Efficient and mild procedure for reductive methylation of amines using N-methylpiperidine zinc borohydride

Article abstract of DOI:10.1080/00397910600943667

A simple and efficient procedure for reductive methylation of primary and secondary amines using N-methylpiperidine zinc borohydride (ZBNMPP), giving tertiary amines, is described. The reaction is carried out in methanol at room temperature under neutral conditions. Copyright Taylor & Francis Group, LLC.

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Efficient and Mild Procedure for
Reductive Methylation of Amines Using
N‐Methylpiperidine Zinc Borohydride
a
a
a
Heshmatollah Alinezhad , Mahmood Tajbakhsh & Reza Zamani
a
Department of Chemistry, Mazandaran University, Babolsar, Iran
Published online: 24 Nov 2006.
To cite this article: Heshmatollah Alinezhad , Mahmood Tajbakhsh & Reza Zamani (2006) Efficient and
Mild Procedure for Reductive Methylation of Amines Using N‐Methylpiperidine Zinc Borohydride, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:23,
3609-3615, DOI: 10.1080/00397910600943667
To link to this article: http://dx.doi.org/10.1080/00397910600943667
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Synthetic Communications , 36: 3609–3615, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600943667
Efficient and Mild Procedure for Reductive
Methylation of Amines Using
N-Methylpiperidine Zinc Borohydride
Heshmatollah Alinezhad, Mahmood Tajbakhsh,
and Reza Zamani
Department of Chemistry, Mazandaran University, Babolsar, Iran
Abstract: A simple and efficient procedure for reductive methylation of primary
and secondary amines using N-methylpiperidine zinc borohydride (ZBNMPP),
giving tertiary amines, is described. The reaction is carried out in methanol at room
temperature under neutral conditions.
Keywords: Amines, formaldehyde, reductive methylation, ZBNMPP
INTRODUCTION
Amines and their derivatives show biological activities and are important
[1]
precursors used in pharmaceutical and agricultural industries. The introduc-
tion of methyl groups into a primary or secondary amine by reductive alky-
lation with formaldehyde is a useful method for the preparation of tertiary
[
2]
methylated amines.
A number of reagents have been used for this transformation, including
[
NaBH CN, NaBH in neat liquid carboxylic acid media
3]
[4a]
or in aqueous
[6]
borane-methylsulfide, zinc-modified cyanoborohydride,
3
4
[
4b]
[5]
sulfuric acid,
[
7]
[8]
Ti(OiPr) -NaBH , and Zr(BH ) Cl (dabco) . However, most of these
2
4
4
4 2
2
reagent have drawbacks. For example, the use of expensive and highly toxic
NaBH CN carries the risk of producing residual cyanide in the product as well
3
Received in the U.K. February 2, 2006
Address correspondence to Heshmatollah Alinezhad, Department of Chemistry,
Mazandaran University, Babolsar, Iran. E-mail: heshmat@umz.ac.ir
3
609

3
610
H. Alinezhad, M. Tajbakhsh, and R. Zamani
Scheme 1.
as in the workup stream and generates a complex mixture of starting material and
[
9]
partially methylated products. Sodium borohydride should be used in the
presence of acid or in a protic solvent, reaction media that restrict its use for
molecules containing acid-sensitive and easily solvolysed groups. These
factors demonstrate the need for futher exploration beyond the existing
reductive methylation synthetic repertoire. We expected from our pervious
results for the reductive amination of aldehydes and ketones withN-methylpiper-
[10]
idine zinc borohydride (ZBNMPP)
that this reducing agent could be used
effectively for reductive methylation of amines under mild conditions.
ZBNMPP is an inexpensive, stable, and safe reducing agent.
Therefore we herein report a mild and efficient method for the N-methyl-
ation of primary and secondary amines that affords tertiary amines (Scheme 1).
RESULTS AND DISCUSSION
The efficient and smooth reductive methylation of a variety of amines
proceeded well in the presence of a 37% aqueous solution of formaldehyde
using ZBNMPP under neutral conditions. The pH of the medium was
adjusted to neutrality by addition of a 10% solution of HCl in methanol.
Under such a condition, tertiary methylated amines were afforded in the
absence of any other products. Complete chemoselectivity is observed in
the reductive methylation of functionalized amines bearing other reducible
functional groups. In general the reactions were carried out with 1 equivalent
of amine, 5 equivalents of formaldehyde, and 1 equivalent of ZBNMPP in
MeOH at room temperature under neutral conditions.
The reductive methylation of a variety of primary and secondary amines
was successful and gave the desired tertiary methylated products in good to
excellent yields (80–95%), as shown in Table 1. Initially we examined the
reductive methylation of aniline (1 mmol) with 37% aqueous formaldehyde
(
(
(
5 mmol) in methanol (5 mL) under neutral conditions, using ZBNMPP
1 mmol) at room temperature. After 30 min, thin-layer chromatography
TLC) showed complete disappearance of aniline. After the usual workup,
N,N-dimethylaniline was obtained in high yield (Table 1, entry 1). The
secondary amines reacted faster than the primary amines and steric

Reductive Methylation of Amines
3611
a
Table 1. Reductive methylation of amines with ZBNMPP
Time Yield
c
(min) (%)
b
Entry
1
Compound
Product
Ref.
[12]
30
40
88
92
85
95
82
2
3
4
5
[12]
[12]
[6]
90
18
120
[13]
6
7
8
15
6
88
89
80
[11]
[14]
[14]
6
9
15
97
[12]
1
1
0
1
24
18
90
91
[12]
[6]
(
continued)

3
612
H. Alinezhad, M. Tajbakhsh, and R. Zamani
Table 1. Continued
Time Yield
c
(min) (%)
b
Entry
Compound
Product
Ref.
[15]
1
2
45
84
1
3
20
89
[16]
a
All reactions were carried out at room temperature; the molar ratio of amine/
formaldehyde/reagent was 1 : 5 : 1.
b
1
All products were characterized spectroscopically ( H NMR, IR) and showed
physical and spectral data in accordance with their expected structures and those of
authentic samples.
c
Yields refer to pure isolated products.
hindrance posed no problem; the hindered amines N-methylaniline and
piperidine underwent clean and complete methylation (Table 1, entries 6,
7), although morpholine reacted in lower yield (Table 1, entry 8). We also
employed the same methodology to examine the chemoselective reductive
methylation of functionalized amines bearing other reducible functional
groups. As shown in Table 1, anilines having a nitro group underwent
reductive methylation to give the corresponding N,N-dimethylaniline in
good yield without reduction of the nitro group (Table 1, entry 3). The
effect of the nature of the substituted groups on the aromatic ring of aniline
is quite clear: electron-releasing groups such as methyl increase the rate of
reaction in relation to electron-withdrawing groups such as nitro and bromo
(
Table 1, entries 2–4).
To show the advantages and drawbacks of our method, we have compared
some of our results with those reported in the literature in Table 2. This shows
that our method in most cases gives lower reaction times and higher yields of
the corresponding amines.
In conclusion, ZBNMPP is a good substitute for NaBH CN, NaBH CN/
3
3
ZnCl , and zinc-modified cyanoborohydride for the preparation of tertiary
2
methylated amines. Moreover, the mildness, ease of reaction workup, effi-
ciency, chemoselectivity, high yields, and lack of need for an inert atmosphere
make this reagent a useful addition to the group of reagents that can be used
for the reductive methylation of amines.
EXPERIMENTAL
Materials were purchased from Fluka and Merck companies. The reactions
were monitored by TLC using silica-gel plates. The products were purified

Table 2. Comparison of the results obtained by ZBNMPP with other reducing agents for reductive methylation of amines
NaBH CN/
ZnCl2
3
Zinc-modified
ZBNMPP
NaBH CN
3
cyanoborohydride Zr(BH ) Cl (dabco)
2
4 2
2
Time Yield Time Yield Time Yield Time
(min)
Yield
(%)
Time
(min)
Yield
(%)
Entry
1
Amine
Product
(min)
(%)
(min)
(%)
(min)
(%)
30
86
120
92
120
86
—
—
—
—
—
87
81
2
3
4
40
18
24
92
95
90
60
—
87
—
84
—
—
—
—
—
—
—
120
—
0
—
18
6
83
—
120

3
614
H. Alinezhad, M. Tajbakhsh, and R. Zamani
by flash-column chromatography on silica gel (Merck; 230–400 mesh) and
identified by comparison of their spectral and physical data with those of
1
authentic samples. H NMR spectra were measured at 300 MHz on a JEOL
spectrometer with tetramethylsilane (Me Si) as an internal reference and
4
CDCl as the solvent. IR spectra were recorded on Pye-unicam SP1100
3
spectrophotometer.
Preparation of N-Methylpiperidine Zinc Borohydride (ZBNMPP)
To a freshly prepared ethereal solution of zinc borohydride (200 ml,
0.03 mol), N-methylpiperidine (2.97 g, 0.03 mol) was added dropwise over
20 min. Then the mixture stirred at room temperature for 1 h under a
nitrogen atmosphere. The precipitate was filtered off and washed with Et O
2
(10 mL), and the resulting white powder was dried in a vacuum desicator to
produce 4.5 g (85% yield).
Typical Procedure for Reductive Methylation of Amines
with ZBNMPP
The preparation of N,N-dimethyl-p-toluidine is representative. A stirred
solution of p-toluidine (0.107 g, 1 mmol) and 37% aqueous formaldehyde
(
0.4 mL, 5 mmol) in methanol (5 mL) was prepared, and the pH was
adjusted to neutral conditions by addition of a 10% solution of HCl in
MeOH. ZBNMPP (0.194 g, 1 mmol) was added, and the mixture was stirred
at room temperature (18 min). Silica gel (2 g) was added when no amine
remained (TLC). The solvent was evaporated, and the resulting material
was applied on a silica-gel column and eluted with hexane/EtOAc 10/1
(100 mL). After evaporation of solvent, pure N,N-dimethyl-p-toluidine was
obtained (0.128 g, 95% yield; Table 1, entry 4).
ACKNOWLEDGMENT
Financial support of this work from the Research Council of Mazandaran
University is gratefully acknowledged.
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3615
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