Novel and efficient one-pot synthesis of N'-alkyl-N,N-dimethylacetamidines

Article abstract of DOI:10.3184/174751911X556963

An efficient method for the synthesis of N'-alkyl-N,N-dimethylacetamidine derivatives under mild conditions and in excellent yields involved reacting primary alkylamines with N,N-dimethylacetamide in the presence of LiCl as a catalyst and methanol as the acetalising reagent.

Full text of DOI:10.3184/174751911X556963

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 119
FEBRUARY, 119–120
Novel and efficient one-pot synthesis of
Np-alkyl-N,N-dimethylacetamidines
Zhe-Qi Lia and Hui-Long Wangb*
aEnvironmental Science & Engineering Institute, Dalian Jiaotong University, Dalian 116023, P. R. China
bDepartment of Chemistry, Dalian University ofTechnology, Dalian 116023, P. R. China
An efficient method for the synthesis of Np-alkyl-N,N-dimethylacetamidine derivatives under mild conditions and
in excellent yields involved reacting primary alkylamines with N,N-dimethylacetamide in the presence of LiCl as a
catalyst and methanol as the acetalising reagent.
Keywords: N′-alkyl-N,N-dimethylacetamidine, N,N-dimethylacetamide, primary amines, lithium chloride, methanol
Results and discussion
Amidine derivatives are an important class of intermediates
and precursors for the synthesis of nitrogen heterocyclic com-
pounds.1 Some amidine derivatives possess physiological
activity and have been used as antibiotics, diuretics, antiphlo-
gistic drugs, anthelmintics and broad-spectrum acaricides.2–4
In recent years, long-chain alkyl amidine tertiary amine com-
pounds have attracted attention for their potential use as new
types of switchable surfactants.5–7 For example, N′-alkyl-N,N-
dimethylacetamidines can reversibly be converted to bicarbon-
ate salt surfactants by using carbon dioxide and the nitrogen
as a trigger, respectively.8 Such a surfactant would be suitable
for recycling.
N′-Alkyl-N,N-dimethylacetamidines generally are synthe-
sised by heating an equimolar amount of the appropriate long
chain primary amine with dimethylacetamide dimethyl acetal,
which can be obtained from the reaction of N,N-dimethylacet-
amide (DMAc) with dimethyl sulfate followed by the treat-
ment with sodium methoxide (Scheme 1).9,10 This method,
however, requires harsh reaction conditions, large quantities
of highly toxic volatile dimethyl sulfates, and tedious separa-
tions for the synthesis of the moisture and oxygen sensitive
dimethylacetamide dimethyl acetal. This reaction gives very
poor yields. Therefore, the development of a convenient, eco-
nomic, environmental-friendly and high-yielding preparative
procedure for N′-alkyl-N,N-dimethylacetamidines is of practi-
cal importance.
The purpose of this study was to develop a mild, simple and
efficient procedure for the synthesis of N′-alkyl-N,N-dimethyl-
acetamidines starting from DMAc, methanol and alkyl amine
directly. The whole reaction proceeded in three stages, that is,
the coordination activating reaction between LiCl and DMAc,
LiCl catalysed acetal formation between DMAc and methanol,
and then the formation of the amidine from the alkyl amine. In
the first stage, the reaction temperature, time and molar ratios
of DMAc and LiCl are the three major factors affecting the
target product yields. It was found that the best yields could be
obtained at 80°C for 90 min under the conditions of n(DMAc):
n(LiCl) = 1:0.2. In the second stage, the temperature of reac-
tion between DMAc and methanol has a profound effect on
the product yields. We also examined the effect of reaction
temperature in the second stage of acetal formation on the
product yields with the optimum DMAc/methanol molar ratio
of 1/2.5 and found that the best yields could be obtained at
80°C for 45 min. This reaction was slower at a lower tempera-
ture (< 80°C) whilst a side reaction, involving alcoholysis
increased if the reaction temperature was higher than 80°C. A
series of target products were prepared in the third stage. The
amidine formation step in the overall reaction is fast. The best
yields could be obtained at 70°C for 60 min with the optimum
DMAc/alkyl amine molar ratio of 1/1.5. A temperature higher
than 70°C lowered the yield of the product because of the
occurrence of aminolysis as a side reaction.
Herein, we report a novel and convenient protocol for the
synthesis of N′-alkyl-N,N-dimethylacetamidines from DMAc
and alkylamines in one pot using methanol as an acetalizing
reagent and LiCl as a catalyst under mild conditions
(Scheme 2).
Experimental
LiCl was calcined in a muffle furnace at 320°C for 2 h. DMAc was
dried over CaSO4 and further purified by distillation at reduced
Scheme 1 Traditional synthetic route to Np-alkyl-N,N-dimethylacetamidines.
* Correspondent. E-mail address: hlwang@dlut.edu.cn

120 JOURNAL OF CHEMICAL RESEARCH 2011
Np-Hexyl-N,N-dimethylacetamidine (3): Colourless liquid in 85%
1
yield. IR: 2955, 2926, 2857, 1626 cm−1. H NMR: 0.88 (t, 3H, J =
7.2 Hz, CH3), 1.25–1.4 (m, 6H, CH3–(CH2)3–), 1.50 (m, 2H, –CH2–
CH2–N=), 1.89 (s, 3H, –N=C(CH3)–N,), 2.85 (s, 6H, –N–(CH3)2),
3.16 (t, 2H, J = 7.2 Hz, –CH2–N=). MS: m/z 171.2 (M+H+). Anal.
Calcd for C10H22N2: C,70.53; H, 13.02; N, 16.45. Found: C, 70.46; H,
13.06; N, 16.48%.
Np-Heptyl-N,N-dimethylacetamidine (4): Colourless liquid in 89%
1
yield. IR: 2956, 2926, 2855, 1626 cm−1. H NMR: 0.88 (t, 3H, J =
7.1 Hz, CH3), 1.25–1.4 (m, 8H, CH3–(CH2)4–), 1.51 (m, 2H, –CH2–
CH2–N=), 1.87 (s, 3H, –N=C(CH3)–N,), 2.86 (s, 6H, –N–(CH3)2),
3.14 (t, 2H, J=7.1Hz, –CH2–N=). MS: m/z 185.2 (M+H+). Anal. Calcd
for C10H22N2: C,71.68; H, 13.12; N, 15.20. Found: C, 71.60; H, 13.16;
N, 15.24%.
Np-Octyl-N,N-dimethylacetamidine (5): Colourless liquid in 92%
1
yield. IR: 2955, 2924, 2852, 1628 cm−1. H NMR: 0.88 (t, 3H, J =
6.1 Hz, CH3), 1.25–1.4 (m, 10H, CH3–(CH2)5–), 1.51 (m, 2H, –CH2–
CH2–N=), 1.89 (s, 3H, –N=C(CH3)–N,), 2.88 (s, 6H, –N–(CH3)2),
3.17 (t, 2H, J = 6.9 Hz, –CH2–N=). MS: m/z 199.2 (M+H+). Anal.
Calcd for C12H26N2: C, 72.66; H, 13.21; N, 14.12. Found: C, 72.58; H,
13.26; N, 14.14%.
Scheme 2 One-pot synthesis of
Np-alkyl-N,N-dimethylacetamidines.
pressure. The distillate was collected at 76°C under 4.79 kPa. All
other chemicals were of AR grade and used as received without any
further purification. 1H NMR spectra were recorded on a Varian
INOVA 400 spectrometer at ambient temperature in CDCl3 using
TMS as internal standard, and NMR chemical shifts (δ) were quoted
in parts per million (ppm). Coupling constants (J values) were given
in Hz. Mass spectra were measured using Agilent HP 1100 HPLC/
MSD system. IR spectra were measured on a Nicolet Avatar 360
FT-IR instrument using KBr discs in the 4000–400 cm−1 regions.
Elemental analyses were obtained in an EA 1112 elemental analyser.
Typical procedure: In a four-necked flasks equipped with mechani-
cal stirrer, dropping funnel, thermometer, and condenser, DMAc
(0.5 mol) and LiCl (0.1 mol) were mixed together and stirred at 80°C
for 90 min. Afterwards, 1.25 mol of methanol was added to the stirred
mixture of DMAc and LiCl. After the addition was complete, stirring
was continued at 80°C for 45 min. Then, 0.75 mol of alkylamine
was introduced and the reaction mixture was stirred at 70°C for about
60 min. The crude product was washed with water to remove LiCl.
The organic phase was separated and the aqueous phase was extracted
with dichloromethane. The combined organic phases were dried and
the volatile materials were removed on a rotary evaporator. The resi-
due was distilled under reduced pressure and further purified by silica
gel column chromatography to give the pure target products.
Np-Dodecyl-N,N-dimethylacetamidine (6): White solid in 93%
1
yield. IR: 2954, 2922, 2850, 1627 cm−1. H NMR: 0.88 (t, 3H, J =
6.8 Hz, CH3), 1.25–1.4 (m, 18H, CH3–(CH2)9–), 1.53 (m, 2H, –CH2–
CH2–N=), 1.89 (s, 3H, –N=C(CH3)–N,), 2.87 (s, 6H, –N–(CH3)2),
3.16 (t, 2H, J=6.9Hz, –CH2–N=). MS: m/z 255.3 (M+H+). Anal. Calcd
for C16H34N2: C, 75.52; H, 13.47; N, 11.01. Found: C, 75.48; H, 13.49;
N, 11.03%.
Np-hexadecyl-N,N-dimethylacetamidine (7): White solid in 95%
1
yield. IR: 2952, 2921, 2848, 1626 cm−1. H NMR: 0.89 (t, 3H, J =
6.8 Hz, CH3), 1.25–1.4 (m, 26H, CH3–(CH2)13–), 1.52 (m, 2H, –CH2–
CH2–N=), 1.87 (s, 3H, –N=C(CH3)–N,), 2.87 (s, 6H, –N–(CH3)2),
3.17 (t, 2H, J=7.0Hz, –CH2–N=). MS: m/z 311.3 (M+H+). Anal. Calcd
for C20H42N2: C, 77.33; H, 13.64; N, 9.02. Found: C, 77.29; H, 13.66;
N, 9.04%.
We thank the Natural Science Foundation of China for finan-
cial support (Grant No. 21073027).
Received 15 November 2010; accepted 4 January 2010
Paper 1000437 doi: 10.3184/174751911X556963
Published online: 10 February 2011
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Np-Butyl-N,N-dimethylacetamidine (1): Colourless liquid in 86%
1
yield. IR: 2956, 2929, 2856, 1627 cm−1. H NMR: 0.88 (t, 3H, J =
1
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