Safe and efficient reductive methylation of primary and secondary amines using N-methylpyrrolidine zinc borohydride

Article abstract of DOI:10.1080/00397910903249606

An efficient, general procedure for reductive methylation of primary and secondary amines with 37% formaldehyde using N-methylpyrrolidine zinc borohydride (ZBHNMP) as a reducing agent gave the corresponding tertiary amines in excellent yields. The reaction was carried out in tetrahydrofuran under neutral conditions at 0-10°C. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903249606

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Safe and Efficient Reductive Methylation
of Primary and Secondary Amines Using
N-Methylpyrrolidine Zinc Borohydride
Heshmatollah Alinezhad a , Mahmood Tajbakhsh a , Fatemeh Salehian
a & Kazem Fazli a
a Faculty of Chemistry, Mazandaran University, Babolsar, Iran
Version of record first published: 26 Jul 2010
To cite this article: Heshmatollah Alinezhad, Mahmood Tajbakhsh, Fatemeh Salehian & Kazem
Fazli (2010): Safe and Efficient Reductive Methylation of Primary and Secondary Amines Using N-
Methylpyrrolidine Zinc Borohydride, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:16, 2415-2420
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Synthetic Communications1, 40: 2415–2420, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903249606
SAFE AND EFFICIENT REDUCTIVE METHYLATION
OF PRIMARY AND SECONDARY AMINES USING
N-METHYLPYRROLIDINE ZINC BOROHYDRIDE
Heshmatollah Alinezhad, Mahmood Tajbakhsh,
Fatemeh Salehian, and Kazem Fazli
Faculty of Chemistry, Mazandaran University, Babolsar, Iran
An efficient, general procedure for reductive methylation of primary and secondary amines
with 37% formaldehyde using N-methylpyrrolidine zinc borohydride (ZBHNMP) as a
reducing agent gave the corresponding tertiary amines in excellent yields. The reaction
was carried out in tetrahydrofuran under neutral conditions at 0–10 ꢀC.
Keywords: Amine; formaldehyde; reductive methylation; ZBHNMP
Synthesis of amines is an objective of high priority from the perspective of drug
discovery.[1] The synthesis of tertiary amines by the reductive methylation of
primary and secondary amines with formaldehyde has been often used as a synthetic
tool in organic chemistry.[2] Because the reduction of imine or enamine, generated in
situ by the reaction of amine with formaldehyde, can compete with the reduction of
the starting compound, the reducing agents must reduce the imine or enamine with
high selectivity. Sodium or potassium hydridotetracarbonylferrate in ethanol or tet-
rahydrofuran,[3] NaBH4 in methanol,[4] and NaBH3CN in acetonitrile[5] are the most
commonly used agents for this transformation. However, most of these reagents
have drawbacks such as tedious workup, use of expensive and highly toxic reagents,
and residual cyanide in the product as well as in the workup stream.
[6]
Other methods such as NaBH4-ZnCl2 and NaBH4 in tetrahydrofuran
(THF),[7] borane–methylsulfide,[8] zinc-modified cyanoborohydride,[9] Zr(BH4)2-
Cl2(DABCO)2,[10] and N-methylpyrrolidine zinc borohydride (ZBNMPP)[11] have
been used for this purpose.
ZBHNMP is an inexpensive, stable, and safe-to-handle reducing agent for
reduction of a variety of organic compounds such as aldehydes, ketones, acid chlor-
ides, and esters.[12] Recently, we reported the reductive amination of aldehydes and
ketones using this reducing agent.[13] In continuation, we expected that ZBHNMP
could be used effectively for reductive methylation of amines under neutral
conditions. Here, we report the reductive methylation of primary and secondary
amines for the preparation of methylated tertiary amines (Scheme 1).
Received August 3, 2009.
Address correspondence to Heshmatollah Alinezhad, Faculty of Chemistry, Mazandaran
University, Babolsar, Iran. E-mail: heshmat@umz.ac.ir
2415

2416
H. ALINEZHAD ET AL.
Scheme 1. Reductive methylation of amines using N-methylpyrrolidine zinc borohydride (ZBHNMP).
To find the optimum condition for reductive methylation of amines with
ZBHNMP, we chose aniline as a model compound. Reductive methylation of aniline
was first investigated in different solvents such as THF, CH3OH, CH2Cl2, and n-hex-
ane. We observed that THF was best solvent for this purpose. The amount of
ZBHNMP in this reaction was also examined with different molar ratios of reduc-
tant to substrate in the presence of formaldehyde (37% aq) under neutral conditions
in THF at 0 to 10 ꢀC. A molar ratio of reductant to aniline to formaldehyde of 2:1:4
was found to be ideal for complete conversion to N,N-dimethyl aniline; the reaction
remained incomplete with lesser amounts of reducing agent, for example, 1 or 1.5.
Table 1 summarizes the reductive methylation of various aliphatic and aromatic
amines with formaldehyde by using this procedure to furnish the corresponding
N,N-dimethyl amines in good to excellent yields.
As indicated in Table 1, reductive methylation of aromatic amines with
different substituents gives excellent yields of the corresponding amines (Table 1,
entries 1–11). We did not encounter any problem in the methylation of low basicity
amines such as p-nitroaniline and o, m, p-chloroanilines. Also, o-ethylaniline and
o-toluidine, which might exhibit steric hindrance to N-substitution, were converted
into the N,N-dimethyl derivatives. We also found that reductive methylation of ali-
phatic amines such as cyclohexylamine, pyrrolidine, morpholine, and benzylamine
was performed in less time and gave better yields (Table 1, entries 12–15).
We compare some of the results obtained by ZBHNMP with other methods
used for this purpose in Table 2. This shows that our method is a good substitute
for NaBH3CN and zinc-modified cyanoborohydride for the preparation of tertiary
methylated amines, and also in most cases it gave better yields of the corresponding
amines in less reaction time.
In conclusion, a new, efficient, reductive methylation method was developed
using ZBHNMP as a mild reducing agent and formaldehyde (37% aq) in one-pot
method with excellent yields. Notable advantages of the present method include
the mildness, ease of reaction workup, efficiency, excellent yields, neutral conditions,
and no need for an inert atmosphere.
EXPERIMENTAL
General
The ZBHNMP used in this study was prepared easily in good yield from
commercially available starting materials.[12] Amines were purchased from Merck.

REDUCTIVE METHYLATION OF AMINES USING ZBHNMP
2417
Table 1. Reductive methylation of primary and secondary aromatic and aliphatic amines with ZBHNMP
in THFa
Entry
Substrate
Productb
Time (min)
10
Yield (%)c
90
Ref.
[5]
1
2
3
15
20
93
92
[5]
[14]
4
20
90
[5]
5
6
20
20
90
89
[14]
[5]
7
8
9
25
20
15
88
88
90
[15]
[7]
[7]
10
15
92
[7]
11
12
13
15
10
10
92
92
89
[9]
[5]
[16]
(Continued )

2418
H. ALINEZHAD ET AL.
Table 1. Continued
Entry
14
Substrate
Productb
Time (min)
10
Yield (%)c
88
Ref.
[16]
15
10
94
[9]
aAll reactions were carried out in THF at 0–10 ꢀC, and the molar ratio of amine=formaldehyde=
reductant was 2:1:4.
bAll products were characterized spectroscopically (1H NMR, IR) and showed physical and spectral
data in accordance with their expected structure by comparison with authentic samples.
cYields refer to pure isolated products.
Reaction monitoring and purity determination of the products were accomplished by
thin-layer chromatography (TLC) or gas chromatography (GC). All the products are
known compounds and were identified by comparison of their spectra and physical data
with those of the authentic samples. Infrared (IR) spectra were recorded on a Bruker
Vector 22 spectrometer. 1H NMR spectra were measured on Bruker DRX 500 Avance
(500-MHz) and GNM-EX90A (90-MHz) spectrometers, using CDCl3 as solvent.
Typical Procedure for the Reductive Methylation of Amines with
ZBHNMP
The preparation of N,N-dimethylaniline is representative. In an Erlenmeyer
flask, a solution of the aniline (0.093 g, 1 mmol) and 37% aqueous solution of formal-
dehyde (4 mmol) in THF (5 mL) was prepared, and ZBHNMP (0.36 g, 2 mmol) was
added. The pH was adjusted to neutral conditions with 10% aqueous solution of
Table 2. Comparison of ZBHNMP with the other reducing agents in reductive methylation of amines
ZBHNMP
ZBNMPP
NaBH3CN
Zn-NaBH3CN
ZrBDC
Time Yield Time Yield Time Yield Time
(min)
Yield Time Yield
(min) (%)
Entry
1
Substrate
(min) (%) (min) (%) (min) (%)
(%)
10
90
30
88
120
92
120
—
86
6
80
2
3
4
15
15
10
93
92
89
40
18
24
92
95
90
60
—
87
—
84
—
83
—
45
18
6
95
87
81
120
—
120

REDUCTIVE METHYLATION OF AMINES USING ZBHNMP
2419
sulfuric acid. The mixture was stirred at 0 to 10 ꢀC, and progress of the reaction was
followed by TLC (eluent: n-hexane=EtOAc 4:1). After completion of the reaction,
the mixture was diluted with water (10 mL) and then extracted with diethyl ether
(2 Â 20 mL). The combined organic layers were dried on anhydrous MgSO4 and eva-
porated. The crude product was purified by column chromatography on silica gel
and eluted with 2% solution of ethyl acetate in n-hexane to afford pure N,N-dimethy-
laniline (0.114 g, 94%).
ACKNOWLEDGMENT
Financial support of this work from the Research Council of Mazandaran
University is gratefully acknowledged.
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