Tetrahedron Letters 48 (2007) 7680–7682
Reductive methylation of primary and secondary amines and
amino acids by aqueous formaldehyde and zinc
a
b
a,
*
Renato A. da Silva, Id a´ lia H. S. Estevam and Lothar W. Bieber
a
Departamento de Qu ı´ mica Fundamental, Universidade Federal de Pernambuco, Cidade Universit a´ ria, 50670-901 Recife, PE, Brazil
b
Departamento de Ci eˆ ncias Exatas e da Terra, Universidade do Estado da Bahia, Cabula, 41195-001 Salvador, BA, Brazil
Received 13 June 2007; revised 23 August 2007; accepted 24 August 2007
Available online 31 August 2007
Abstract—Amines can be methylated when treated with formaldehyde and zinc in aqueous medium. Selective mono- or dimethyl-
ation can be achieved by proper choice of pH, stoichiometry and reaction time. This method can also be applied for amino acids.
Ó 2007 Elsevier Ltd. All rights reserved.
The introduction of an amino group into an organic
structure is one of the most important synthetic opera-
tions in view of the outstanding role of amines and their
recent studies on the zinc promoted aminomethylation
of alkyl halides, the formation of N-methylated tertiary
6
amines as side products in some cases prompted us to
explore this process for the simple, general, and selective
N-methylation of primary and secondary amines. The
generally accepted mechanism involves in the first step
an acid catalyzed condensation of amine 1 and
formaldehyde to the well-known Mannich type interme-
diate, iminium ion 2. The highly electrophilic carbon
atom of 2 reacts easily with a hydride source to give
amine 3 (Scheme 1).
1
derivatives in biological processes and chemotherapy.
Unfortunately, the obvious nucleophilic substitution
generally is not a useful synthetic method because poly-
alkylation cannot be avoided. For the introduction of
only one new alkyl group reductive alkylation of
amines, also known as reductive amination of carbonyl
compounds, is an interesting alternative as it proceeds
via reversible condensation to imines, enamines, or imin-
ium ions which can be reduced by different methods to
selectively monoalkylated products. Besides the classical
An aqueous acidic medium is not only needed to solubi-
lize all reagents and products and to catalyze the revers-
ible condensation, but is also necessary as a proton
source when zinc is used in the reduction step. In the
case of cyclic amines and the lower dialkyl amines (Ta-
ble 1, entries 1–6), aqueous acetic acid revealed to be the
best compromise to guarantee sufficient reactivity in the
electron transfer and, on the other side, to avoid unnec-
essary consumption of metal by hydrogen evolution.
Granulated commercial zinc was completely satisfactory
to achieve nearly quantitative methylation to 3 by sim-
ple stirring at room temperature. The reaction times var-
ied from 2 to 20 h according to the steric hindrance of
2
Leuckart–Wallach or Eschweiler–Clarke procedures,
this reaction is normally performed in organic solvents
3
,4
using several borohydride reagents. For the simplest
carbonyl compound, formaldehyde, aqueous medium
is often preferred, but sometimes monomethylation can-
not be controlled. However, when the dimethylation of
primary amines or monomethylation of secondary
amines is desired, aqueous formaldehyde is an efficient
and cheap methylating agent. Instead of the expensive
and sometimes toxic borohydride reagents, catalytic
hydrogenation, and different reactive metals have also
2
been used occasionally as reducing agents.
Especially metallic zinc is a cheap and safe electron
source, recently rediscovered in mild and efficient aque-
ous Barbier–Grignard type alkylations. During our
+
R
H
R'
H
Zn, H+
R
R'
R
R' H , CH O
2
5
N
N
N
H
CH3
1
2
3
*
2
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.092