N-Alkoxymethylation of Carboxamides Catalyzed by Br?nsted Acids

Article abstract of DOI:10.1055/s-2003-42090

The reaction of carboxamides and dialkoxymethanes can be affected by sulfonic acids (methanesulfonic acid, p-toluene-sulfonic acid, and Nafion-H SAC-13 silica nanocomposite) to yield N-alkoxymethylcarboxamides. Various types of N-alkyl- and N-aryl-substituted acetamides can be reacted in a one-step procedure to give the products in moderate to good yields.

Full text of DOI:10.1055/s-2003-42090

LETTER
2255
N-Alkoxymethylation of Carboxamides Catalyzed by Brønsted Acids
N
-Alkox
s
ymethylat
t
ion of
C
v
arboxamide
á
s
n Ledneczki,a Pál M. Agócs,b Árpád Molnár*a
a
Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary
b
PACIFIC Ltd., Lóczy L. 10/A., Veszprém, 8200, Hungary
Fax +36(62)544200; E-mail: amolnar@chem.u-szeged.hu
Received 7 August 2003
amides and phosphonamides in the presence of various
Lewis acids was disclosed.10 Specifically, dimethoxy-
methane and diethoxymethane were applied to synthesize
the corresponding N-alkoxymethylated derivatives in
Abstract: The reaction of carboxamides and dialkoxymethanes can
be affected by sulfonic acids (methanesulfonic acid, p-toluene-
sulfonic acid, and Nafion-H SAC-13 silica nanocomposite) to yield
N-alkoxymethylcarboxamides. Various types of N-alkyl- and N-
aryl-substituted acetamides can be reacted in a one-step procedure good to excellent yields.
to give the products in moderate to good yields.
Even though that earlier results with Brønsted acid cata-
lysts did not seem to be promising,11,12 we have found that
the title procedure can be successfully carried out under
such conditions. Here we report our findings with respect
to the application of dialkoxymethanes as alkoxymeth-
ylating agents for the N-alkoxymethylation of carbox-
amides catalyzed by Brønsted acids.
Key words: acetals, amides, carbocations, catalysis, protecting
groups
N-Aryl-N-alkoxyalkyl derivatives of chloroacetamide
called chloroacetanilide herbicides, are important com-
mercial herbicides, which are used to control annual
grasses and certain broadleaf weeds. Typical N-Aryl-N-
alkoxymethyl products are alachlor (1a), acetochlor (1b),
propisochlor (1c), and butachlor (1d) (Figure 1).1
Preliminary attempts by applying various Brønsted acid
catalysts in the reaction of dimethoxymethane and chloro-
acetanilide under reflux indicated that the reaction is slow
and gives the desired product in very low yield. Then we
turned our attention to higher acetal homologues and
found that by continuously removing the corresponding
alcohol formed in the process shifts the equilibrium to-
wards product formation. In fact, alcohols and the corre-
sponding dialkoxymethanes form azeotropic mixtures,
which having lower boiling points can be distilled off eas-
ily. Unfortunately, the azeotropic mixture of methanol
and dimethoxymethane contains a very high amount of
the acetal (91.8 weight%).13 Since azeotrope distillation
quickly removes most of the reagent, this method cannot
be applied for the synthesis of N-methoxymethylated car-
boxamides. Representative examples collected in Table 1,
consequently, are given for ethoxymethylation, isopro-
poxymethylation, and butoxymethylation reactions
(Scheme 1).14,15
Figure 1
These compounds are prepared by multi-step procedures,
which involve the corresponding azomethine and N-chlo-
romethyl derivatives. These intermediates are not easy to
handle and the methods give the desired products in low
overall yields.2–4 Another possibility to introduce the
alkoxymethyl moiety into carboxamides is the use of
chloromethyl alkyl ethers.5 However, the only such re-
agent easily available is chloromethyl methyl ether. Even
though N-methoxymethylated carboxamides were shown
to be easily converted into other N-alkoxymethylated de-
rivatives,6 this process is limited because of the known
carcinogenity of chloromethyl methyl ether.
Earlier reports showed, however, that methoxymeth-
ylation by formaldehyde dimethylacetal induced by
Lewis acids7,8 or phosphorous pentoxide9 is a feasible
procedure. This indicated the possibility of the use of di-
alkoxymethanes as alkoxymethylating agents. Indeed, in
a recent article the general use of dialkoxymethanes for
the N-alkoxymethylation of secondary amides, sulfon-
Scheme 1
Since a part of the reacting acetal is removed from the
reaction mixture during the reaction the method requires
the use of an excess of the acetal. Varying the ratio of the
reacting compounds we found that a molar excess of 15 of
the acetal is necessary to achieve satisfactory conversions.
In addition, the use 20 mol% of p-toluenesulfonic acid the
best Brønsted acid found is required.
SYNLETT 2003, No. 14, pp 2255–2257
0
6
.1
1
.2
0
0
3
Advanced online publication: 15.10.2003
DOI: 10.1055/s-2003-42090; Art ID: G20103ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2256
I. Ledneczki et al.
LETTER
Working with diethoxymethane we always encountered showed, however, that dimers are not formed under the
the problem of low yields of product formation (entries 2, reaction conditions applied in the present study.
4 and 9, compounds 2a, 4a, and 10a). This appears to be
In addition to p-toluenesulfonic acid comparative studies
associated with the problem of low solubility. The starting
with other Brønsted acids, the commercially available
carboxamides do not completely dissolve in diethoxy-
Nafion-H silica nanocomposite (SAC-13), and some
methane and a part of the starting material was still found
Lewis acids were also carried out in the synthesis of com-
as undissolved solid after the usual 5 hour reaction, which
pound 5b [N-phenyl-N-(isopropoxymethyl)acetamide]
was satisfactory for other acetals. In addition to this
using identical reaction conditions. As seen (Table 2) the
solubility problem, the tendency of N-alkoxymethyl car-
yield with methanesulfonic acid is close to that found
for p-toluenesulfonic acid, and the solid acid Nafion-H
SAC-13 silica nanocomposite gives identical result. In
contrast, Lewis acids are less effective possibly due to the
boxamides to undergo hydrolysis during workup and their
solubility in water observed earlier10 result in relatively
low yields in some other cases (entries 1–3).
A further possible reason for such low yields may be the loss of the acid catalysts as a result of distilling off the
formation of dimers as was observed in other studies.8,12 alcohol–acetal azeotrope mixture.
Careful analysis of the reaction mixtures before work-up
Table 2 Synthesis of 5b Using Various Brønsted and Lewis Acids
Entry
Acid
GC yield (%)
Table 1 N-Alkoxymethyl Derivatives of Carboxamides (Scheme 1)
1
2
3
4
5
6
concd H2SO4
CF3COOH
CH3SO3H
SAC-13
BF3·OEt2
SnCl4
32
3
En- Car-
try boxa-
mide
Product
Isolated
yield (%)
64
79
51
26
X
R1
(RO)2CH2
1
2
H
H
Bu
a) R = i-Pr
b) R = Bu
a) R = Et
2a
2b
3a
3b
3c
42 (49)a
25 (30)
43 (50)
51 (59)
52 (69)
48 (55)
48 (61)
44
The reaction can be interpreted by invoking a carbocation-
ic mechanism (Scheme 2). Dialkoxymethanes undergo
C–O bond cleavage on the action of the Brønsted acid to
form the corresponding primary alkoxymethyl cation
stabilized by charge delocalization with the neighboring
oxygen atom.16 This is sufficiently reactive to attack the
weakly nucleophilic carboxamide nitrogen to form, after
deprotonation, the product N-alkoxymethylcarboxamides.
i-Bu
b) R = i-Pr
c) R = Bu
a) R = i-Pr
b) R = Bu
a) R = Et
3
4
H
H
c-Hex
4a
4b
5a
5b
5c
Ph
b) R = i-Pr
c) R = Bu
70
72
5
6
7
8
9
Cl 2,6-di-MePh a) R = i-Pr
b) R = Bu
6a
6b
7a
1d
8a
8b
9a
9b
10a
72 (80)
77 (85)
60 (66)
67
Cl 2,6-di-EtPh a) R = i-Pr
b) R = Bu
Scheme 2
Cl 4- i-PrPh
a) R = i-Pr
b) R = Bu
a) R = i-Pr
b) R = Bu
a) R = Et
71
60 (73)
66 (77)
69 (77)
50
Acknowledgment
H
H
4-BrPh
We are most grateful for the financial support from the Hungarian
National Science Foundation (OTKA grant T042603).
4-MeOPh
b) R = i-Pr 10b
c) R = Bu 10c
71
71 (79)
a GC yield (%).
Synlett 2003, No. 14, 2255–2257 © Thieme Stuttgart · New York

LETTER
N-Alkoxymethylation of Carboxamides
2257
N-Isobutyl-N-(isopropoxymethyl)acetamide (3b). 1H
NMR (500 MHz, CDCl3): major component d = 0.88 (d,
3J = 6.6, 6 H, 2 × CH3), 1.18 (d, 3J = 6.0, 6 H, 2 × CH3),
1.92–2.00 (m, 1 H, CH), 2.17 (s, 3 H, CH3), 3.24 (d, 3J = 7.4,
2 H, CH2), 3.65 (m, 1 H, CH), 4.67 (s, 2 H, CH2); minor
component d = 0.93 (m, 6 H, 2 × CH3), 1.15 (m, 6 H,
2 × CH3), 1.92–2.00 (m, 1 H, CH), 2.12 (s, 3 H, CH3), 3.16
(d, 3J = 7,6, 2 H, CH2), 3.70 (m, 1 H, CH), 4.89 (s, 2 H, CH2).
13C NMR (500 MHz, CDCl3): major component d = 171.5
(CO), 77.8 (NCH2O), 68.8 (OCH), 53.4 (NCH2), 27.3 (CH2),
21.9 (CH2), 21.2 (CH3CO), 20.0 (2 × CH3); minor
component d = 171.5 (CO), 72.2 (NCH2O), 68.9 (OCH),
53.9 (NCH), 27.6 (CH2), 22.1, (2 × CH3), 21.7 (CH3CO),
19.9 (2 × CH3). Anal. Calcd for C10H21NO2: C, 64.13; H,
11.30; N, 7.48. Found: C, 63.72; H, 11.15; N, 7.17.
N-(4-Isopropylphenyl)-N-(isopropoxymethyl)chloro-
acetamide (8a). 1H NMR (500 MHz, CDCl3): d = 1.21 (d,
3J = 5.9, 6 H, 2 × CH3), 1.26 (d, 3J = 6.9, 6 H, 2 × CH3),
2.92–2.97 (m, 1 H, CH), 3.87 (s, 2 H, CH2Cl), 3.90–3.94 (m,
1 H, CH), 5.11 (s, 2 H, CH2), 7.16 (d, 3J = 8.1, 2 H, Ar-H),
7.28 (d, 3J = 7.9, 2 H, Ar-H). 13C NMR (500 MHz, CDCl3):
d = 167.2 (CO), 149.7 (CPh), 137.5 (NPh) 128.0 (Ph), 127.8
(Ph), 75.9 (NCH2O), 69.8 (OCH), 42.2 (CH2Cl), 33.7
(PhCH), 23.8 (2 × CH3), 22.2 (2 × CH3). Anal. Calcd for
C15H22NO2Cl: C, 63.48; H, 7.81; N, 4.94. Found: C, 63.38;
H, 7.66; N, 4.53.
References
(1) The Pesticide Manual, 11th Ed.; Tomlin, C. D. S., Ed.;
British Crop Protection Council: Farnham, 1997.
(2) Olin, J. F. U.S. Patent 3442945, 1969.
(3) Vogel, C.; Aebi, R. German Patent 2328340, 1973; Chem.
Abstr. 1974, 80, 82440.
(4) Vértesi, E.; Huszák, G. y.; Pelyva, J.; Kovács, M.; Damján,
J.; Kolonics, Z.; Kulcsár, L.; Sümegi, E.; Gyrfi, B.; Vass, A.;
Lendvai, L.; Tömördi, E.; Szabó, L. J.; Nagy, B.; Nádasdy,
M.; Haas, A.; Hung, Patent 177876, 1979.
(5) Venkov, A. P.; Minkov, M. M.; Lukanov, L. K. Synth.
Commun. 1989, 19, 2133.
(6) Danikiewicz, W.; Szmigielski, R. Synth. Commun. 2001, 31,
3047.
(7) Dardoize, F.; Gaudemar, M.; Goasdoue, N. Synthesis 1977,
567.
(8) Lukyanov, O. A.; Pokhvisneva, G. V.; Ternikova, T. V. Izv.
Akad. Nauk SSSR Ser. Khim. 1994, 1452.
(9) Alzeer, J.; Nock, N.; Wassner, G.; Masciadri, R.
Tetrahedron Lett. 1996, 37, 6857.
(10) Szmigielski, R.; Danikiewicz, W. Synlett 2003, 372.
(11) Bicking, J. B.; Kwong, S. F.; Fisher, M. H.; Nicholson, W.
H. J. Med. Chem. 1965, 8, 95.
(12) Cauliez, P.; Rigo, B.; Fasseur, D.; Coutuier, D. J.
Heterocycl. Chem. 1991, 28, 1143.
(13) Horsley, L. H. Adv. Chem. Ser. 1952, 6, 64.
(14) General Procedure: A mixture of the secondary amide
(7 mmol) and the dialkoxymethane (105 mmol) was refluxed
in the presence of p-toluenesulfonic acid (1.4 mmol) under
magnetic stirring for 5 h and the azeotrope of the
corresponding alcohol formed and the original acetal was
distilled off to shift the equilibrium for the formation of the
N-alkoxy-methylated products (in the case of
N-(4-Bbromophenyl)-N-(butoxymethyl)acetamide (9b).
1H NMR (500 MHz, CDCl3): d = 0.92 (t, 3J = 7.4. 3 H, CH3),
1.33–1.40 (m, 2 H, CH2), 1.54–1.58 (m, 2 H, CH2), 1.89 (s,
3 H, CH3), 3.56 (s, 2 H, CH2), 5.04 (s, 2 H, CH2), 7.11 (d,
3J = 8.4, 2 H, Ar-H), 7.54 (d, 3J = 8.1, 2 H, Ar-H). 13C NMR
(500 MHz, CDCl3): d = 170.9 (CO), 141.3 (NPh), 132.6
(Ph), 129.7 (Ph), 122.0 (BrPh), 77.2 (NCH2O), 68.6
(OCH2), 31.6 (CH2), 22.6 (CH3CO), 19.2 (CH2), 13.7 (CH3).
Anal. Calcd for C13H18NO2Br: C, 52.01; H, 6.04; N, 4.67.
Found: C, 51.88; H, 5.93; N, 5.10.
N-(4-Methoxylphenyl)-N-(ethoxymethyl)acetamide
(10a). 1H NMR (500 MHz, CDCl3): d = 1.21 (t, 3J = 7.1, 3
H, CH3), 1.87 (s, 3 H, CH3), 3.64 (q, 3J = 7.0, 2 H, CH2), 3.83
(s, 3 H, CH3), 5.05 (s, 2 H, CH2), 6.92 (d, 3J = 8.7, 2 H, Ar-
H), 7.12 (d, 3J = 8.7, 2 H, Ar-H). 13C NMR (500 MHz,
CDCl3): d = 171.7 (CO), 159.1 (CH3OPh), 135.0 (NPh),
129.1 (Ph), 114.7 (Ph), 77.1 (NCH2O), 64.0 (OCH2), 55.3
(CH3O), 22.7 (CH3CO), 15.0 (CH3). Anal. Calcd for
C12H17NO3: C, 64.55; H, 7.67; N, 6.27. Found: C, 64.96; H,
7.63; N, 6.22.
diethoxymethane, a 20-cm column with glass Fenske
packing was used). After cooling the reaction mixture was
neutralized with saturated aq NaHCO3, washed with NaCl
solution and dried (Na2SO4). The unreacted acetal still
present in the organic layer was removed by distillation at
atmospheric pressure (in the case of diethoxymethane) or
under reduced pressure (in the case of diisopropoxymethane
and dibutoxymethane). The product was purified by column
chromatography on silica gel using hexane–EtOAc mixture
as the eluent.
(15) Properties are given for compounds 3b, 8a, 9b, and 10a as
representative examples of new compounds.
The presence of isomers (rotamers), the major and minor
components in the case of compound 3b, is due to the
hindered rotation about the carbonyl C–N bond in
carboxamides.17 Because of the conjugation between the
lone pair of electrons of nitrogen and the carbonyl p-bond an
electron delocalization occurs resulting in a significant p
character of the C–N bond.
(16) (a) Ogata, Y.; Kawasaki, A. In The Chemistry of the
Carbonyl Group; Zabicky, J., Ed.; Interscience: London,
1970, 20. (b) Olah, G. A.; Prakash, G. K. S.; Sommer, J.
Superacids; Wiley-Interscience: New York, 1985, 116.
(17) Stewart, W. E.; Siddal, T. H. III Chem. Rev. 1970, 70, 517.
Synlett 2003, No. 14, 2255–2257 © Thieme Stuttgart · New York