Categories: C-N Bond Formation > Amines >
Synthesis of secondary and tertiary amines
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Reductive Amination
Recent Literature
Cesium hydroxide promotes a selective N-monoalkylation of primary
amines to prepare various secondary amines efficiently. This methodology is
highly chemoselective, favoring mono-N-alkylation over dialkylation.
R. N. Salvatore, A. S. Nagle, S. E. Schmidt, K. W. Jung,
Org. Lett., 1999, 1, 1893-1896.
A Cp*Ir complex bearing a functional 2,2′-bibenzimidazole ligand is a highly
effective and general catalyst for the N-methylation of a variety of
amines with methanol in the presence of a weak base.
R. Liang, S. Li, R. Wang, L. Lu, F. Li, Org. Lett.,
2017, 19, 5790-5793.
Iridium complexes bearing an N-heterocyclic carbene (NHC) ligand exhibited
high catalytic performance for the N-methylation of both aliphatic and
aromatic primary amines using methanol as the methylating agent. For aliphatic
amines, selective N,N-dimethylation was achieved at low temperatures. For
aromatic amines, selective N-monomethylation and selective N,N-dimethylation
were accomplished.
G. Toyooka, A. Tuji, K.-i. Fujita, Synthesis, 2018, 50,
4617-4626.
[(p-cymene)Ru(2,2'-bpyO)(H2O)] is a general and efficient
catalyst for the N-methylation of amines and sulfonamides with methanol
in the presence of a carbonate salt. The reaction tolerates a series of
sensitive substituents, such as nitro, ester, cyano, and vinyl groups.
P. Liu, N. T. Tung, X. Xu, J. Yang, F. Li, J. Org. Chem., 2021, 86,
2621-2631.
Borane-trimethylamine is an efficient reducing agent for the selective
methylation and formylation of amines with 1 atm CO2 under metal-free
conditions. 6-Amino-2-picoline serves as a highly efficient catalyst for the
methylation of various secondary amines, whereas in its absence, the formylation
of primary and secondary amines was achieved in high yield with high
chemoselectivity.
Y. Zhang, H. Zhang, K. Gao, Org. Lett., 2021, 23,
8282-8286.
An iridium catalyst bearing an N-heterocyclic carbene mediates an
N,N-dimethylamination of primary alcohols with aqueous dimethylamine in the
absence of additional organic solvents via an atom-efficient and environmentally
benign borrowing hydrogen process.
J. Jeong, K.-i. Fujita, J. Org. Chem., 2021, 86,
4053-4060.
The mechanism, scope, and catalyst evolution for a ruthenium-based coupling of
amines and alcohols are described. The method selectively produces secondary
amines through a hydrogen borrowing mechanism and is successfully applied to
several heterocyclic carbinol substrates.
V. Cherepakhin, T. J. Williams, ACS Catal., 2020, 10,
56-65.
Cp*-iridium half-sandwich complexes are highly reactive and selective
catalysts for the alkylation of amines with alcohols. [Cp*Ir(Pro)Cl] (Pro =
prolinato) is active under mild conditions in either toluene or water without
the need for base or other additives, tolerates a wide range of alcohols and
amines, and gives secondary amines in good to excellent isolated yields.
A. Wetzel, S. Wöckel, M. Schelwies, M. K. Brinks, F. Rominger, P. Hofmann, M.
Limbach, Org. Lett., 2013,
15, 266-269.
A simple amino amide ligand enables a ruthenium-catalyzed one-pot alkylation of
primary and secondary amines with simple alcohols. Using the alcohol as solvent,
alkylation was achieved under mild conditions with high conversion and
selectivity. Reactions can also be carried out at high temperatures in organic
solvent with high selectivity using stoichiometric amounts of the alcohol.
A. B. Enyong, B. Moasser, J. Org. Chem., 2014,
79, 7559-7563.
Microwave heating enables a Borrowing Hydrogen strategy to form C-N bonds from
alcohols and amines, removes the need for solvent and reduces the reaction times,
while the results are comparable with those using thermal heating.
A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J. Org. Chem., 2011,
76, 2328-2331.
The addition of 4 Å molecular sieves enables an efficient cobalt(II)-catalyzed
N-alkylation of both aromatic and aliphatic amines with alcohols with high
chemoselectivity (amines vs imines). A hydrogen-borrowing mechanism is
responsible for the tandem acceptorless dehydrogenation/condensation/hydrogenation
process.
G. Zhang, Z. Yin, S. Zheng, Org. Lett., 2016, 18,
300-303.
A silver-loaded titanium dioxide (Ag/TiO2) photocatalyst enables a
facile N-methylation of amines with methanol at room temperature under UV-vis
light irradiation. This method tolerates various functional groups including
N-benzyl, N-allyl, N-Boc, hydroxyl, ether, acetal, carboxamide,
formamide, and olefin groups.
V. N. Tsarev, Y. Morioka, J. Caner, Q. Wang, R. Ushimaru, A. Kudo, H. Naka, S.
Saito, Org. Lett.,
2015,
17, 2530-2533.
A magnesium-catalyzed reduction of linear and cyclic carbamates, including
N-Boc protected amines, provides N-methyl amines and amino alcohols
which are of significant interest due to their presence in many biologically
active molecules. Furthermore, the reduction can be extended to the formation of
N-trideuteromethyl labeled amines.
M. Magre, M. Szewczyk, M. Rueping,
Org. Lett., 2020, 22, 3209-3214.
A catalytic system generated in situ from a tetranuclear Ru-H complex with a
catechol ligand enables a direct deaminative coupling of two primary amines to
form secondary amines. The analogous coupling of aniline with primary amines
formed aryl-substituted secondary amines.
P. T. K. Arachchige, H. Lee, C. S. Yi, J. Org. Chem., 2018, 83,
4932-4947.
The selective mono-alkylation of aliphatic amines by unactivated, hindered
halides is a challenge in organic synthesis. Primary aliphatic amines can be
cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of
visible light and a copper catalyst. The method operates under mild conditions
(-10 °C) and displays good functional-group compatibility.
C. D. Matier, J. Schwaben, J. C. Peteres, G. C. Fu, J. Am. Chem. Soc., 2017,
139, 17707-17710.
A one-pot two-step sequence involving an oxidation/imine-iminium formation/reduction
allowed the N-alkylation of amines by alcohols. Optically active alcohols
and amines can be converted without any epimerization.
C. Guérin, V. Bellosta, G. Guillamot, J. Cossy, Org. Lett., 2011,
13, 3478-3481.
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.
Using 0.5 mol % [Ru(p-cymene)Cl2]2 with the bidentate
phosphines dppf or DPEphos as the catalyst, primary amines have been converted
into secondary amines, and secondary amines into tertiary amines. N-Heterocyclization
reactions of primary amines have been achieved, as well as alkylation reactions
of primary sulfonamides.
M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J.
A. Watson, J. M. J. Williams, J. Am. Chem. Soc., 2009,
131, 1766-1774.
An efficient, environmentally benign and practical one-pot reductive tandem
mono-N-alkylation of both aromatic and aliphatic azides using dialkylboron
triflates as alkylating agents enables the syntheses of various secondary alkyl
as well as aryl amines, including the synthesis of N10-butylated
pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones via in situ azido
reductive-cyclization process.
N. Shankaraiah, N. Markandeya, V. Srinivasulu, K. Sreekanth, C. S. Reddy, L. S.
Santos, A. Kamal, J. Org. Chem., 2011,
76, 7017-7026.
An iridium complex catalyzes pH-dependent selective N-allylation or
N-alkylation of amines with allylic alcohols in outstanding yields with
water as the environmental benign solvent.
N. Luo, Y. Zhong, H. Shui, R. Luo, J. Org. Chem., 2021, 86,
15509-15521.
Manganese dioxide is employed as an in situ oxidant for the one-pot conversion
of alcohols into imines. In combination with polymer-supported cyanoborohydride
(PSCBH), a one-pot oxidation-imine formation-reduction sequence enables alcohols
to be converted directly into both secondary and tertiary amines.
L. Blackburn, R. J. K. Taylor, Org.
Lett., 2001, 3, 1637-1639.
(Cyanomethyl)phosphonium iodides are easy to prepare and to handle. These
reagents efficiently promote the direct, intermolecular N-alkylation of
amines with alcohols.
F. Zaragoza, H. Stephensen, J. Org. Chem, 2001,
66, 2518-2521.
Well-defined Co(II) complexes stabilized by a PCP ligand catalyze efficient
alkylations of aromatic amines by primary alcohols into mono-N-alkylated
amines in very good yields. The inexpensive, earth-abundant nonprecious metal
catalysts make this acceptorless alcohol dehydrogenation concept environmentally
benign.
M. Mastalir, G. Tomsu, E. Pittenauer, G. Allmaier, K. Kirchner, Org. Lett.,
2016, 18, 3462-3465.
A direct, stereospecific amination of alkylboronic and borinic esters can be
accomplished by treatment with methoxyamine and
potassium tert-butoxide. In addition, this process also
enables the direct amination of tertiary boronic esters in an efficient fashion.
E. K. Edelstein, A. C. Grote, M. D. Palkowitz, J. P. Morken,
Synlett, 2018, 29, 1749-1752.
A highly enantio- and regioselective copper-catalyzed hydroamination reaction of
alkenes with hydroxylamine esters in the presence of diethoxymethylsilane
enables the conversion of a wide variety of substituted styrenes, including
trans-, cis-, and β,β-disubstituted styrenes, to yield α-branched
amines. In addition, aliphatic alkenes gave exclusively the anti-Markovnikov
hydroamination products.
S. Zhu, N. Niljianskul, S. L. Buchwald, J. Am. Chem. Soc., 2013,
135, 15746-15749.
A method for highly selective anti-Markovnikov hydroamination of terminal
alkenes involves hydroboration of the alkene followed by a novel electrophilic
amination of the alkyl borane catalyzed by an NHC-Cu complex. Terminal alkenes
are successfully transformed into tertiary alkyl amines in the presence of a
variety of functional groups in very good yields ranging with excellent
regioselectivity.
R. P. Rucker, A. M. Whittaker, H. Dang, G. Lalic, J. Am. Chem. Soc., 2012,
134, 6571-6574.
A base-mediated hydroamination protocol with substoichiometric amounts of a
hydrosilane and potassium tert-butoxide operates under mild conditions.
Many aryl- and heteroatom-substituted olefins as well as arylamines are
tolerated, affording the desired products with complete regioselectivity.
P. Li, B. C. Lee, X. Zhang, M. J. Koh, Synthesis, 2022, 54,
1566-1576.
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.
A new synthetic method for the preparation of potassium
organotrifluoroborates through nucleophilic substitution of potassium bromo-
and iodomethyltrifluoroborates is described. Potassium
halomethyltrifluoroborates have been prepared via in situ reaction of n-BuLi
with dibromo- and diiodomethane, respectively, in the presence of trialkyl
borates, followed by treatment with KHF2.
G. A. Molander, J. Ham, Org. Lett.,
2006,
8, 2031-2034.
A copper-catalyzed electrophilic amination of simple and functionalized aryl,
heteroaryl-, benzyl, n-alkyl, sec-alkyl, and tert-alkyl
diorganozinc nucleophiles with R2NOC(O)Ph and RHNOC(O)Ph reagents
as electrophilic nitrogen sources provides tertiary and secondary amines,
respectively, in generally good yields. In many cases, the product may be
isolated analytically pure after a simple extractive workup. A Cu-catalyzed
amination of Grignard reagents using cocatalysis by ZnCl2 is
described.
A. M. Berman, J. S. Johnson, J. Org. Chem.,
2006,
71, 219-224.
Umpolung reactions of N-trimethylsilyl α-iminoester with organometallics
provide deprotected N-alkylaminoesters. Furthermore, tandem N,N-
or N,C-dialkylation reactions enable efficient syntheses of pyrrolidines,
piperidines, and iminodiacetate derivatives.
I. Mizota, Y. Tadano, Y. Nakamura, T. Haramiishi, M. Hotta, M. Shimizu,
Org. Lett., 2019, 21, 2663-2667.
An iron-catalyzed hydroamination and
hydroamidation of allylic alcohols provides γ-amino and γ-amido alcohols,
respectively. The catalytic system,
consisting of a pincer Fe-PNP complex, a weak base, and a nonpolar
solvent, offers exclusive anti-Markovnikov selectivity, broad substrate scope, and good functional group tolerance.
W. Ma, X. Zhang, J. Fan, Y. Liu, W. Tang, D. Xue, C. Li, J. Xiao, C. Wang, J. Am. Chem. Soc.,
2019,
141, 13506-13515.
Selective mono-N-alkylation of 3-amino alcohols relies on formation
of a stable chelate with 9-BBN. Three prototypical amino alcohols featuring
various bridging units led selectively to the monoalkylated derivatives in
very high yields.
G. Bar-Haim, M. Kol, Org. Lett., 2004, 6, 3549-3551.
A
wide range of chiral propargylamines can be prepared in a one-pot
three-component reaction between an alkyne, an aldehyde and a secondary
amine at room temperature in the presence of CuBr and (R)-quinap in
good yield and good enantioselectivity.
N. Gommermann, C. Koradin, K. Polborn, P. Knochel, Angew. Chem., 2003,
115, 5941-5944.
An efficient palladium-catalyzed asymmetric amination of 2,3-allenyl
phosphates with nitrogen nucleophiles such as amines, hydroxylamines, and
imides can be performed in presence of SEGPHOS or MeOBIPHEP ligand,
affording the corresponding optically active 1-aminated derivatives with
high enantiomeric excess.
Y. Imada, M. Nishida, K. Kutsuwa, S.-I. Murahashi, T. Naota, Org. Lett.,
2005,
7, 5837-5839.
An aryloxotitanium complex is a highly chemo- and regioselective catalyst for
intermolecular hydroamination of terminal alkynes. Branched imines are obtained
in good yield with various primary aromatic and aliphatic amines.
V. Khedkar, A. Tillak, M. Beller, Org. Lett., 2003, 5,
4767-4770.
A polymer-bound, triphenylphosphine-supported reagent allows a one-pot, two-step
synthesis of secondary amines from the corresponding azide and a reactive alkyl
halide.
S. Ayesa, B. Samuelsson, B. Classon, Synlett, 2008,
89-93.
β-Piperidinoethylsulfides can be oxidized by m-chloroperbenzoic acid to
intermediates containing both N-oxide and sulfone functions. These
undergo a Cope-type elimination to a vinylsulfone that can be captured by amines
to afford β-aminoethylsulfones. The synthetic methodology developed can be
utilized in multiple-parallel format and has numerous potential applications in
medicinal chemistry.
R. J. Gruffin, A. Henderson, N. J. Curtin, A. Echalier, J. A. Endicott, I. R.
Hardcastle, D. R. Newell, M. E. M. Noble, L.-Z. Wang, B. T. Golding, J. Am. Chem. Soc., 2006,
128, 6012-6013.
Related
A photoredox catalyzed, thiyl-radical mediated, reversible hydrogen atom
transfer enables a stereoselective α-amino C-H epimerization of exocyclic amines
to provide thermodynamically controlled anti:syn isomer ratios. The method is
applicable to different substituents and substitution patterns.
M. Vargas-Rivera, A. S. Liu, J. A. Ellman, Org. Lett., 2023, 25,
9197-9201.