Organic synthesis
Kamil Paruch
Masaryk University, Brno
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Kamil Paruch Organic Synthesis C4450Reduction
LiAlH4
• strong, quite unselective reducing agent
J. Org. Chem. 1958, 23, 1483.
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Kamil Paruch Organic Synthesis C4450Reduction
J. Org. Chem. 1989, 54, 2620.
epoxides: typically, attack of H- on less substituted C
reduction of C=O: attack at less sterically hindered site
reduction of carbonyl compounds with LAH: typically no racemization (epimerization)
J. Chem. Soc., Perkin Trans. 1 1981, 909.
a,b-unsaturated ketones: predominant 1,2-reduction
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Kamil Paruch Organic Synthesis C4450Reduction
J. Chem. Soc., Perkin Trans. 1 1980, 212.
J. Org. Chem. 1989, 54, 1548.
LiAlH4 can act as a base:
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Kamil Paruch Organic Synthesis C4450Reduction
LiBH4 • reduction of esters to alcohols (in the presence of carboxylic acids, amides, nitriles)
Synlett. 2000, 1363.
BH3 : sold as BH3.THF or BH3.Me2S
• reduction of carboxylic acids in the presence of esters and other functional groups
• hydroboration of alkenes
J. Am. Chem. Soc. 1980, 102, 2117.
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Kamil Paruch Organic Synthesis C4450Reduction
LiEt3BH (Super Hydride)
• donor of strongly nucleophilic hydride
• reduction of halides, sulfonates, opening of epoxides (attack on less sterically hindered C)
J. Am. Chem. Soc. 1973, 95, 8486.
J. Am. Chem. Soc. 1983, 105, 6736.
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Kamil Paruch Organic Synthesis C4450Reduction
Selectrides
• bulky donors of hydride
• frequently used for diastereoselective reductions (substrate control)
L-Selectride K-Selectride
J. Org. Chem. 1988, 53, 4006.
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Kamil Paruch Organic Synthesis C4450Reduction
enantioselective reduction
Alpine-borane
Ipc2BCl
chiral oxazaborolidines + BH3
chiral boranes
• more reactive
• catalytic amount
• activation of BH3 by complexation
J. Am. Chem. Soc. 1993, 115, 4419.9
Kamil Paruch Organic Synthesis C4450Reduction
Corey-Bakshi-Shibata reduction (CBS reduction)
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Kamil Paruch Organic Synthesis C4450
enantioselective reduction
Reduction
catalytic hydrogenation (of b-ketoesters)
J. Am. Chem. Soc. 1988, 110, 629.
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Kamil Paruch Organic Synthesis C4450
enantioselective reduction
Reduction
DIBAL : i-Bu2AlH
• formation of stable tetrahedral adduct after first reduction -> another reduction does not proceed
• reduction of esters to aldehydes (low temperature)
Org. Synth. 1996, 74, 194.
• reduction of nitriles to imines (which are hydrolyzed to aldehydes during work-up)
J. Am. Chem. Soc. 1993, 115, 3146.
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Kamil Paruch Organic Synthesis C4450Reduction
NaBH4
• selective reductant: reduction of aldehydes, ketones and acid chlorides in the presence of other reducible
groups
• compatible with alcoholic solvents (CO2R, CN, NO2, epoxides)
J. Am. Chem. Soc. 1992, 114, 3162.
a,b-unsaturated ketones: 1,2-reduction (in combination with lanthanide salts - Luche reduction )
J. Am. Chem. Soc. 1978, 100, 2226.
J. Am. Chem. Soc. 1997, 119, 10073.13
Kamil Paruch Organic Synthesis C4450Reduction
• complementary to 1,2-reduction of a,b-unsaturated ketones, aldehydes, nitriles, sulfones
• highly chemoselective: isolated C=C, C=O and many protecting groups typically not affected
• [(Ph3P)CuH]6 commercially available
Stryker reduction: 1,4-reduction
note
Tetrahedron Lett. 1990, 31, 3237.
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Kamil Paruch Organic Synthesis C4450Reduction
chemoselective reduction of aldehydes vs. ketones
with NaBH(O-CH(CF3)2)3
Synlett 2008, 16, 2523.
reductive amination: NaBH4, NaBH(OAc)3, NaBH3CN
• selective reduction of imines and iminium salts; stable under mildly acidic conditions
• optimal pH: typically 4-5 (equilibrium of protonated/non-protonated carbonyl & imine & amine)
J. Am. Chem. Soc. 1988, 110, 4329.
Tetrahedron Lett. 1984, 25, 5449.
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Kamil Paruch Organic Synthesis C4450Reduction
note: „Cs effect“ mono-alkylation J. Org. Chem. 2002, 67, 674.
irreproducible in our hands: phenethyl amine + BnBr
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Kamil Paruch Organic Synthesis C4450Reduction
alkylative amination
• formally analogous to reductive amination -> complex tertiary amines (frequent motifs in medchem)
• but historically difficult to carry out Nature 2020, 581, 415.
Staudinger reaction
Tetrahedron Lett. 1983, 24, 763.
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Kamil Paruch Organic Synthesis C4450Reduction
„ionic hydrogenation“
• combination of proton donor (CF3COOH) and hydride donor (Et3SiH)
• typically selective with ketones, alkenes and lactoles
Angew. Chem. Int. Ed. Engl. 1999, 38, 2934.
SmI2
• reduction of aldehydes and ketones in the presence of carb. acids and esters
J. Am. Chem. Soc. 1990, 112, 7001.
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Kamil Paruch Organic Synthesis C4450Reduction
Clemmensen reduction
• strongly acidic conditions; limited use
J. Org. Chem. 1969, 34, 1109.
reduction of thioacetals (thioketals), also thiols, thioethers, sulfoxides and sulfones
• Ra-Ni (+ H2)
Heterocycles 1991, 32, 663.
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Kamil Paruch Organic Synthesis C4450Reduction
Kizhner-Wolff reduction
traditional protocol:
Can. J. Chem. 1979, 57, 1064.
low temperature variant: t-BuOK, DMSO
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Kamil Paruch Organic Synthesis C4450Reduction
Shapiro reaction
• ketones (aldehydes) –> tosylhydrazones -> alkenes
Can. J. Chem. 1983, 61, 1111.
reduction of tosylhydrazones by hydrides
• mild & chemoselective (esters, amides, nitro, nitriles… tolerated) removal of O from carbonyl
J. Org. Chem. 1991, 56, 2947.
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Kamil Paruch Organic Synthesis C4450Reduction
Barton-McCombie deoxygenation
J. Am. Chem. Soc. 1986, 108, 3443.
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Kamil Paruch Organic Synthesis C4450Reduction
radical dehalogenation
• radical source: Bu3SnH
• Br a I more reactive than Cl a F
• also useful for removal of NO2
J. Am. Chem. Soc. 1991, 113, 8980.
J. Org. Chem. 1979, 44, 151.
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Kamil Paruch Organic Synthesis C4450Reduction
radical reactions: possibility of alternative pathways (-> side reactions)
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Kamil Paruch Organic Synthesis C4450Reduction
dehalogenation with Zn/AcOH
• chemoselective reduction of a-haloketones, a,b-unsaturated ketones
J. Org. Chem. 1988, 53, 1100.
J. Org. Chem. 1989, 54, 2781.
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Kamil Paruch Organic Synthesis C4450Reduction
catalytic hydrogenation (of alkenes)
• substituted alkenes are typically less reactive
• syn- addition from sterically less hindered site
but: addition of H2 can be directed using proper polar substituents
J. Chem. Soc. 1957, 3107.
but:
Tetrahedron 1972, 28, 3583.
heterogenous: typically with Pd/C, Pd(OH)2, Pt, PtO2 etc.
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Kamil Paruch Organic Synthesis C4450Reduction
J. Am. Chem. Soc. 1985, 107, 4339.
homogenous
Wilkinson catalyst: RhCl(PPh3)3
• compatible with CO, COOR, CN, NO2
• stereoselective cis- hydrogenation
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Kamil Paruch Organic Synthesis C4450Reduction
Crabtree‘s catalyst:
• frequently used for directed hydrogenations
Organometallics 1987, 2, 681.
Crabtree: >99.9% <0.1%
Pd/C 20% 80%
(Pd/C: cis-isomer)
J. Am. Chem. Soc. 1983, 105, 1072.
(only the desired diastereomer)
J. Org. Chem. 2017, 82, 3382.
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Kamil Paruch Organic Synthesis C4450Reduction
asymmetric catalytic hydrogenation (of olefins)
• complexes of metals with chiral phosphines
J. Am. Chem. Soc. 1987, 109, 1596.
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Kamil Paruch Organic Synthesis C4450Reduction
reduction with diimide
• in situ generation
• selective cis- reduction of C=C
• tolerated: C=O, C=N, NO2, OBn etc.
J. Am. Chem. Soc. 1985, 107, 256.
J. Org. Chem. 1977, 42, 3987.
alternative generation of diimide: thermal decomposition
Tetrahedron 1976, 32, 2157.
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Kamil Paruch Organic Synthesis C4450Reduction
reduction of alkynes
cis: H2 + Lindlar catalyst (Pd/BaSO4)
J. Org. Chem. 1972, 37, 4317.
note. used also for chemoselective reduction of COCl to CHO (Rosenmund reduction)
Helv. Chim. Acta 1989, 72, 1400.
Helv. Chim. Acta 1990, 73, 405.
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Kamil Paruch Organic Synthesis C4450Reduction
newer protocols:
e.g. Ir catalyst in EtOH (serving as a reducing medium): conversion of 1 to 2
J. Am. Chem. Soc. 2021, 143, 4824.
trans: modern methods: Pd- or Ru-catalyzed semi-hydrogenation
Angew. Chem. Int. Ed. 2013, 52, 806.
Angew. Chem. Int. Ed. 2013, 52, 355.
• cyclic & acyclic alkynes
• tolerated: OH, OTs, NO2, SMe, COOH etc.
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Kamil Paruch Organic Synthesis C4450Reduction
trans: Na in liquid NH3
Birch reduction
• Na, K, Li in liquid NH3 -> reduction of aromatic rings
• product is generated from the corresponding radical-anion
(regioselectivity is given by its stabilization -> depends on substituents)
J. Org. Chem. 1977, 42, 2032.
J. Am. Chem. Soc. 1963, 85, 41.
J. Org. Chem. 1991, 56, 741.33
Kamil Paruch Organic Synthesis C4450Reduction
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Kamil Paruch Organic Synthesis C4450Reduction
Angew. Chem. Int. Ed. 2021, 60, 9666.
alkylation of the in situ formed radical-anion:
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Kamil Paruch Organic Synthesis C4450Reduction
visible light-driven Birch reduction
J. Am. Chem. Soc. 2020, 142, 13573.
modern (more user-friendly) variant of Birch reduction
Science 2021, 374, 741.
Li (wire) + NH2CH2CH2NH2 in THF, ice bath
elimination of H2O
Burgess reagent
J. Org. Chem. 1973, 38, 26.• for sec. & tert. OH
Martin sulfurane
• for sec. & tert. OH
J. Am. Chem. Soc. 1971, 93, 4327.
J. Am. Chem. Soc. 2005, 127, 11176.
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Kamil Paruch Organic Synthesis C4450Reduction