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Barton Deoxygenation
Radical-induced deoxygenation of O-thiocarbonate derivatives of alcohols in the
presence of hydrogen-atom donors is a versatile and widely-used method for the
preparation of an alkane from the corresponding alcohol.
The Barton deoxygenation is a two-step process. In the initial step, the alcohol is
acylated to generate an O-thiocarbonate derivative, which is then typically reduced by
heating in an aprotic solvent in the presence of a hydrogen-atom donor.
The method has been adapted for the deoxygenation of primary, secondary, and
tertiary alcohols. In addition, monodeoxygenation of 1,2- and 1,3-diols has been
achieved.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
http://www.organic-chemistry.org/namedreactions/barton-mccombie-reaction.shtm
Barton Deoxygenation - Mechanism
Mechanism of this reduction proceeds by attack of a tin radical on the thiocarbonyl sulfur
atom. Subsequent fragmentation of this intermediate generates an alkyl radical which
propagates the chain.
Initiation
The catalytic cycle, in which low concentration of .SnBu3 effects the reaction:
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
http://www.organic-chemistry.org/namedreactions/barton-mccombie-reaction.shtm
Applications
In the following example, the radical generated during the deoxygenation reaction
undergoes 6-exo-trig radical cyclization. (Baldwin's Rules for Ring Closure)
Tin-Free Barton-Type Reduction
Employing Water as a Hydrogen
Atom Source:
Simple concentration of the
reaction mixture provides products
in high purity.
Trialkylborane acts as both the
radical initiator and an activator of
water prior to hydrogen
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Barton Decarboxylation
O-Esters of thiohydroxamic acids are reduced in a radical chain reaction by tin
hydride reagents.
These are typically prepared by the reaction of commercial N-hydroxypyridine-2thione with activated carboxylic esters.
Proceed via free radical pathway
Barton, D. H. R.; Circh, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun. 1983, 939-941.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Barton Decarboxylation - Mechanism
The initiation of the Barton
Decarboxylation ( Bu3Sn-H ->
Bu3Sn. ) is effected with a radical
initiator, and as with the BartonMcCombie Deoxygenation, the
driving force for the reaction itself
is the formation of the stable S-Sn
bond.
In addition, Barton esters can also be cleaved photolytically or thermally:
If an excess of a suitable radical
trapping agent is present in the
reaction medium, substitution
will occur; otherwise, radical
recombination takes place to
give the pyridyl sulfide:
http://www.organic-chemistry.org/namedreactions/barton-decarboxylation.shtm
Diazene-Mediated Deoxygenation
Deoxygenation proceeds by Mitsunobu displacement of the alcohol with
onitrobenzenesulfonylhydrazine (NBSH) followed by in situ elimination of o-nitrobenzene
sulfinic acid. The resulting monoalkyl diazene is proposed to decompose by a freeradical mechanism to form deoxygenated products.
The deoxygenation is carried out in a single step without using metal hydride
reagents.
The method is found to work well for unhindered alcohols, but sterically encumbered
and‎β- oxygenated alcohols fail to undergo the Mitsunobu displacement and are
recovered unchanged from the reaction mixture.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Applications
In the following example, the radical generated from decomposition of the diazene
intermediate underwent a rapid 5-exo-trig radical cyclization. This generated a second
radical that was trapped with oxygen to provide the cyclic carbinol shown after work-up
with methyl sulfide.
Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc. 1997, 119, 8572-8573.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Deoxygenation via Alkyl Tosylates
p-Toluenesulfonate ester derivatives of alcohols are reduced to the corresponding
alkanes with certain powerful metal hydrides.
Among hydride sources, lithium triethylborohydride (Super Hydride, LiEt3BH) has
been shown to rapidly reduce alkyl tosylates efficiently, even thoes derived from
hindered alcohols.
Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41, 3064-3066
Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chem. Soc. 1990, 112, 5290-5313.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Advancement
In related studies, it was shown that alkyllithium reagents add to N-tert-butyldimethylsilyl
aldehyde tosylhydrazones at –78 °C and that the resulting adducts can be made to
extrude dinitrogen in a free-radical process.
Myers, A. G.; Movassaghi, M. J. Am. Chem. Soc. 1998, 120, 8891-8892.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Corey–Bakshi–Shibata (CBS) reduction
Corey–Bakshi–Shibata (CBS) reduction is a type of reduction in which reaction in
which an ketone is enantioselectively reduced to produce the corresponding chiral
alcohol, non-racemic alcohol. For this reaction a mixture of borane and a chiral
oxazaborolidine as catalyst (CBS catalyst) is used. CBS reagents predictably give one
enantiomer as the major product of ketone reduction, as illustrated with
acetophenone as the starting material. Using CIP rules if the substituents rank high
priority to low priority clockwise then this is the Re –face . If they rank high priority to
low priority anti-clockwise then this is the Si-face.
• Borane in catalyst is Lewis acid; Nitrogen is Lewis base to coordinate second borane
• One B—H bond serves as the source of hydride in this reduction. Borane coordination
increases Lewis acidity of catalyst (at B) and activates BH3 as hydride donor
• Carbonyl coordination trans to bulky or electron rich group
• Hydride transfer via 6-membered TS
• Disproportionation between 8 and BH3 + (RO)2BH allows <1 equiv BH3
http://en.wikipedia.org/wiki/Corey%E2%80%93Itsuno_reduction
CBS - Mechanism
http://en.wikipedia.org/wiki/Corey%E2%80%93Itsuno_reduction
CBS – Mechanism – key points
First step coordination of BH3 to the nitrogen atom of the oxazaborolidine CBS
catalyst
Activation the BH3 as a hydride donor which enhance the Lewis acidity of the
catalyst’s endocyclic boron
Endocyclic boron of the catalyst coordinates to the ketone at the sterically
more accessible electron lone pair (i.e. the lone pair closer to the smaller
substituent, Rs).
Binding in 3 acts to minimize the steric interactions between the ketone and
the R’ group of the catalyst aligns the carbonyl and the coordinated borane for a
favorable, face-selective hydride transfer through a six-membered transition
state 4
Hydride transfer yields chiral boron enolate 5, which upon acidic workup yields
the chiral alcohol 6.
Last step to regenerate the catalyst may take place by two different pathways
(Path 1 or 2).
The predominant driving force for this face-selective, intramolecular hydride transfer is
the simultaneous activation of the borane reagent by coordination to the Lewis basic
nitrogen and the enhancement of the Lewis acidity of the endocyclic catalyst boron for
coordination to the ketone.
http://en.wikipedia.org/wiki/Corey%E2%80%93Itsuno_reduction
Radical Dehalogenation
Alkyl bromides and iodides are reduced efficiently to the corresponding alkanes in a
free-radical chain mechanism with tri-n-butyltin hydride.
The reduction of chlorides usually requires more forcing reaction conditions and alkyl
fluorides are practically unreactive.
The reactivity of alkyl halides parallels the thermodynamic stability of the radical
produced and follows the order: tertiary > secondary > primary.
Triethylboron-oxygen is a highly effective free-radical initiator. Reduction of bromides
and iodides can occur at –78 °C with this initiator.
Neumann, W. P. Synthesis 1987, 665-683.
Curran, D. E.; Chen, M.-H. Tetrahedron Lett. 1985, 26, 4991-4994.
In the above reaction, the radical generated during the dehalogenation reaction
undergoes a tandem radical cyclization.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Radical Cyclization
The radical can react with multiple bonds in an intramolecular fashion to yield cyclized radical intermediates. The
two ends of the multiple bond constitute two possible sites of reaction. If the radical in the resulting intermediate
ends up outside of the ring, the attack is termed "exo"; if it ends up inside the newly formed ring, the attack is
called "endo." In many cases, exo cyclization is favored over endo cyclization (macrocyclizations constitute the
major exception to this rule). 5-hexenyl radicals are the most synthetically useful intermediates for radical
cyclizations, because cyclization is extremely rapid and exo selective. Although the exo radical is less
thermodynamically stable than the endo radical, the more rapid exo cyclization is rationalized by better
orbital overlap in the chair-like exo transition state.
http://en.wikipedia.org/wiki/Radical_cyclization
Reduction of Acid Halides
The Rosemund reduction is a classic method for the preparation of aldehydes from
carboxylic acids by the selective hydrogenation of the corresponding acid chloride.
Over-reduction and decarbonylation of the aldehyde product can limit the usefulness
of the Rosemund protocol.
The reduction is carried out by bubbling hydrogen through a hot solution of the acid
chloride in which the catalyst, usually palladium on barium sulfate, is suspended.
Sodium tri-tert-butoxyaluminohydride (STBA), generated by the reaction of sodium
aluminum hydride with 3 equivalents of tert-butyl alcohol, reduces aliphatic and aromatic
acid chlorides to the corresponding aldehydes in high yields.
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Hydrogenation of Olefines
The‎reduction‎of‎alkenes‎by‎hydrogen‎in‎the‎presence‎of‎a‎metal‎catalyst‎(“catalytic‎hydrogenation”)‎
a reaction developed by Paul Sabatier and got Nobel Prize for Chemistry in 1912 along with Victor
Grignard. The products of this reaction are a part of our daily lives – modern margarine is produced
from hydrogenation of vegetable oils.
Heterogeneous catalysts means the form of catalysis where the phase of
the catalyst differs from that of the reactants; like finely divided insoluble platinum,
palladium or nickel catalysts.
Homogeneous catalysts means that involve a catalyst in the same phase as
the reactants; catalyst (typically rhodium or ruthenium based) is soluble in the reaction
medium – Wilkinson’s‎catalyst‎is‎[RhCl(PPh3)3]
This process is called a reduction or hydrogenation
An unsaturated compound becomes a saturated (with hydrogen) compound
http://en.wikipedia.org/wiki/Hydrogenation
Mechanism
Heterogeneous catalysts
Homogeneous catalysts
http://en.wikipedia.org/wiki/Asymmetric_hydrogenation
Hydrogenation of Alkynes
Hydrogenation: syn addition – Synthesis of cis-alkene
It involve the treatment of the alkyne with hydrogen gas and a metal catalyst (Ni, Pd. Pt
etc). To modify the behavior of the catalyst such that it is powerful enough to reduce the
first pi‎bond‎but‎not‎reactive‎enough‎to‎affect‎the‎second.‎In‎other‎words,‎“poisoning”‎its‎
reactivity. In practice, this is done by combining palladium on carbon with lead
carbonate (PbCO3) and quinoline (an aromatic amine). The resulting mixture, known as
“Lindlar’s‎catalyst”‎after‎its‎inventor,‎is‎effective‎for‎the‎partial‎reduction‎of‎alkynes.
Other Similar conitions; Ni–B (nickel boride), Pd-CaCO3, palladium on barium sulfate,
Pd-CaCO3-quinoline
Lindlar, H.; Dubuis, R. (1973), "Palladium Catalyst for Partial Reduction of Acetylenes", Org. Synth.; Coll. Vol. 5:
880
Hydrogenation of Alkynes
Hydrogenation: anti addition – Synthesis of trans-alkenes
A dissolving metal reaction which uses lithium or sodium metal in low temperature
ammonia or amine solvent produces trans-alkenes.
This dissolving metal reduction process is different than other catalytic hydrogenation
process. In this reaction, electrons from Na metal sequentially add to the alkyne,
resulting in an anion that is protonated by the NH3 solvent. An interesting aspect of this
reaction is the stereochemistry: due to electronic repulsion, the geometry of the
resulting alkene is trans.
The dissolving metal reductions always form the more stable trans product
preferentially.
Hydrogenation of Alkynes - Mechanism
The trans alkene is formed because the vinyl carbanion intermediate that is formed is
more stable when the larger R groups are further away from each other to avoid steric
interactions. Protonation of this anion leads to the more stable trans adduct.
Sodium metal has an extremely
low ionization energy and will
readily give up its electron.
http://www.masterorganicchemistry.com/
Reduction of α,β-Unsaturated Carbonyl to carbonyl
The carbon-carbon‎double‎bond‎of‎α,β-unsaturated carbonyl compounds can be
reduced selectively by catalytic hydrogenation, affording the corresponding carbonyl
compounds.
This method is not compatible with olefins, alkynes, and halides.
α,β-Unsaturated carbonyl compounds undergo selective 1,4-reduction with
[(Ph3P)CuH]6.
[(Ph3P)CuH]6 is stable indefinitely, provided that the reagent is stored under an inert
atmosphere. The reagent can be weighed quickly in the air, but the reaction solutions
must be deoxygenated. The reaction is unaffected by the presence of water (in fact,
deoxygenated water is often added as a proton source).
The reduction is highly steroselective, with addition occurring to the less hindered face of
the olefin:
http://www.masterorganicchemistry.com/
Reduction of miscellaneous species
Reduction deselenation
Beilstein J. Org. Chem. 2013, 9, 2669–2674
Reduction of miscellaneous species
Reduction silylation
JOC, 1979, 44, 421
Reduction of miscellaneous species
Reduction desilylation
Org. Lett. 2006, 8, 179–182
Reduction of miscellaneous species
Corey–Winter olefin synthesis
Mechanism
The reaction mechanism involves the formation of a cyclic thio-carbonate from the diol and thiophosgene. The
second step involves treatment with trimethyl phosphite, which attacks the sulfur atom, producing
S=P(OMe)3 (driven by the formation of a strong P=S double bond) and leaving a carbene. This carbene collapses
with loss of carbon dioxide to give the olefin.
http://en.wikipedia.org/wiki/Corey%E2%80%93Winter_olefin_synthesis
Reduction of miscellaneous species
Eastwood Deoxygenation: A vicinal diol is treated with ethyl orthoformate at high
temperature (140-180 °C), followed by pyrolysis of the resulting cyclic orthoformate
(160-220 °C) in the presence of a carboxylic acid (typically acetic acid) --- The
elimination is stereospecific --- Not suitable for functionalized substrates.
Crank, G.; Eastwood, E. W. Aust. J. Chem. 1964, 17, 1385
Base Induced Decomposition of Benzylidene Acetals
Key points;
The elimination is stereospecific.
Long reaction times and high temperature under extremely basic conditions make this
an unsuitable method for functionalized substrates.
J. Chem. Soc. Chem. Commun. 1964, 1593
www.chem.harvard.edu/groups/myers/handouts/1_Reduction.pdf‎
Reduction of miscellaneous species
Desulfurization
Beilstein J. Org. Chem. 2010, 6, No. 17.
Reduction of miscellaneous species
Desulfonylation
http://en.wikipedia.org/wiki/Desulfonylation_reactions
Reduction of Alkyl halides
Addition of Hydride
Addition of metals
R3C-X + 2Li ——> R3C-Li + LiX
R3C-X + Mg ——> R3C-MgX
An Alkyl Lithium Reagent
A Grignard Reagent
Reduction of Alkyl halides
Mechanism
J. Org. Chem., 2010, 75 (8), pp 2645–2650
Reduction of epoxides
Reduction cynation
Selective Cleavage of C-O and/or Si-O Bonds
Komiya, S. et al. Organometallics, 1985, 4, 1504-1508
Mechanism – cleavage of C-O bond
Komiya, S. et al. Organometallics, 1985, 4, 1504-1508
Mechanism – cleavage of Si-O bond
Komiya, S. et al. Organometallics, 1985, 4, 1504-1508
Mechanism – cleavage of Si-O bond
Komiya, S. et al. Organometallics, 1985, 4, 1504-1508
Overview - Reduction