Selective N-methylation of primary aliphatic amines with dimethyl carbonate in the presence of alkali cation exchanged Y-faujasites

Article abstract of DOI:10.1016/j.tetlet.2003.09.016

The N-methylation of aliphatic amines [XC₆H₄(CH ₂)_nNH₂; n=1, X=H (1a), o-MeO (1b), p-MeO (1c); n=2, X=H (2a), o-MeO (2b); 1d: PhCH(Me)NH₂] with dimethyl carbonate (DMC) is efficiently catalysed by NaY faujasite: on condition that CO ₂ (a co-product of the reaction) is carefully removed, N-methyl- and N,N-dimethyl-amines (RNHMe and RNMe₂) are obtained in good overall yields (70-90%). Otherwise, in the presence of CO₂, carbamates (RNHCO₂Me) form competitively to a large extent. The reaction probably proceeds through a B_Al2 displacement of the amine on DMC.

Full text of DOI:10.1016/j.tetlet.2003.09.016

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8139–8142
Selective N-methylation of primary aliphatic amines with
dimethyl carbonate in the presence of alkali cation exchanged
Y-faujasites
Maurizio Selva* and Pietro Tundo
Dipartimento di Scienze Ambientali dell’Universita` Ca’ Foscari, Calle Larga S. Marta 2137, 30123 Venezia, Italy
Received 17 July 2003; revised 18 August 2003; accepted 3 September 2003
Abstract—The N-methylation of aliphatic amines [XC6H4(CH2)nNH2; n=1, X=H (1a), o-MeO (1b), p-MeO (1c); n=2, X=H
(2a), o-MeO (2b); 1d: PhCH(Me)NH2] with dimethyl carbonate (DMC) is efficiently catalysed by NaY faujasite: on condition that
CO2 (a co-product of the reaction) is carefully removed, N-methyl- and N,N-dimethyl-amines (RNHMe and RNMe2) are
obtained in good overall yields (70–90%). Otherwise, in the presence of CO2, carbamates (RNHCO2Me) form competitively to a
large extent. The reaction probably proceeds through a BAl2 displacement of the amine on DMC.
© 2003 Elsevier Ltd. All rights reserved.
In the presence of alkali cation exchanged Y-faujasites
(e.g. NaY and KY), the reaction of dimethyl carbonate
with primary aromatic amines affords the correspond-
ing mono-N-methyl derivatives with unprecedented
selectivity (92–99%). This holds even for anilines deacti-
vated by both electronic and steric effects (Scheme 1).1
to the carbonyl (BAc2) and to the methyl (BAl2)
groups of DMC, were possible without any discrimina-
tion.
In this paper, we wish to report a further investigation
on this reaction which discloses the synthetic potential
for the preparation of N-methyl amines and some
relevant features of the methylation/methoxycarbonyla-
tion mechanisms of aliphatic amines with DMC.
Besides the synthetic outcome, this reaction shows rele-
vant environmentally benign features: it uses a non-
toxic methylating agent (DMC) coupled with eco-safe
solids (zeolites) as catalysts, it does not require addi-
tional solvents, and neither organic nor inorganic by-
products are formed.2
Initially, benzylamine 1a, o- and p-methoxybenzyl-
amine, and (a-methyl)benzylamine (compounds 1b, 1c,
and 1d respectively) were chosen as substrates (Table
1). In a typical procedure (entry 7), a three-necked,
jacketed, 25 mL round-bottomed flask fitted with a
N2-bubbler, an adapter for the withdrawal of samples,
a reflux condenser connected to a gas flowmeter, and a
magnetic bar, was loaded with a solution of benzyl-
amine (1a, 0.3 g, 2.8 mmol) in dimethyl carbonate (20
mL), and NaY (0.9 g). The flask was heated at the
reflux temperature of DMC (90°C), while the mixture
was vigorously stirred. A N2 flow of ꢀ25 mL/min was
As a part of our research program on the reactivity of
DMC over Y zeolites, we were interested in the N-
methylation of primary aliphatic amines as well. The
higher nucleophilicity of these substrates posed a severe
limitation to the reaction selectivity, due not only to
the double N-methylation but primarily, to the forma-
tion of carbamates (Scheme 2).1a,c Apparently,
BAc2 and BAl2 mechanisms, i.e. the attack of the amine
Scheme 1. Mono-N-methylation of anilines with DMC.
* Corresponding author. Tel.: +39 041 234 8687; fax: +39 041 234 8620; e-mail: selva@unive.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.016

8140
M. Sel6a, P. Tundo / Tetrahedron Letters 44 (2003) 8139–8142
ucts C and MC, Scheme 2) and the oxidative deamina-
tion (product E: XC6H4CH2N=CHPh) of the amine 1a
take place to a large extent.4 The Bro¨nsted acidic zeolite
(HY) is even more unsatisfactory (entry 6): at a 30%
conversion, SMet is only 33%. We suggest that a strong
acid-base interaction may hold amine within the cata-
lyst pores,5 so that any advantage due to the smaller
size of the cation is cancelled.
Scheme 2. R=CH2Ph, Cy.
bubbled into the mixture and mantained throughout
the reaction. At intervals, samples (0.1 mL) were with-
drawn and were analyzed by both GC and GC/MS.
The structures of the products were also confirmed by
comparison with authentic samples of N-methylbenzyl-
amine, N,N-dimethylbenzylamine, methyl N-benzyl
carbamate, and methyl N-benzyl, N-methyl carbamate.
Much better results can be gathered for the N-methyla-
tion of compound 1a as well as of 1b–d, when reactions
are performed over NaY—a commercially available
faujasite—in the presence of a N2 stream (entries 7–10):
SMet of 91–100% are attained at conversions of 70–94%.
This improvement arises not only from the increase
of the methylation versus carbamation selectivity
(SMet/Carb), but also from a fall in formation of the
side-product E.
The same reaction was also performed under a static
N2-atmosphere (entries 1–6).
According to our previous experiments,1c without the
N2-bubbling, the increase of Lewis acidity of the cata-
lyst (going from CsY to LiY faujasites)3 shows a posi-
tive effect on the reaction rate (compare entries 1–2 and
5).
The same procedure is profitable also for the reaction
of phenethylamine (2a) and its o-methoxyderivative [2b:
o-MeOC6H4(CH2)2NH2] with DMC. The presence of a
N2 flow is an extremely simple and efficient method to
allow an excellent N-methylation selectivity (91–98%)
for compounds 2a–b, while the carbamation reaction is
practically ruled out.
However, at higher conversions (89 and 97%: entries
3–4), the selectivity (SMet) towards the N-methylation
reaction is clearly variable (43 and 64%, respectively).
Competitive side reactions, i.e. the carbamation (prod-
The data in Table 1 give a clear indication of the major
role played by the CO2 which, as is shown in Scheme 1,
Table 1. N-Methylation of amines 1a–d and 2a–b with DMC over MY zeolites
Products (%)a
SMet/Carb (%) SMet (%)
b
c
Entry
Amine
MY
T (°C)
t (h)
N2 flow
Conv. (%)
M
D
C
MC
E
1
2
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2b
LiY
90
90
90
110
90
90
90
90
90
90
90
90
7
7
No
No
No
No
No
No
Yes
Yes
Yes
Yes
Yes
Yes
43
40
89
97
36
30
94
70
90
70
90
63
34
30
8
-
18
6
20
30
37
48
39
20
9
NaY
NaY
NaY
CsY
HY
NaY
NaY
NaY
NaY
NaY
NaY
7
49
42
8
3
3
56
23
22
23
48
23
22
68
24
26
7
16
13
27
12
12
10
12
1
74
49
64
43
72
33
96
4d
5
6
7
8
9
4
8
3
5
1
55
98
91
70
34
51
22
48
37
1
1
91
98
99
10e
11
12
100
98
91
100
98
91
2
7
a The structures of all products were assigned by GC/MS analyses and by comparison with authentic samples.
b Methylation versus carbamation selectivity, SMet/Carb=[M+D/(M+D+C+MC)]×100.
c Overall N-methyl selectivity, SMet=[M+D/(M+D+C+MC+E)]×100.
d Entry 4: the reaction was carried out in a stainless-steel autoclave of 150 mL.
e Products M, D, C, and MC of entry 10 were obtained according to the structure of the reacting substrate 1d: PhCH(Me)NH2.

M. Sel6a, P. Tundo / Tetrahedron Letters 44 (2003) 8139–8142
8141
is an intrinsic co-product of DMC-mediated methyla-
tion reactions. As far as the methylation proceeds, CO2
chemisorbs into the catalyst cages,6 where it becomes
available for the reactant amine to form the corre-
sponding urethanes (Eq. (1)).7
for the lack of mono-N-methyl selectivity in such reac-
tions. In fact, the mechanism proposed for the forma-
tion
of
mono-N-methylanilines
as
well
as
mono-C-methyl derivatives of CH2-active com-
pounds—though with different catalysts—involves the
sequence shown in Scheme 4.1,10 The nucleophile
(NuH2) reacts first with DMC via the BAc2 mechanism
2RNH2+CO2 X RNHCO−2 RNH3+D“MCRNHCO2Me
(1)
to
yield
the
methoxycarbonylated
derivative
[Nu(CO2Me)H, Eq. (2)]. Then methylation (BAl2 mech-
anism) and demethoxycarbonylation reactions (Eqs. 5–
6) lead to the final product [Nu(Me)H]. The sequence
of BAc2–BAl2 processes preserves NuH2 from a double
methylation.
The BAc2 mechanism of Scheme 2 through the attack of
the amine to the carbonyl of DMC cannot take place
directly. On the other hand, when the zeolite surface is
kept free from CO2, the carbamation is hindered and
the aliphatic amine reacts only via the BAl2 mechanism:
N-methylation takes place exclusively (Eq. (2)).
By contrast, the more nucleophilic aliphatic amines
directly attack the methyl group of DMC as is shown in
Eq. (2), and when CO2 is purged from the reaction
mixture, a reversible methoxycarbonylation reaction is
not possible. Any selectivity towards mono-N-methyl
products is ruled out.
(2)
It should be noted that this behavior is peculiar to the
explored conditions and particularly to the catalyst
used. While the reaction of aliphatic amines and DMC
does not proceed significantly without a catalyst, in the
presence of g-Al2O3, carbamates form in good to excel-
lent yields (80–95%).8 Furthermore, this reaction occurs
without any CO2 promotion: under the conditions of
entries 7–12 of Table 1, benzylamine reacts with DMC
over g-Al2O3,9 to give methyl N-benzylcarbamate as the
sole product (24% after 4 h, Scheme 3).
On the whole, the following conclusions can be drawn:
(i) MY faujasites are efficient catalysts for the N-
methylation of aliphatic amines, but a high
chemoselectivity (methylation versus carbamation)
is reached through the tuning of the acid–base
properties of the zeolites and most of all, through
the removal of CO2 from the reactant mixture;
(ii) The BAl2 displacement of the amine on DMC is
the likely reaction mechanism. Accordingly, since
the mono-N- versus N,N-dimethylation selectivity
cannot be controlled, the procedure has valuable
potential for synthesis of tertiary amines.
Acknowledgements
Scheme 3. Direct BAc2 attack of benzylamine on DMC.
The direct BAc2 attack of the amine on the DMC
carbonyl is allowed in this case.
MIUR (Italian Ministry of University and Research)
and INCA (Interuniversity Consortium Chemistry for
the Environment; grant ‘Piano Ambiente Terrestre:
Chimica per l’Ambiente’ Legge 488/92) are gratefully
acknowledged for financial support.
With Y faujasites, the involvement of CO2 in the reac-
tion of aliphatic amines with DMC may also account
Scheme 4. Mono-methylation selectivity with DMC. NuH2: nucleophile susceptible of double alkylation; B: a basic site of the
catalyst.

8142
M. Sel6a, P. Tundo / Tetrahedron Letters 44 (2003) 8139–8142
Toshikazu, H.; Masayoshy, H.; Isao, I.; Yoshiki, O. J.
References
Chem. Soc., Chem. Comm. 1993, 194–195; (b) Kim, J. M.;
Cho, I. S.; Mariano, P. S. J. Org. Chem. 1991, 56,
4943–4955.
1. (a) Selva, M.; Bomben, A.; Tundo, P. J. Chem. Soc.,
Perkin Trans. 1 1997, 1041–1045; (b) Selva, M.; Tundo,
P.; Perosa, A. J. Org. Chem. 2001, 66, 677–680; (c) Selva,
M.; Tundo, P.; Perosa, A. J. Org. Chem. 2002, 67,
9238–9247.
5. (a) Narayan, S.; Deshpande, K. J. Mol. Catal. 1995, 104,
L109–L113; (b) Fesenko, E. A.; Barnes, P. A.; Parkes, G.
M. B.; Brown, D. R.; Naderi, M. J. Phys. Chem. B. 2001,
105, 6178–6185.
6. Zecchina, A.; Lamberti, C.; Bordiga, S. Catal. Today
1998, 41, 169–177.
7. (a) Aresta, M.; Quaranta, E. Tetrahedron 1991, 47, 9489–
9502; (b) Aresta, M.; Dibenedetto, A.; Quaranta, E.;
Boscolo, M.; Larrson, R. J. Mol. Catal. 2001, 174, 7–13;
(c) Selva, M.; Tundo, P.; Perosa, A. Tetrahedron Lett.
2002, 43, 1217–1219.
8. Vauthey, I.; Valot, F.; Gozzi, C.; Fache, F.; Lemaire, M.
Tetrahedron Lett. 2000, 41, 6347–6350.
9. We used the same g-Al2O3 (oxid C) reported in Ref. 8:
this catalyst was a generous gift from Degussa.
10. Selva, M.; Marques, C. A.; Tundo, P. J. Chem. Soc.,
Perkin Trans. 1 1994, 1323–1328.
2. Selva, M.; Tundo, P. Acc. Chem. Res. 2002, 35, 706–716.
3. The LiY and CsY zeolites were prepared from NaY
through known procedures (Onaka, M.; Ishikawa, K.;
Izumi, Y Chem. Lett. 1982, 1783–1786). The Lewis acid-
ity of these solids is higher with cations having a higher
charge to mass ratio: particularly, Li+ and Na+ mitigate
the amine nucleophilicity and due to their smaller size,
they allow an easier diffusion of reactants through the
zeolite cages. (a) Eberly, P. E. In Zeolite Chemistry and
Catalysis; 171, ACS Monograph, Rabo J. A., 1976; (b)
Barthomeuf, D. J. Phys. Chem. 1984, 88, 42–45; (c) Rao,
J. V. Chem. Commun. 1998, 269; (d) Su, B.; Barthomeuf,
D. Stud. Surf. Sci. Catal. 1995, 94, 598–605.
4. In all probability, the formation of product E is pro-
moted by O2 traces in the reaction mixture. (a)