A simple and effective procedure for the N-permethylation of amino-substituted naphthalenes

Article abstract of DOI:10.1002/ejoc.200390085

A wide range of amino-substituted naphthalenes can be N-permethylated by the system Me₂SO₄/Na₂CO₃/ H₂O(alcohols) with good to excellent yields. Steric hindrance does not prevent the reaction. Some amines with electron-withdrawing groups, especially at nonconjugated positions, are also alkylated. The procedure allows the combination of a reduction (catalytic or by tin dichloride in acidic media) and a methylation in a one-pot process. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).

Full text of DOI:10.1002/ejoc.200390085

FULL PAPER
A Simple and Effective Procedure for the N-Permethylation of
Amino-Substituted Naphthalenes
Vladimir I. Sorokin,[a] Valery A. Ozeryanskii,*[a] and Alexander F. Pozharskii[a]
Keywords: Amines / Fused-ring systems / Alkylation
A wide range of amino-substituted naphthalenes can be N-
permethylated by the system Me2SO4/Na2CO3/H2O(alco-
hols) with good to excellent yields. Steric hindrance does not
prevent the reaction. Some amines with electron-with-
also alkylated. The procedure allows the combination of a
reduction (catalytic or by tin dichloride in acidic media) and
a methylation in a one-pot process.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
drawing groups, especially at nonconjugated positions, are Germany, 2003)
N-Peralkylated naphthylamines are very interesting and
synthetically useful compounds, especially those bearing di-
alkylamino groups in peri-positions of the naphthalene
ring, due to their high basicity (known as ‘‘proton
sponges’’).[1] Two common approaches to the synthesis of
such compounds and other N,N-dialkylarylamines from
primary and secondary amines exist (Scheme 1; methyl-
ation, as the most routine procedure, is exemplified). The
first one consists of an NϪH bond ionization/alkylation se-
quence (Scheme 1, path a),[2] the main drawback of which
is its inefficiency for amines with very low NϪH acid-
ity.[2f,2g] The second technique proceeds through a sequence
of quaternization/deprotonation steps (path b),[3] which are
most effective for amines with increased N-nucleophilicity.
Moreover, alkylation by means of path a, despite its wide
spread laboratory usage,[2] requires an inert atmosphere be-
cause highly reactive N-anions are generated during the re-
action.
Herein we propose a simple and effective system
(Me2SO4/Na2CO3/H2O) for the N-permethylation of differ-
ent aminonaphthalenes at room temp. (20Ϫ25 °C). The re-
action proceeds according to Scheme 1 (path b) and gives
the best results with four equivalents of Me2SO4 and
Na2CO3 per amino group of the starting amine (see Exp.
Sect. for details). This is a modification of the method sug-
gested earlier for several anilines and α- and β-aminonaph-
thalenes[3b] that was never adapted for arenes with several
amino groups.
The results of N-permethylation of various naphthylam-
ines with the system proposed and those for other al-
kylation methods are collected in Table 1. As one can see,
this simple and cheap technique allows the methylation of
a wide range of amines under very mild conditions with
good to excellent yields. The only complications were ob-
served in the case of tetraaminonaphthalenes: 1,4,5,8-tetra-
aminonaphthalene gave only tarry products, and 1,2,7,8-
tetraaminonaphthalene is only alkylated in low yield (entry
8); and could not be solved by addition of a large excess of
Me2SO4 and Na2CO3 (up to 10 equivalents of both these
compounds per NH2 group were tested) or increasing the
reaction time. This can be attributed to the extremely fast
oxidation of the corresponding tetraamines.
The position of the amino group (α or β) in the naph-
thalene core does not influence the rate and effectiveness of
the reaction for simple amines (cf. entries 1, 2), although
for polyamines with peri-NH2 groups, the rate of the al-
kylation is somewhat faster for α-amino groups due to the
formation of hydrogen-bond-stabilized cations such as 1
during the methylation process. This is illustrated by the
methylation of 1,2,7,8-tetraaminonaphthalene. When the
reaction is conducted for five, rather than ten, hours (entry
Scheme 1
[a]
1
Department of Organic Chemistry, Rostov State University
8), the H NMR spectrum of the reaction mixture shows
the presence of compounds 2, 3 with partially methylated
β-amino groups.
344090, Rostov-on-Don, 7 ul. Zorge, Russia
Fax: (internat.) ϩ 7-8632/223-958
E-mail: vv ozer2@chimfak.rsu.ru
Ϫ
496
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0496 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 496Ϫ498

N-Permethylation of Amino-Substituted Naphthalenes
FULL PAPER
Table 1. Comparative results of exhaustive N-methylation of
amino-substituted naphthalenes
The spatial proximity of the substituents does not prevent
methylation by this method, but a longer time is needed to
complete the reaction (entries 9, 10, 11).
It has repeatedly been stressed that ortho- and peri-substi-
tuted N,N-dimethylarylamines normally do not undergo
quaternization or give unstable quaternary bases.[4] Even
though the protocol employed is conducted entirely at room
temp. and a rather large excess of Me2SO4 is used, the
formation of quaternary salts of the amines is not a major
process (see entries 2, 3, 7, 10).
In several cases the proposed procedure does not work
properly even after prolonged stirring due to the low solu-
bility of some of the amines. In order to increase their solu-
bility and avoid this disadvantage, a large excess of Me2SO4
or a change of solvent from water to a water/methanol mix-
ture (1:1) was attempted (entries 12, 13).
4-Nitro-α-naphthylamine, even in the presence of a 40-
fold excess of dimethylsulfate in water/methanol and after
stirring for 70 hours, gives a mixture of starting compound
(44%) and N-methylated (45%) and N,N-dimethylated
(11%) derivatives. Even more deactivated amino groups in
compound 4 do not undergo quaternization at all.
Interestingly, certain amines bearing electron-with-
drawing groups that are not conjugated with the amino
groups also undergo methylation. Thus, 8-nitro-1-naphthyl-
amine was solely converted into the corresponding N-per-
methylated derivative by this method with 90% yield.[5]
One of the useful features of our method is the possibility
of combining the reduction of a nitro compound with the
subsequent methylation of the resulting amine. Known al-
kylation techniques[2,3] require amines to be isolated after
reduction of the nitro precursors as a change of solvent is
sometimes needed[2,3] or the dry amines are necessary.[2] In
our case, the reduction and the methylation steps can be
merged, especially when the nitro compound is reduced by
tin dichloride in an acidic medium. After completion of the
reduction, the pH of the resulting mixture was made neut-
ral, and the methylation agent and the base were introduced
directly into the reaction mixture. The effectiveness of this
one-pot procedure is the same or higher than in the tradi-
tional two-step approach. For example, 1,2,7,8-tetraami-
nonaphthalene (entry 8) can be obtained either by catalytic
hydrogenation in methanol or reduction of 2,7-diamino-1,8-
dinitronaphthalene by tin dichloride. In the first case, after
the isolation of the amine followed by methylation, the yield
of 1,2,7,8-tetrakis(dimethylamino)naphthalene is 5%. Using
the tin dichloride reduction and the one-pot procedure, the
compound is obtained in 8% yield. For 1,4,5-triaminonaph-
thalene the yields are 50 and 52%, respectively. Generally
[a]
A: Me2SO4/NaHCO3/H2O/10 °C; B: Me2SO4/Na2CO3/H2O/room
temp.; C: MeI/ CaCO3/MeOH/H2O/reflux; D: MeI/KOH/DMF/100
°C; E: Me2SO4/NaH/ THF/reflux; F: MeI/KOH/DMSO/100 °C; G:
MeI/NaH/THF/reflux; H: Me2SO4/Na2CO3/MeOH/H2O/room temp.
[b]
[c]
[d]
Isolated yield. This work.
Yield from the corresponding nitro
[e]
derivative. Elemental analysis and spectroscopic data are consistent
with the proposed structure. Full characterisation of the product will
be described elsewhere.
Eur. J. Org. Chem. 2003, 496Ϫ498
497

V. I. Sorokin, V. A. Ozeryanskii, A. F. Pozharskii
FULL PAPER
all peralkylations of the amines presented in the table can
be performed in such a way.
Acknowledgments
This work was supported by RFBR (grants NN 99-03-33133a, 02-
03-32080a).
Alkylation with Me2SO4 can be conducted entirely in al-
cohols instead of water with the same efficiency. This pecu-
liarity is important when combining catalytic hydrogenation
and methylation because hydrogenation reactions are gener-
ally performed in alcohols. In this case, a longer reaction
time is required. For example, α-aminonaphthalene is con-
verted into the corresponding N,N-dimethyl derivative in
one hour in water (entry 1) whereas the same reaction re-
quires four hours in methanol; methylation of 1,8-diami-
nonaphthalene takes six hours (compare with entry 4) and
addition of water decreases the reaction time.
Finally, the protocol described here opens new horizons
for the synthesis of previously mal- or inaccessible poly-
functional arylamines. We hope that this method, which is
an excellent complement to the well-known techniques, will
find a wide application in the synthesis of ‘‘proton sponge’’-
like compounds and other peralkylated arylamines.
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Experimental Section
[4] [4a]
General Methylation Procedure: Me2SO4 (freshly distilled; 4 mmol
per amino group) followed by 5 mL of water (alcohol) and
Na2CO3·10H2O (in a quantity equimolar to Me2SO4) were added
to 1 mmol of amine. The reaction mixture was stirred well (CO2
evolution!) for the appropriate time (see Table 1; TLC control). The
reaction mixture was then basified with 20% KOH to a strongly
basic pH of 11Ϫ13, and the methylation products were extracted
with benzene and purified either by crystallisation or by chromato-
graphy on alumina. Spectroscopic and physical properties of all
methylated products are identical with those of authentic samples.
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[5]
Received September 3, 2002
[O02495]
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Eur. J. Org. Chem. 2003, 496Ϫ498