Categories: C-N Bond Formation > Amines > Secondary and tertiary amines, Aryl amines >
Reductive Amination
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 Reduction of imines |
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Hitchhiker's guide to reductive amination
E. Podyacheva, O. I. Afanasyev, A. A. Tsygankov, M. Makarova, D. Chusov
By optimizing the metal hydride/ammonia mediated reductive amination of
aldehydes and hemiacetals, primary amines were selectively prepared with no or
minimal formation of the usual secondary and tertiary amine byproduct. The
methodology was performed on a range of functionalized aldehyde substrates,
including in situ formed aldehydes from a Vasella reaction.
E. M. Dangerfield, C. H. Plunkett, A. L. Win-Mason, B. L. Stocker, M. S. M.
Timmer, J. Org. Chem., 2010,
75, 5470-5477.
Cp*Ir complexes bearing a 2-picolinamide moiety effectively catalyze a direct
reductive amination of ketones to give primary amines under transfer
hydrogenation conditions using ammonium formate as both the nitrogen and
hydrogen source.
K. Tanaka, T. Miki, K. Murata, A. Yamaguchi, Y. Kayaki, S. Kuwata, T. Ikariya,
M. Watanabe, J. Org. Chem., 2019,
84, 10962-10977.
A simple and convenient procedure enables the reductive alkylation of primary
and secondary amines and N,N-dimethylation of amino acids using sodium
borohydride as reducing agent in 2,2,2- trifluoroethanol without use of a
catalyst or any other additive. The solvent can be revovered and reused.
M. Taibakhsh, R. Hosseinzadeh, H. Alinezhad, S. Ghahari, A. Heydari, S. Khaksar, Synthesis, 2011,
490-496.
Sodium triacetoxyborohydride is a general, mild, and selective reducing agent
for the reductive amination of various aldehydes and ketones. 1,2-Dichloroethane
(DCE) is the preferred reaction solvent, but reactions can also be carried out
in tetrahydrofuran and occasionally in acetonitrile. Acetic acid may be used as
catalyst with ketone reactions. Acid sensitive functional groups
such as acetals and ketals, and reducible functional groups such as C-C multiple
bonds and cyano and nitro groups are tolerated.
A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C.
A. Maryanoff, R. D. Shah, J. Org. Chem., 1996, 61,
3849-3862.
In the reductive amination of some aldehydes with primary amines where dialkylation is a problem, a stepwise procedure involving imine formation in MeOH followed by reduction with
NaBH4 was developed.
A. F. Abdel-Magid, K. G. Carson, B. D. Harris, C.
A. Maryanoff, R. D. Shah, J. Org. Chem., 1996, 61,
3849-3862.
Stannous chloride catalyzes a chemoselective reductive amination of various
carbonyl compounds with aromatic amines using inexpensive
polymethylhydrosiloxane as reducing agent in methanol. The present method is
applicable for the synthesis of tertiary and secondary amines.
O. S. Nayal, V. Bhatt, S. Sharma, N. Kumar, J. Org. Chem.,
2015,
80, 5912-5918.
Reductive amination between aldehydes or ketones and amines occurs smoothly
within the hydrophobic cores of nanomicelles in water. A broad range of
substrates can be converted under mild conditions in the presence of 0.20 mol %
Pd/C and triethylsilane, leading to high chemical yields of the desired
secondary and tertiary amines.
R. R. Thakore, B. S. Takale, G. Casotti, E. S. Gao, H. S. Jin, B. H. Lipshutz,
Org. Lett., 2020, 22, 6324-6329.
Dibutyltin dichloride catalyzes a direct reductive amination of aldehydes and
ketones in the presence of phenylsilane as a stoichiometric reductant. Suitable
amines included anilines and dialkylamines but not monoalkylamines.
R. Apodaca, W. Xiao,
Org. Lett., 2001, 3, 1745-1748.
The [RuCl2(p-cymene)]2/Ph2SiH2
catalytic system is very efficient for the reductive amination of aldehydes with
anilines to provide secondary amines and tertiary amines in good yields. The
method is highly chemoselective and tolerates a wide range of functional groups,
such as NO2, CN, CO2Me, F, Cl, Br, OMe, Me, furyl and
alkyl.
B. Li, J. Zheng, W. Zeng, Y. Li, L. Chen, Synthesis, 2017,
49, 1349-1355.
In a straightforward process for the N-alkylation of amines, readily available
carboxylic acids and silanes as the hydride source enable an effective C-N bond
construction under mild conditions and allow obtaining a broad range of
alkylated secondary and tertiary amines, including fluoroalkyl-substituted
anilines as well as the bioactive compound Cinacalcet HCl.
I. Sorribes, K. Jung, M. Beller,
J. Am. Chem. Soc., 2014,
136, 14314-14319.
Aldehydes and ketones were easily converted to the corresponding amines by
the reaction of amines in methanol using decaborane (B10H14)
at room temperature under nitrogen. The reaction is simple and efficient.
J. W. Bae, S. H. Lee, Y. J. Cho, C. M. Yoon, J. Chem. Soc., Perkin Trans. 1, 2000, 145-146.
A cyclopentadienyl iron(II) tricarbonyl complex is
able to catalyze a chemoselective reductive alkylation of various functionalized
amines with functionalized aldehydes at room temperature. The reaction tolerates alkenes, esters, ketones, acetals, unprotected hydroxyl groups, and
phosphines.
A. Lator, Q. G. Gaillard, D. S. Mérel, J.-F. Lohier, S. Gaillard, A. Poater,
J.-L. Renau, J. Org. Chem., 2019, 84,
6813-6829.
Cobalt-rhodium heterobimetallic nanoparticles catalyze a tandem reductive
amination of aldehydes with nitroaromatics without any additives under mild
conditions (1 atm H2 and 25 °C). This procedure can be scaled up to
the gram scale, and the catalyst can be reused more than six times without loss
of activity.
I. Choi, S. Chun, Y. K. Chung, J. Org. Chem.,
2017, 82, 12771-12777.
A copper-catalyzed protocol for reductive methylation of amines and imine with
formic acid as a C1 source and phenylsilane as a reductant provides the
corresponding methylamines in good to excellent yields under mild conditions.
C. Qiao, X.-F. Liu, X. Liu, L.-N. He, Org. Lett.,
2017, 19, 1490-1493.
Reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH
system is highly chemoselective and can be applied to various cyclic, acyclic,
aromatic, and aliphatic amines. Functionalities including ester, hydroxyl,
carboxylic acid, and olefin are tolerated.
O.-Y. Lee, K.-L. Law, C.-Y. Ho, D. Yang, J. Org. Chem., 2008,
73, 8829-8837.
A simple and convenient procedure allows the reductive amination of aldehydes
and ketones using sodium borohydride as reducing agent and boric acid, p-toluenesulfonic
acid monohydrate or benzoic acid as activator under solvent-free conditions.
B. T. Cho, S. K. Kang, Tetrahedron, 2005,
61, 5725-5734.
Nickel nanoparticles catalyse the reductive amination of aldehydes by transfer
hydrogenation with isopropanol at 76°C.
F. Alonso, P. Riente, M. Yus, Synlett, 2008, 1289-1292.
N-heterocyclic carbene boranes (NHC-boranes) are among the most nucleophilic
classes of neutral hydride donors. Reductions of highly electron-poor C=N and
C=C bonds provide hydrogenation products along with new, stable borylated
products. The results suggest that NHC-boranes have considerable untapped
potential as neutral organic reductants.
M. Horn, H. Mayr, E. Lacôte, E. Merling, J. Deaner, S. Well, T. McFadden, D. P. Curran, Org. Lett., 2012,
14, 82-85.
An effective reductive alkylation of electron-deficient o-chloroarylamines
was developed. The derived N-alkylated o-chloroarylamines were
elaborated to N-alkylazaindoles and N-alkylindoles via a novel
one-pot process comprising copper-free Sonogashira alkynylation and a
base-mediated indolization reaction.
M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett.,
2006,
8, 3307-3310.
An efficient methodology for the reductive alkylation of secondary amines with
aldehydes and Et3SiH using an iridium complex as a catalyst has been developed. In addition, a cheaper, easy-to-handle, and
environmentally friendly reducing reagent such as polymethylhydrosiloxane (PMHS)
in place of Et3SiH was also useful.
T. Mizuta, S. Sakaguchi, Y. Ishii, J. Org. Chem., 2005,
70, 2195-2199.
An oxidation/imine-iminium formation/reduction cascade using
TEMPO-BAIB-HEH-Brønsted acid catalysis in DMPU as solvent enables a mild and
atom-economical nonepimerizing chemo- and enantioselective N-alkylating
procedure of amines with alcohols.
I. A. Khan, A. K. Saxena, J. Org. Chem., 2013,
78, 11656-11669.
Copper N-heterocyclic carbene complexes serve as catalysts for both aerobic
oxidation of alcohols to aldehydes and reduction of imines to amines. A one-pot
tandem synthetic strategy affords useful secondary amines from benzylic alcohols
and anilines via an oxidation-reduction strategy.
L.-W. Zhan, L. Han, P. Xing, B. Jiang, Org. Lett.,
2015,
17, 5990-5993.
Cooperative catalysis of an Ir(III)-diamine complex and a chiral phosphoric
acid or its conjugate base enables a direct reductive amination of a wide range
of ketones.
C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc., 2009,
131, 6967-6969.
A direct and efficient palladium-catalyzed reductive coupling of nitroarenes
with phenols provides various N-cyclohexylaniline derivatives in good
yields using safe and inexpensive sodium formate as the hydrogen donor.
K.-J. Liu, X.-L. Zeng, Y. Zhang, Y. Wang, X.-S. Xiao, H. Yue, M. Wang, Z. Tang,
W.-M. He, Synthesis, 2018, 50,
4637-4644.
A reductive cross-amination between imine intermediates generated through
partial hydrogenation of aniline or nitroarene derivatives and alkylamines
provides N-alkylated cyclohexylamine derivatives in the presence of
heterogeneous Rh/Pt bimetallic nanoparticles under mild conditions. The catalyst
was recovered and reused for five runs, keeping high activity.
A. Suzuki, H. Miyamura, S. Kobayashi, Synlett, 2019,
30,
387-392.
Use of porous TiO2 nanosheets-supported Pt nanoparticles (Pt/P-TiO2)
as heterogeneous catalyst enables a challenging reductive amination of
biomass-derived levulinic acid at ambient temperature and H2 pressure.
Pt/P-TiO2 also showed good applicability for reductive amination of
levulinic esters, 4-acetylbutyric acid, 2-acetylbenzoic acid, and
2-carboxybenzaldehyde.
C. Xie, J. Song, H. Wu, Y. Hu, H. Liu, Z. Zhang, P. Zhang, B. Chen, B. Han, J. Am. Chem. Soc.,
2019,
141, 4002-4009.
α-Imino esters derived from aryl and alkyl keto esters could be reduced
to the corresponding α-amino esters in excellent yields and in high enantiomeric
excesses using 5 mol-% of a chiral phosphoric acid as catalyst, Hantzsch ester
as hydride donor, and toluene as solvent.
G. Li, Y. Liang, J. C. Antilla, J. Am. Chem. Soc., 2007,
129, 5830-5831.
Brønsted acid catalysis enables highly efficient, regioselective, and
enantioselective transfer hydrogenation of α-keto ketimines and reductive
amination of diketones. A series of chiral α-amino ketones is prepared in high
yields, excellent regioselectivities, and enantioselectivities.
W. Wen, Y. Zeng, L.-Y. Peng, L.-N. Fu, Q.-X. Guo, Org. Lett.,
2015,
17, 3922-3925.
A direct reductive amination of ketones using the Hantzsch ester in the presence
of S-benzyl isothiouronium chloride as a recoverable organocatalyst
converts a wide range of ketones as well as aryl amines to the expected products
in good yields.
Q. P. B. Nguyen, T. H. Kim, Synthesis, 2012, 44,
1977-1982.
A biomimetic direct reductive amination of ketones relies on selective imine
activation by hydrogen bond formation with thiourea as hydrogen bond donor
and utilizes the Hantzsch ester for transfer hydrogenation. The method
allows the efficient synthesis of structurally diverse amines.
D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter, S. Rudolph, Org. Lett.,
2006,
8, 741-744.
A hydrogen-bond-catalyzed, acid- and metal-free direct reductive amination of aldehydes uses thiourea as organocatalyst and the
Hantzsch ester for transfer-hydrogenation. This methods allows for the high-yielding
synthesis of diverse amines.
D. Menche, F. Arikan, Synlett,
2006, 841-844.
A selective and direct access to secondary amines by reductive
mono-N-alkylation of primary amines with carbonyl compounds in the presence
of Ti(i-PrO)4 and NaBH4 gave exclusively
secondary amines.
H. J. Kumpaty, S. Bhattacharyya, E. W. Rehr, A. M. Gonzalez, Synthesis,
2003, 2206-2210.
An experimentally simple Microwave-assisted reductive alkylation of methyl
carbamate with a range of aldehydes provides, after basic work-up, structurally
diverse primary amines. This method is particularly amenable to high-throughput
synthesis.
F. Lehmann, M. Scobie, Synthesis, 2008,
1679-1681.
Treatment of ketones with
ammonia in ethanol and titanium(IV) isopropoxide, followed by in situ reduction
with sodium borohydride allows a highly chemoselective reductive
mono-alkylation of ammonia. A simple workup afforded primary amines in good to
excellent yields. Reductive alkylation of ammonia with aldehydes afforded the corresponding symmetrical secondary amines selectively.
B. Miriyala, S.
Bhattacharyya, J. S. Williamson, Tetrahedron, 2004, 60,
1463-1471.
A mild and efficient one-pot
reductive amination of aldehydes and ketones with amines using α-picoline-borane
as a reducing agent in the presence of small amounts of AcOH is described.
The reaction has been carried out in MeOH, in H2O, and in neat
conditions. This is the first successful reductive amination in water and
in neat conditions.
S. Sato, T. Sakamoto, E. Miyazawa, Y. Kikugawa, Tetrahedron,
2004, 60, 7899-7906.
N-Alkylaminobenzenes
were prepared in a simple and efficient one-pot synthesis by reduction of
nitrobenzenes followed by reductive amination with decaborane (B10H14)
in the presence of 10% Pd/C.
J. W. Bae, Y. J. Cho,
S. H. Lee, C.-O. M. Yoon, C. M. Yoon, Chem. Commun., 2000,
1857-1858.
J. W. Bae, Y. J. Cho,
S. H. Lee, C.-O. M. Yoon, C. M. Yoon, Chem. Commun., 2000,
1857-1858.
An efficient, directed reductive amination of β-hydroxy-ketones allows the
stereoselective preparation of 1,3-syn-amino alcohols using Ti(iOPr)4
for coordination of the intermediate imino alcohol and PMHS as the reducing
agent.
D. Menche, F. Arikan, J. Li, S. Rudolph, Org. Lett., 2007,
9, 267-270.
An efficient method for the direct reductive alkylation of hydrazine derivatives
with α-picoline-borane provided various N-alkylhydrazine derivatives upon
fine-tuning of the substrates and the reagent equivalency in a one-pot manner.
The method was applied to the synthesis of active pharmaceutical ingredients of
therapeutic drugs such as isocarboxazid.
Y. Kawase, T. Yamagishi, J.-y. Kato, T. Kutsuma, T. Kataoka, T. Iwakuma, T.
Yokomatsu, Synthesis, 2014, 46,
455-464.
An achiral amine in combination with a catalytic amount of a chiral Brønsted
acid can accomplish an aldol addition-dehydration-conjugate reduction-reductive
amination with 2,6-diketones to provide cyclohexylamines as potential
intermediates of pharmaceutically active compounds in good yields and excellent
enantioselectivities.
J. Zhou, B. List, J. Am. Chem. Soc., 2007,
129, 7498-7499.
A one-pot, tandem reductive amination-transamidation-cyclization reaction
produces substituted piperazin-2-ones in good yields.
D. C. Beshore, C. J. Dinsmore, Org. Lett., 2002, 4,
1201-1204.
