Reductive amination

Reductive amination
The reductive amination of aldehydes and ketones is an important method for the
synthesis of primary, secondary, and tertiary amines.
Iminium ions can be reduced selectively in the presence of their carbonyl precursors.
Reductive aminations are often conducted by in situ generation of the imine (iminium
ion) intermediate in the presence of a mild acid.
Reagents such as sodium cyanoborohydride and sodium triacetoxyborohydride
react selectively with iminium ions and are frequently used for reductive aminations.
Reductive amination - Mechanism
Applications in Asymmetric compounds
Reduction of Amides - Amine
Substrates
Amide
Hydride Donors
LiAlH4
DIBAL
NaAlH(OtBu)3
AlH3
NaBH4
NaCNBH4
Na(AcO) 3BH
B2H6
Li(Et)3
BH
H2
(catalyst)
Amine
Amine
or
Aldehyde
Amine
(slow)
Amine
--
--
Amine
(slow)
Amine
(slow)
Alcohol
(tertiary
amide)
Amine
A typical Reduction of amide with LiAlH4
LiAlH4 reduction of amides (R-C(=O)-NR'2) gives primary amines (RCH2- NH2), secondary amines
(R-CH2-NHR') or tertiary amines (R-CH2-NR'2) depending on the number of H's on N. The
intermediate formed in the first reaction of LiAlH4 with an amide is equivalent to that formed in the
first reaction when LiAlH4 reacts with other R-C(=O)-X compounds. However in the case of amides,
the X group is NR'2 and the -NR'2 anion is such a poor leaving group that an "O-Al" anion leaves
instead giving an intermediate iminium ion. Subsequent reduction of that iminium ion (or its imine
form) gives the amine.
Reduction of Amides with NaBH4
An expeditious and practical method for the reduction of various amides and lactams to
amines in good to excellent yields is consisted of activation with Tf2O followed by
reduction with sodium borohydride in THF at room temperature. This method offers
TBDPS-group tolerance, short reaction time, and a simple workup.
S.-H. Xiang, J. Xu, H.-Q. Yuan, P.-Q. Huang, Synlett, 2010, 1829-1832.
Reduction of carbamates
Reduction of Weinreb Amide
The Weinreb–Nahm ketone synthesis is a chemical reaction used to synthesize ketones.
Discovered ----- in 1981 by Steven M. Weinreb and Steven Nahm. The original reaction
involved two subsequent nucleophilic acyl substitutions: the conversion of an acid
chloride into an N,O-dimethylhydroxyamide, known as a Weinreb–Nahm amide, and
subsequent treatment of this species with an organometallic reagent such as
a Grignard reagent ororganolithium reagent. Nahm and Weinreb also reported the
synthesis of aldehydes by reduction of the amide with an excess of lithium aluminum
hydride.
http://en.wikipedia.org/wiki/Weinreb_ketone_synthesis
Reduction of Weinreb Amide - Mechanism
R2 = H-, R-
Reduction of Nitrile Group with metal Hydrides
Reduction of nitrile group to primary amine or aldehyde using metal hydride (LiAlH4 or
DIBAL) or hydrogen and a metal catalyst.
Reduction of Nitrile Group with Hydrogen + Metal
The carbon-nitrogen triple bond in a nitrile can also be reduced by reaction with
hydrogen gas in the presence of a variety of metal catalysts.
Commonly quoted catalysts are palladium, platinum or nickel.
The reaction will take place at a raised temperature and pressure. It is impossible to
give exact details because it will vary from catalyst to catalyst.
For example, ethanenitrile can be reduced to ethylamine by reaction with hydrogen in
the presence of a palladium catalyst.
Reduction of Nitro Group
Reduction to hydrocarbons
Hydrodenitration (replacement of a nitro group with hydrogen) is difficult to achieve, but
can be completed by catalytic hydrogenation over platinum on silica gel at high
temperatures. (M. J. Guttieri, M. J.; Maier, W. F. J. Org. Chem. 1984, 49, 2875–2880).
Reduction to Amines
Aliphatic nitro compounds can be reduced to aliphatic amines using several
different reagents: Catalytic hydrogenation using platinum(IV) oxide (PtO2) or Raney
nickel
Metal and acidic medium (H+)
Samarium diiodide
α,β-Unsaturated nitro compounds can be reduced to saturated amines using:
Catalytic hydrogenation over palladium-on-carbon
Iron metal
Lithium aluminium hydride (Note: Hydroxylamine and oxime impurities are typically
found.) http://en.wikipedia.org/wiki/Reduction_of_nitro_compounds and reference therein
Reduction of Nitro Group
Reduction to Amines
Aliphatic nitro compounds can be reduced to aliphatic amines using several
different reagents: Catalytic hydrogenation using platinum(IV) oxide (PtO2) or Raney
nickel
Metals, such as Fe, Zn, Sn can be used with H+ to reduce the nitro group by a
sequence of single electron transfer (SET)/protonation reactions
Samarium diiodide
α,β-Unsaturated nitro compounds can be reduced to saturated amines using:
Catalytic hydrogenation over palladium-on-carbon
Lithium aluminium hydride (Note: Hydroxylamine and oxime impurities are typically
found.) http://en.wikipedia.org/wiki/Reduction_of_nitro_compounds and reference therein
Reduction of Nitro Group
Reduction to Amines
Metals, such as Fe, Zn, Sn can be used with H+ to reduce the nitro group by a
sequence of single electron transfer (SET)/protonation reactions
Mechanism for the Zn/H+ reaction
Reduction of Nitro Group
Reduction to Amines
Samarium diiodide
Lithium aluminium hydride (Note: Hydroxylamine and oxime impurities are typically
found.)
Reduction of conjugated Nitroalkene
To Ketones and Aldehydes: Iron/HCl, Sodium hypophosphite (NaPO2H2 )/Raney
Nickel, Chromium(II) Chloride (CrCl2), 3% HCl, or lithium tris-sec-butylborohydride and
then subsequent acidic work give ketones or aldehydes.
To Oximes: sodium hypophosphite (NaPO2H2 )/Pd (C), CrCl2, Sodium stannite,
tin(II)chloride, lead or hydrogen/Pd (C) give oximes.
Cathodic reduction of a nitroalkene can give the oxime in good yield.
Wessling, M.; Schäfer, H.J. "Cathodic reduction of 1-nitroalkenes to oximes and primary amines". Chem.
Ber. 1991, 124, 2303–2306. and http://en.wikipedia.org/wiki/Electrosynthesis#cite_note-9
Reduction of conjugated Nitroalkene
At higher negative reduction potentials, the nitroalkene can be reduced further, giving
the primary amine but with lower yield
Wessling, M.; Schäfer, H.J. "Cathodic reduction of 1-nitroalkenes to oximes and primary amines". Chem.
Ber. 1991, 124, 2303–2306. and http://en.wikipedia.org/wiki/Electrosynthesis#cite_note-9
Reduction of N-Heterocycles
Common Reduction Methods:
Stoichiometric reactions with alkali metals in alcohol or ammonia
Borohydrides
Reduced pyridines (reduction by Hantsch’s ester or disproportionation of
dihydropyridines)
Regioselective hydrosilylation of pyridines to 1,4-dihydropyridines
Reduction of N-Heterocycles
Stoichiometric reactions with alkali metals in alcohol --- Dissolved metal reduction --Birch Reduction
Described by Australian chemist Arthur Birch (1915–1995) ---- Converts aromatic
compounds having a benzenoid ring into a product, 1,4-cyclohexadienes, in which two
hydrogen atoms have been attached on opposite ends of the molecule. It is the organic
reduction of aromatic rings in liquid ammonia with sodium, lithium or potassium and
an alcohol, such as ethanol and tert-butanol. This reaction is quite
unlike catalytic hydrogenation, which usually reduces the aromatic ring all the way to
a cyclohexane.
Mechanism
http://www.organic-chemistry.org/namedreactions/birch-reduction.shtm
Advancement
“ Abstract: The reduction of a series of hetero- and carbocyclic aromatic compounds
under ammonia free conditions is described. By using LiDBB (Lithium Di-tertbutylbiphenyl) as a source of electrons, bis(methoxyethyl)amine (BMEA) as a
protonating agent, and THF as a solvent, we were able to accomplish reductions more
usually performed under Birch-type conditions. Moreover, the use of these conditions
was further enhanced by the tolerance of the reducing system toward reactive
electrophiles that cannot be used successfully in ammonia.”
Donohoe, T. J.; House, D. J. Org. Chem., 2002, 67 (14), pp 5015–5018
Mechanism
In this article it was “demonstrated that the conditions traditionally used for accomplishing a Birch
reduction of both pyrroles and furans (i.e., Na or Li in ammonia) could be replaced by an
“ammonia free” variant that provides a practicable alternative for partial reduction and reductive
alkylation. In this new regimen, lithium naphthalenide 2 provides the electrons, and
bis(methoxyethyl)amine (BMEA) is a convenient acid. A proposed mechanism shows belows
described that the reaction proceeds via an intermediate, reactive, dianion species B capable of
deprotonating an amine.”
Donohoe, T. J.; House, D. J. Org. Chem., 2002, 67 (14), pp 5015–5018
Reduction of N-Heterocycles
Borohydrides (zinc borohydride)
Even Lithium triethylborohydride (super hydride) gives low reduction product in the case
of quinoline.
Ranu, B. C.; Jana, U.; Sarkar, A. Synth. Commun. 1998, 28, 485
Reduced pyridines (reduction by Hantsch’s ester or disproportionation of
dihydropyridines)
Abstract: A new double axially chiral phosphoric acid catalysts 1 based on bis-binol
scaffold were used for asymmetric transfer hydrogenation. 2-Aryl- and 2-alkylsubstituted quinolines gave tetrahydroquinolines in excellent yields and with up to
98 % ee and 2,3-disubstituted tetrahydroquinolines were prepared in high diastereo- and
enantioselectivities (up to >20:1 and 92 % ee)”.
Guo, Q. S.; Du, D. M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759
Reduction of N-Heterocycles
Zheng, C.; You, S.-L. Transfer hydrogenation with Hantzsch esters and related organic hydridedonors,
Chem. Soc. Rev., 2012,41, 2498-2518
Reduction of N-Heterocycles
Regioselective hydrosilylation of pyridines to 1,4-dihydropyridines
Nikonov , G. I. et al. Organometallics, 2013, 32 (16), pp 4457–4464
Mechanism
Ionic hydrosilylation
mechanism for catalytic
hydrosilylation of pyridines.
Nikonov , G. I. et al. Organometallics, 2013, 32 (16), pp 4457–4464