Grignard type addition of umpolung hydrazones
to carbonyls
Proposed mechanism
A: Rapidly metalate
B: Rearrangement
C: Addition product(N2)
2/21/2020 34
N2

35. Classical strategies for amine synthesis
 Nucleophilic addition of organometallic reagents
 Coupling of carbonyl compounds with imines(Mannich reaction)>>> Enolate chemistry
 Unpolung coupling of aldehydes and imines
Pinacol type coupling
Benzoin type coupling
 Aldehydes as alkyl carbanion equivalents for Amine synthesis
Ru-Catalyzed Addition of Hydrazone with Imines
Scope of aldehydes for the Ru-catalyzed addition of umpolung hydrazones to imine
2/21/2020 35

36. Characteristics
 [Ru(p-cymene)Cl2]2 providing the highest yield>>> The least expensive one
 Favored by electron-rich phosphines(1,2-bis(dimethylphosphino)ethane (dmpe) and
tri(tert-butyl)-Phosphine
 ligand-to-metal ratio(1:1)
 K3PO4(Superior reactivity)
 Cesium fluoride(CeF)>>>Additive
 Removal of a chloride(Silver triflate)
Scope of Substrates
 Aromatic aldehydes showed good reactivity
 Halide substituents had a minor influence on the reactivity(Ortho-Least reactive)
Aromatic
Aliphatic
Heterocyclic
2/21/2020 36

37. Ru-Catalyzed Addition of Hydrazone with CO2
CO2 as a carbon feedstock
 High abundance
 Low cost
 Low toxicity
 Renewability
Umpolung carboxylation
 Operationally simple
protocol
 High reactivity
 Selectivity under mild
conditions
 Good functional group
tolerance
 Readily scalable
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38. Cross-Coupling Reactions
Ni-Catalyzed Negishi-type Coupling
 Efficient construction of C–C bonds
 Ni(cod)2/PMe3 system with DBU
 Electron-donating PMe3, PPh2Me,Or PPhMe2 were
effective
 Chlorobenzene and fluorobenzene did not react
Ar-X Vinyl-X Alkyl-X
X= -Otf,Ots,Oms,Br,I etc…
2/21/2020 38

39.  Tunable site selectivity between aryl iodide and tosylate
 Broader substrate scope
 Greater functional group compatibility
 Chemoselectivity
Characteristics
2/21/2020 39

40. Proposed Mechanism
Proposed mechanism for the cross-couplings between aryl electrophiles
2/21/2020 40
Liu, Y. H.; Tang, D. L.; Cao, K. H.; Yu, L.; Han, J.; Xu, Q. J. Catal.2018

41. Pd-Catalyzed Tsuji–Trost Alkylation Reaction
Palladium-catalyzed allylic alkylation
Allylic electrophiles are less reactive
Using the electron-rich NHC ligand (IPr, 1,3-bis(2,6-diisopropylphenyl)
imidazole-2-ylidene)
Characteristics
 Good functional group compatibility(ortho,meta,para)
 Highly chemo- and regioselective C-alkylated products
 High to excellent yields
2/21/2020 41

42. 2/21/2020 42
A tentative mechanism for the palladium-catalyzed allylic alkylation of umpolung carbonyls

43. Conclusion
Exploring synthetic
chemistry inspired
from old classical
reactions
provide a foundation
for the next generation
of chemical syntheses
towards sustainability
Develop fundamental
reaction tools for more
efficient and greener
chemical transformations
Efficient transformation of
natural abundant organic
compounds into chemical
products

44. 2/21/2020 44
Reference
(1) Kishner, N. J. Russ. Phys. Chem. Soc. 1911, 43, 582.
(2) Wolff, L. Justus Liebigs Ann. Chem. 1912, 394, 86.
(3) Li, J. J. Name Reactions, 5th ed; Springer: Switzerland, 2014.
(4) Kuethe, J. T.; Childers, K. G.; Peng, Z.; Journet, M.; Humphrey, G.R.; Vickery, T.; Bachert, D.; Lam, T. T. Org. Process
Res. Dev. 2009,13, 576.
(5) Huang-Minion J. Am. Chem. Soc.1946, 68, 2487
(6) Osdene, T. S.; Timmis, G. M.; Maguire, M. H.; Shaw, G.;Goldwhite, H.; Saunders, B. C.; Clark, E. R.; Epstein, P.
F.;Lamchen, M.; Stephen, A. M.; Tipper, C. F. H.; Eaborn, C.;Mukerjee, S. K.; Seshadri, T. R.; Willenz, J.; Robinson,
R.;Thomas, A. F.; Hickman, J. R.; Kenyon, J.; Crocker, H. P.; Hall, R.H.; Burnell, R. H.; Taylor, W. I.; Watkins, W. M.; Barton,
D. H. R.;Ives, D. A. J.; Thomas, B. R. J. Chem. Soc. 1955, 2038.
(7) Grundon, M. F.; Henbest, H. B.; Scott, M. D. J. Chem. Soc. 1963,1855.
(8) Caglioti, L.; Magi, M. Tetrahedron 1963, 19, 1127.
(9) Cram, D. J.; Sahyun, M. R. V. J. Am. Chem. Soc. 1962, 84, 1734.
(10) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436.
(11) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; JohnWiley & Sons: New York, 1989.
(12) Grignard, V. Compt. Rend. 1890, 130, 1322.
(13) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;Pergamon Press: New York, 1992.
(14) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20,3437.

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