Reaction of functionalized anilines with dimethyl carbonate over NaY faujasite. 3. Chemoselectivity toward mono-N-methylation

Article abstract of DOI:10.1021/jo034548a

In the presence of NaY faujasite, dimethyl carbonate (MeOCO₂Me, DMC) is a highly chemoselective methylating agent of functionalized anilines such as aminophenols (1), aminobenzyl alcohols (2), aminobenzoic acids (3), and aminobenzamides (4). The reaction proceeds with the exclusive formation of N-methylanilines without any concurrent O-methylation or N-/O-methoxy carbonylation side processes. Particularly, only mono-N-methyl derivatives [XC₆H₄NHMe, X = o-, m-, and p-OH; o- and p-CH ₂OH; o- and P-CO₂H; o- and p-CONH₂] are obtained with selectivity up to 99% and isolated yields of 74-99%. DMC, which usually promotes methylations only at T > 120 °C, is activated by the zeolite catalyst and it reacts with compounds 1, 2, and 4, at 90 °C. Aminobenzoic acids (3) require a higher reaction temperature (≥130 °C).

Full text of DOI:10.1021/jo034548a

Rea ction of F u n ction a lized An ilin es w ith Dim eth yl Ca r bon a te
over Na Y F a u ja site. 3. Ch em oselectivity tow a r d
Mon o-N-m eth yla tion
Maurizio Selva,* Pietro Tundo, and Alvise Perosa
Dipartimento di Scienze Ambientali dell’Universita` Ca’ Foscari,
Calle Larga S. Marta 2137, 30123-Venezia, Italy
selva@unive.it
Received April 29, 2003
In the presence of NaY faujasite, dimethyl carbonate (MeOCO2Me, DMC) is a highly chemoselective
methylating agent of functionalized anilines such as aminophenols (1), aminobenzyl alcohols (2),
aminobenzoic acids (3), and aminobenzamides (4). The reaction proceeds with the exclusive
formation of N-methylanilines without any concurrent O-methylation or N-/O-methoxy carbonylation
side processes. Particularly, only mono-N-methyl derivatives [XC6H4NHMe, X ) o-, m-, and p-OH;
o- and p-CH2OH; o- and p-CO2H; o- and p-CONH2] are obtained with selectivity up to 99% and
isolated yields of 74-99%. DMC, which usually promotes methylations only at T > 120 °C, is
activated by the zeolite catalyst and it reacts with compounds 1, 2, and 4, at 90 °C. Aminobenzoic
acids (3) require a higher reaction temperature (g130 °C).
SCHEME 1
In tr od u ction
The mono-N-methylation of primary aromatic amines
is a key transformation in many organic syntheses.1
However, both direct and indirect alkylation methods are
often problematic from synthetic and environmental
standpoints: (i) the reaction selectivity suffers from
competing bis-N-alkylation side reactions,2 (ii) common
methylating reagents (methyl halides and dimethyl
sulfate) are toxic and dangerous,3 and (iii) multistep
sequences (e.g., Eschweiler-Clarke-type reactions4 and
reduction processes5) may require harsh conditions not
compatible with labile functional groups or not readily
available starting materials.
We have recently reported that in the presence of
alkali-metal-exchanged Y-faujasites, a direct and high-
yield mono-N-methylation reaction of anilines can be
performed with the use of both dimethyl and alkylmethyl
carbonates [ROCO2Me; R ) Me, MeO(CH2)2O(CH2)2] as
the alkylating agents.6 Accordingly, the corresponding
N-methylamines are prepared with an unprecedented
selectivity of 90-97% at substantially quantitative con-
versions (Scheme 1).
Besides, the reaction is a truly environmentally friendly
procedure: dialkyl carbonates, particularly dimethyl
carbonate (DMC), are nontoxic compounds, which allow
catalytic alkylation processes without the production of
inorganic or organic wastes.3,6,7
In this paper, we report that the combined use of DMC
and sodium-exchanged Y-zeolite (NaY) is a valuable
protocol for the N-methylation of functionalized anilines
such as aminophenols (1), aminobenzyl alcohols (2),
aminobenzoic acids (3), and aminobenzamides (4). In
these cases, the reaction not only shows a very high
mono-N-methyl selectivity (up to 99%), but it proceeds
with a complete chemoselectivity toward the amino
group, the other functionalities (OH, CO2H, CONH2)
being fully preserved from alkylation and/or transesteri-
fication reactions.
* Corresponding author. Fax: +39 041 234 8620.
(1) (a) March, J . In Advanced Organic Chemistry, 4th Ed.; Wiley:
New York, 1991. (b) Carruthers, W. In Some Modern Synthetic Methods
of Organic Synthesis, 3rd ed.; Cambridge University Press: Cambridge,
1989.
(2) Gibson, M. S. In The Chemistry of the Amino Group; Patai, S.,
Ed.; Interscience Pub.: London 1968; Chapter 2, pp 45-62.
(3) (a) Ono, Y. Pure Appl. Chem. 1996, 68, 367. (b) Selva, M.; Tundo,
P. Acc. Chem Res. 2002, 35(9), 706-716.
(4) (a) Moore, M. L. Org. React. 1949, 5, 301. (b) Krishnamurthy, S.
Tetrahedron Lett. 1982, 3315. (c) Uchiyama, M.; et al. J . Am. Chem.
Soc. 1997, 119, 11425.
Resu lts a n d Discu ssion
Am in op h en ols (1). The direct alkylation, particularly
methylation, of aminophenols with conventional methy-
(6) (a) Selva, M.; Bomben, A.; Tundo, P. J . Chem. Soc., Perkin Trans.
1 1997, 1041; (b) Selva, M.; Tundo, P.; Perosa, A. J . Org. Chem. 2001,
66, 677. (c) Selva, M.; Tundo, P.; Perosa, A. J . Org. Chem. 2002, 67,
9238-9247.
(5) (a) Katritzky, A. R.; Drewniak, M.; Aurrecoechea, J . M. J . Chem.
Soc., Perkin Trans. 1, 1987, 2539. (b) Katritzky, A. R.; Rachwal, S.;
Rachwal, B. J . Chem. Soc., Perkin Trans. 1, 1987, 805. (c) Verardo,
G.; Giumanini, A. G.; Strazzolini, P.; Poiana, M. Synthesis 1993, 121.
(d) Feringa, B. L.; J ansen, J . F. G. A. Synthesis 1988, 184. (e) Kadin,
S. B. J . Org. Chem. 1973, 38, 1348.
(7) (a) Romano, U.; Rivetti, F.; Di Muzio, N., 1979, US Pat. 4,318,-
862, 1981; Chem. Abstr. 80141; (b) Rivetti, F.; Romano, U.; Delledonne,
D. In Green chemistry: Designing Chemistry for the Environment;
Anastas, P., Williamson, T. C., Eds.; ACS Symposium Series, Vol. 626,
1996; pp 70-80. The coproduct alcohol (ROH) can, in principle, be
recycled to the production of the carbonate.
10.1021/jo034548a CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/23/2003
7374
J . Org. Chem. 2003, 68, 7374-7378

Reaction of Anilines with Dimethyl Carbonate
TABLE 1. Rea ction of Am in op h en ols (1a -c) w ith DMCa
products
entry
1
substrate
catalyst
K2CO3
cosolvent (mL)
triglyme (35)
T, °C
t, h
% conv
2.5
%, by GC
% yieldb
1a
135
5
p-HOC6H4NHMe
p-MeOC6H4NH2
p-HOC6H4NHMe
p-MeOC6H4NH2
p-HOC6H4NHMe
p-MeOC6H4NH2
p-MeOC6H4NHMe
p-MeOC6H4NH2
p-MeOC6H4NMe2
1.7
0.7
0.7
0.8
5
2
3
1a
1a
1a
K2CO3
K2CO3
K2CO3
DME (35)
DMF (15)
DMF (15)
150
125
125
5
4
2
8
2
19
77
22
23
18
6
8
99
99
p-MeOC6H4NHCO2Me
p-MeOC6H4N(Me)CO2Me
p-HOC6H4NHMe (5a )
p-HOC6H4NHMe (5a )
p-HOC6H4NHMe, trace
p-HOC6H4NHMe, trace
o-HOC6H4NHMe (5b)
o-HOC6H4NHMe
4
5
6a
6b
7
1a
1a
1a
1a
1b
1b
NaY
NaY
NaY
NaY
NaY
p-TsOH
triglyme (35)
DME (35)
DMF (15)
MeCN (35)
-
90
86
90
81
90
5
7
24
24
3
99
100
<1
<1
100
35
91
99
89
99
15
18
96
8
-
130
4
unidentified productc
m-HOC6H4NHMe (5c)
9
1c
NaY
-
90
7
97
a
Reactions were carried out using a DMC/substrate molar ratio of 13 and of 39 for compounds 1a and 1b,c, respectively. The 1:NaY
weight ratio was of 1. b Isolated yield. c Unknown compound. Mass spectrum (M+, m/z ) 137) suggests the formation of a dimethyl derivative.
SCHEME 2. Mon o-N-m eth yla tion of
p-Am in op h en ol
lating reagents is unsatisfactory: because of the ambi-
dent nucleophilicity of such compounds, both N,N-
dimethyl and N,O-dimethyl byproducts form.8 Indirect
procedures that involve reductive alkylations,4b,9 hydro-
lytic cleavage of benzoxazoles,10 and O-demethylation
reactions11 are often preferred, even though sometimes
N,N-dimethyl derivatives are still the major products.12
To test the applicability of DMC as an alternative
methylating agent, p-aminophenol (1a ) was chosen as a
model compound. Initial reactions were carried out at
temperatures of 90-150 °C using solutions of 1a (1.0 g,
9.2 mmol), DMC (10 mL, 0.12 mol), and a cosolvent
(DMF, DME, triglyme, and MeCN13) in the presence
of both K2CO3 (2 equiv with respect to 1a ) and NaY
(1a : NaY in a 1:1 weight ratio).
Successively, solutions of o-aminophenol (1b) and
m-aminophenol (1c) in DMC (0.31 M, 30 mL) were made
to react with NaY as a catalyst (1b,c: NaY in a 1:1
weight ratio). Both 1b and 1c were sufficiently soluble
in DMC so that a cosolvent was not required. For a
comparison, the reaction of 1b was also run with an acid
catalyst (p-CH3C6H4SO3H, 2 equiv with respect to 1b).
Results are reported in Table 1.
tion of 1a take place simultaneously (entries 1 and 2).
This behavior reflects known aspects of the chemistry of
DMC: DMC, in fact, is reported as an alkylating agent
of phenols,14 and under basic catalysis, it exhibits a
double reactivity with anilines yielding both N-methyl-
anilines and urethanes [ArN(R)CO2Me, R ) H, Me].6,15
By contrast, in the presence of an amphoteric catalyst
such as the NaY zeolite,16 DMC turns out to be an
excellent chemoselective reagent: at quantitative conver-
sions, only N-methylation of 1a takes place in a very high
mono-N-methyl selectivity (>99%) and yield [p-HOC6H4-
NHMe (5a ) in isolated yield of 91%] (entries 4 and 5)
(Scheme 2).
The nature of the cosolvent is critical for the reaction:
glycol-derived dimethyl ethers such as triglyme and DME
give the best results (entries 4 and 5),17 while the
methylation is hindered when carried out in DMF and
MeCN (entry 6). This strong inhibiting effect can be
ascribed to a competitive adsorption of the polar cosolvent
and the substrate for the catalytic cages of the zeolite.6c,18
The data of Table 1 disclose a further relevant aspect.
As described by us and by others,3,14,15,17 DMC-mediated
In the presence of K2CO3, the reaction of 1a is not
selective: for example, at a conversion of 77%, a variety
of products of N- and O-methylation as well as of
N-methoxy carbonylation are observed (entry 3). Even
at very low conversions (∼2%), both N- and O-methyla-
(8) (a) Kalgutkar, A. S.; Kozak, K. R.; Crews, B. C.; Hochgesang, G.
C., J r.; Marnett, L. J . J . Med. Chem. 1998, 41, 4800. (b) Black, T. H.
Org. Prep. Proced. Int. 1989, 21, 179. (c) Yun, H. S. Chem. Abstr. 1974,
83, 42952.
(9) (a) Ehrlich, J . J . Am. Chem. Soc. 1948, 70, 2286. (b) Paucescu,
S. G. V.; Toth, L.; Munteanu, E. G.; Badea, M.; Kurt, S. Patent Appl.
RO 80-101931 (1980, 08/08); Chem. Abstr. 100, 120672.
(10) Sakurai, T.; Yamada, S.; Inoue, H. Bull. Chem. Soc. J pn. 1986,
59, 2666.
(14) (a) Lissel, M.; Schmidt, S.; Neumann, B. Synthesis 1986, 382.
(b) Tundo, P.; Selva, M. Chemtech 1995, 25, 31. (c) Bomben, A.; Selva,
M.; Tundo, P.; Valli, L. Ind. Eng. Chem. Res. 1999, 38, 2075. (d) Trotta,
F.; Tundo, P.; Moraglio, G. J . Org. Chem. 1987, 52, 1300.
(15) Trotta, F.; Tundo, P.; Moraglio, G. J . Org. Chem. 1987, 52, 1300.
(16) Barthomeuf, D. J . Phys. Chem. 1984, 88, 42. The basicity of
the solid comes from the basic oxygen atoms of its framework, while
Lewis acidity is due to alkaline metal cations.
(11) Guo, Z.; Ramirez, J .; Li, J .; Wang, P. G. J . Am. Chem. Soc. 1998,
120, 3726.
(12) J enner, G.; Taleb, A. B. J . Mol. Catal. 1992, 77, 247.
(13) Due to the poor solubility of 1a in DMC, the use of a cosolvent
was necessary. For any given cosolvent, a minumum volume was used
to obtain the complete solubilization of the substrate at room temper-
ature (see Table 1).
(17) Triglyme and diglyme have been already reported by us in the
alkylation of both phenols and amines with dialkyl carbonates. Perosa,
A.; Selva, M.; Tundo, P.; Zordan, F. Synlett 2000, 1, 272-274, and ref
6b.
(18) (a) Espeel, P. H. J .; Vercruysse, K. A.; Debaerdemaker, M.;
J acobs, P. A. Stud. Surf. Sci. Catal. 1994, 84, 1457. (b) J ayat, F.;
Sabater Picot, M. J .; Guisnet, M. Catal. Lett. 1996, 41, 181.
J . Org. Chem, Vol. 68, No. 19, 2003 7375

Selva et al.
TABLE 2. Mon o-N-m eth yla tion of p- a n d o-Am in oben zyl Alcoh ols (2a ,b), p- a n d o-Am in oben zoic Acid s (3a ,b), a n d p- a n d
o-Am in oben za m id es (4a ,b) w ith DMC a n d Na Y a s Ca ta lyst
products
b
entry
substrate (M)a
T, °C
t, h
% conv
% SM/D
%, by GC
% isolated yield
1
2
3
4
5
6
7
2a (0.32)
2b (0.32)
3a (0.12)
3b (0.12)
3b (0.12)
4a (0.15)
4b (0.32)
90
90
130
90
150
90
90
8
12
9
8
5
90
99
100
-
95
94
99
90
(p-HO)CH2C6H4NHMe (6a )
(o-HO)CH2C6H4NHMe (6b)
(p-HO2C)C6H4NHMe (7a )
-
(o-HO2C)C6H4NHMe (7b)
(p-H2NOC)C6H4NHMe (8a )
(o-H2NOC)C6H4NHMe (8b)
85
77
92
74
98
90c
95
93
94
90
89
94
83
86
91
24
22
96
100
a
b
In parentheses, the molar concentration of the solution of the substrate in DMC is reported. SM/D was the selectivity of mono-N-
methyl to N,N-dimethyl derivative expressed as the ratio {[ArNHMe]/([ArNHMe] + [ArNMe2])} × 100. c The product (p-HO2C)CH2C6H4NHMe
could not be analyzed by GC; the reported percentage was calculated from the 1H NMR spectrum.
methylation processes usually take place at high tem-
peratures (120-220 °C). This is also manifest in the
reaction of 1a carried out with K2CO3 (entries 1-3).
However, in the presence of NaY, the reaction of 1a
proceeds smoothly at the boiling point of DMC (90 °C).
The OH-substituent may account for this results with two
effects on the reactant amine: (i) the enhancement of
nucleophilicity and (ii) the easier diffusion/adsorption
through the polar channel and cages of the catalyst. It
should be noted that low-temperature methylations with
DMC have been recently reported in only a few instances
and they require activation with the use of very strong
bases (DBU) or microwave irradiation.19
N-acyl protection of amine groups give moderate yields
of mono-N-methyl products.23
Under the conditions previously described for 1b,c
(Table 1, entries 7 and 9), solutions of p- and o-ami-
nobenzyl alcohols and o-aminobenzamide (2a ,b and 4b)
in DMC (0.32 M, 30 mL) were made to react at 90 °C,
while for p-aminobenzamide 4a and o- and p-aminoben-
zoic acids (3a and 3b)swhich were less soluble in DMC
with respect to compounds 2a ,b and 4bsmore dilute
solutions were used: experiments were run with 0.15 M
(50 mL) solution of 4a and 0.12 M (30 mL) solution of
3a ,b in DMC, respectively. Moreover, reactions of com-
pounds 3 were carried out at a higher temperature (130-
150 °C). In all cases, the weight ratio NaY/substrate was
of 1.
Analogous results in terms of chemo- and mono-N-
methyl-selectivity are obtained in the NaY-catalyzed
reaction of o- and m-aminophenols with DMC: at 90 °C,
compounds 1b and 1c give the corresponding mono-N-
methyl derivatives [XC6H4NHMe, X ) o-OH (5b), m-OH
(5c)] in very high isolated yields (5b, 99%; 5c, 89%) and
without any concurrent O-methylation or methoxycar-
bonylation reactions (entries 7 and 9). On the contrary,
the use of an acidic catalyst (p-TsOH) strongly lowers
the overall reaction selectivity (entry 8).20
Results are reported in Table 2.
It should be first noted that under alkaline conditions,
dimethyl carbonate readily reacts with primary alcohols,
especially benzyl alcohols, and carboxylic acids to yield
transesterification and esterification products, respec-
tively (ArCH2
OCO2Me and RCO2Me).19,24,25 And, although
with more difficulty, carboxamides gives N-methyla-
mides26 (Scheme 3, path a).
The use of NaY as a catalyst completely modifies this
scenario. Table 2 shows that reactions of DMC with
substrates 2-4 are highly chemoselective: only the
amine function undergoes methylation, while OH, CO2H,
and CONH2 groups do not react at all. Particularly, in
all cases the corresponding mono-N-methyl derivatives
[XC6H4NHMe; X ) CH2OH (6), CO2H (7), and CONH2
(8)] are obtained with a selectivity of 90-99% and
isolated yields of 74-92% (Scheme 3, path b).
Table 2 also indicates that aminobenzyl alcohols 2 are
the more active substrates (entries 1 and 2), while
aminobenzamides 4, which still react at 90 °C, require
longer reaction times (entries 6 and 7). Aminobenzoic
acids 3 yield mono-N-methyl derivatives only at temper-
ature over 130 °C (entries 3-5). Although the N-alkyla-
tion of anilines over NaY is expected to occur within the
zeolitic cages,6,18,27,28 this reactivity scale is likely due
Finally, two preliminary experiments were run to
assay the catalytic activity of NaY: solutions of com-
pounds 1b and 1c in DMC (0.31 M, 30 mL) were made
to react in the presence of a lower amount of the zeolite
(1: NaY ) 10 weight ratio). As expected, both reactions
were slower, but isolated yields of 5b and 5c were still
satisfactorily: 93% and 92% after 38 and 42 h, respec-
tively.
Am in oben zyl Alcoh ols (2), Am in oben zoic Acid s
(3), a n d Am in oben za m id es (4). The direct methylation
of compounds 2-4 with MeI or Me2SO4,21 as well as the
reductive methylation,22 affords mainly or exclusively
N,N-dimethyl derivatives, while indirect methods via
(19) (a) Shieh, W.-C.; Dell, S.; Repic, O. Org. Lett. 2001, 3, 4279. (b)
Shieh, W.-C.; Dell, S.; Repic, O. J . Org. Chem. 2002, 67, 2188.
(20) In the reaction of anilines with organic carbonates, activation
by acidic organic catalysts has been already proposed for the synthesis
of carbamates. Aresta, M.; Berloco, C.; Quaranta, E. Tetrahedron 1995,
51, 8073.
(21) (a) Lu, B. Pat. Appl. CN 99-112785, Chem Abstr. 2000, 133,
163940. (b) Wang, C. L. J . PCT Int. Appl. WO 91-US193, Chem. Abstr.
1991, 115, 280027. (c) Wen, S.; Zhu, N. Huaxue Shiji 1990, 12, 243;
Chem. Abstr. 1991, 114, 81171.
(22) (a) J ung, Y. J .; Bae, J . W.; Yoon, C.-O. M.; Byung, W.; Yoon, C.
M. Synth. Commun. 2001, 31, 3417. (b) Nishimura, T.; Takeda, F.;
Wada, M.; Kanamura, Y. J pn. Pat. Appl. J P 98-273619; Chem. Abstr.
2000, 132, 250975.
(23) Skupinski, W.; Pichnej, L.; Pakula, R.; J ahn-Andrychowska, W.;
Trojanowska, Z.; Butkiewicz, K. Arch. Pharm. (Weinheim, Ger.) 1986,
319, 862.
(24) (a) Tundo, P. In Continuous Flow Methods in Organic Synthesis;
Horwood, E. Pub.: Chichester (UK), 1991. (b) Perosa, A.; Selva, M.;
Tundo, P.; Zordan, F. Synlett 2000, 1, 272-274.
(25) (a) Loosen, P.; Tundo, P.; Selva, M. US Patent 5,278,333, 1994.
(b) Shieh, W.; Dell, S.; Repic, O. Tetrahedron Lett. 2002, 43, 5607.
(26) Ben Taleb, A.; J enner, G. J . Mol. Catal. 1993, 84, L131.
7376 J . Org. Chem., Vol. 68, No. 19, 2003

Reaction of Anilines with Dimethyl Carbonate
SCHEME 3
SCHEME 4
by the use of NaY zeolite as a catalyst with amphoteric
properties able to promote exclusively the reactivity of
the amine function. The features of DMC as a methylat-
ing agent additionally increase the synthetic potential
of the procedure, since only mono-N-methyl anilines are
obtained with selectivity up to 99%.
Although the solubility of compounds 1-4 in DMC and,
more generally, reaction conditions need a case-by-case
optimization, other advantageous aspects are the sim-
plicity of the procedure and its intrinsic environmentally
benign character as nontoxic methylating agent/catalyst
are used, no wastes are generated, and derivatization
reactions with protecting groups are avoided.30
Exp er im en ta l Section
to the electronic effects of substituents,29 rather than to
their steric requisites.
A high chemoselectivity was also evident in the NaY-
catalyzed reactions of methyl and ethyl anthranilates
(compounds 9a and 9b) with diethyl carbonate (DEC) and
DMC, respectively (Scheme 4).
All compounds used were ACS grade and were employed
without further purification. The zeolite NaY was dried before
each reaction by heating at 70 °C, under vacuum overnight.
1H NMR spectra were recorded on a 300 MHz spectrometer.
GLC and GC/MS (70 eV) analyses were run using CPSil24CB
and HP5 capillary columns (30 m), respectively.
Rea ction of Com p ou n d s 1, 2, a n d 4 w ith DMC. Gen er a l
P r oced u r e. A two-necked, jacketed, 100 mL round-bottomed
flask fitted with a reflux condenser capped with a CaCl2 tube,
an adapter for the withdrawal of samples, and a magnetic bar
was loaded with the titled compounds and DMC according to
the following concentrations: (i) 0.31 M solutions (30 mL) of
o- and m-aminophenols (1b,c, 1.0 g, 9.2 mmol), (ii) 0.32 M
solutions (30 mL) of o- and p-aminobenzyl alcohols (2a ,b: 1.18
g, 9.6 mmol), (iii) 0.32 M solution (30 mL) of o-aminobenzamide
(4b: 1.30 g, 0.0096 mmol), (iv); 0.15 M solution (50 mL) of
p-aminobenzamide (4a : 1.0 g, 0.0075 mmol). In the case of
p-aminophenol 1a , solutions of 1a (1.0 g, 9.2 mmol), DMC (10
mL, 0.12 mol), and a cosolvent such as triglyme (35 mL), DMF
(15 mL), 1,2-dimethoxyethane (DME, 35 mL), or MeCN (35
mL) were used; the cosolvent was added in the minimun
volume to allow a complete solubilization of the substrate at
room temperature. If not otherwise indicated, the catalyst NaY
was then added in a weight ratio of 1 with respect to the
reactant amines.
Both reactions yielded exclusively the corresponding
mono-N-alkylated derivatives (10a ,b). Although the alky-
lation of the esters 9 was slow even at 150 °C (after 8 h,
conversions of 9a and 9b were of 25% and 65%, respec-
tively), no trace of the transesterification products [(o-
MeO2C)C6H4NHMe or (o-EtO2C)C6H4NHEt] was ob-
served.
Con clu sion s
A powerful method is described for a straightforward
and selective N-methylation of anilines bearing a variety
of functional groups which, though susceptible to undergo
themselves methylation reactions, are kept untouched.
This fine control of the chemoselectivity is made possible
(27) (a) Fu, Z.-H.; Ono, Y. Catal. Lett. 1993, 22, 277. (b) Hari Prasad
Rao, P. R.; Massiani, P.; Barthomeuf, D. Catal. Lett. 1995, 31, 115.
(28) Czjiek, M.; Vogt, T.; Fuess, H. Zeolites 1991, 11, 832.
(29) The OH and CH2OH groups have electron-donating effects on
the aryl ring. For the other substituents, the electron-withdrawing
effect follows the order CO2H > CONH2. (March, J . In Advanced
Organic Chemistry, 4th ed.; Wiley: New York, 1991; pp 681-685).
Accordingly, the nucleophilicity order of the tested amines should be
1 > 2 > 3 > 4.
The flask was heated at the reflux temperature of DMC (90
°C), while the mixture was vigorously stirred. At intervals,
samples (0.1 mL) were withdrawn and were analyzed by GC
and GC/MS.
(30) Anastas, P. T.; Warner, J . C. In Green Chemistry, Theory and
Practice; Oxford University Press: Oxford, 1998.
J . Org. Chem, Vol. 68, No. 19, 2003 7377

Selva et al.
In the case of 1a , when DME and MeCN were used as
cosolvents, reactions were run at 86 and 81 °C, respectively.
Once the reaction was completed, the pale yellow suspension
was filtered and the solid catalyst was thoroughly washed with
MeOH (15 mL). After rotary evaporation, the mono-N-methy-
lated products XC6H4NHMe, X ) o-, m-, and p-OH (5a , 5b,
and 5c); o-CH2OH (6b); and o-CONH2 (8b) were pure (94-
99% by GC) and characterized as such. Compounds 6a
(p-HOCH2C6H4NHMe) and 8a (p-H2NCOC6H4NHMe) were
purified by flash chromatography (eluant: AcOEt/petroleum
ether, 1:4 v/v).
p-Aminophenol 1a was also made to react with DMC in the
presence of K2CO3 as a catalyst. Since no reaction took place
at the reflux temperature (90 °C), experiments were run by
loading an autoclave (150 mL of internal volume) with a
mixture of 1a (1.0 g, 9.2 mmol), K2CO3 (2.53 g, 18.3 mmol),
DMC (10 mL), and a cosolvent [triglyme (35 mL) or DME (35
mL), or DMF (15 mL)], which was heated at the desired
temperature (125-150 °C; see Table 1, entries 1-3) and kept
under magnetic stirring. After a time interval (entries 1-3,
Table 1), the autoclave was cooled to room temperature and
vented. Then, the mixture was analyzed by GC and GC/MS.
Rea ction of Com p ou n d s 3 w ith DMC. Gen er a l P r oce-
d u r e. A stainless steel autoclave (150 mL of internal volume)
was charged with a solution of compound 3a or 3b in DMC
(0.12 M, 30 mL) and NaY (3: NaY ) 1 weight ratio). Before
the reaction, air was removed by purging with N2 stream at
room temperature. The autoclave was then heated by an oil-
circulating jacket at the desired temperature (130-150 °C),
while the mixture was kept under magnetic stirring. A
thermocouple fixed into the autoclave head maintained the
temperature throughout the reaction. Once the reaction was
completed, the autoclave was cooled to room temperature,
vented, and opened. The workup of the suspension was carried
out as described in the procedure above. Both compounds 7a ,b
were purified by flash chromatography (eluant: AcOEt/
petroleum ether, 1:3 v/v).
°C, tends to liquefy at room temperature; 6b, yellow oil, lit.33
bp 84-86 °C/0.3 mm; 7a , mp 151.5-152.5 °C (white solid) (lit.34
mp 155-157); 7b, mp 170-173 °C (lit.34b mp 178-179 °C); 8a ,
mp 137-139 °C (white solid) (lit.34b,35 mp 143-145 °C); 8b,
mp 159-160.5 °C (white solid) (lit.34b mp 162-163 °C).
Compound 7a was characterized by 1H NMR: its structure
was also confirmed by comparison with an authentic com-
mercial sample.
1H NMR and GC/MS spectra of all compounds are available
as Supporting Information.
Rea ction of Com p ou n d s 9 w ith DMC. Gen er a l P r oce-
d u r e. Compounds 9a (methyl anthranilate) and 9b (ethyl
anthranilate) were made to react with DEC (diethyl carbonate)
and DMC, respectively. Experiments were carried out in an
autoclave at 150 °C, using the above-described procedure for
the reaction of compounds 3. In particular, solutions of 9a (1.0
g, 6.6 mmol) in DEC (35 mL, 0.29 mol) and of 9b (0.9 g, 5.5
mmol) in DMC (35 mL, 0.39 mol) were employed. NaY was
the catalyst (weight ratio 9: NaY ) 1). After 8 h, conversions
of 9a and 9b were 25% and of 65%, respectively, with the
formation of the corresponding methyl N-ethylanthranilate [(o-
CO2Me)C6H4NHEt: 10a ,36] and ethyl N-methylanthranilate
[(o-CO2Et)C6H4NHMe: 10b37] as the sole products. Compounds
10a ,b were not isolated from the reaction mixture: their
structure was assigned by GC/MS and the related spectra are
available as Supporting Information.
Ack n ow led gm en t. MIUR (Italian Ministry of Uni-
versity) and INCA (Interuniversity Consortium Chem-
istry for the Environment) are gratefully acknowledged
for financial support.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and GC/
MS spectra for all mono-N-methylated amines 5a -c, 6a ,b,
7a ,b, 8a ,b. This material is available free of charge via the
Internet at http://pubs.acs.org.
Compound 3b was also made to react with DMC at 90 °C
following the procedure above-described for amines 1, 2, and
4.
All compoundssexcept for 7a swere characterized by GC/
MS and by 1H NMR. Spectroscopic and physical properties
were in agreement with those reported in the literature: 5a ,
mp 80-83 °C (dark brow solid) (lit.31 mp 87); 5b, mp 93-95
°C (yellow solid) (lit.31b,32 mp 96-97 °C); 5c, brown oil, lit.31b
bp 190 °C/40 mm (solidifies on standing); 6a , yellow solid at 4
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(31) (a) Guo, Z.; Ramirez, J .; Li, J .; Wang, P. G. J . Am. Chem. Soc.
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7378 J . Org. Chem., Vol. 68, No. 19, 2003