Synthesis of 2-ethyl-3,5-dimethylpyridine by heterocyclization of allylamine, cyclopropylamine, and diallylamine in the presence of palladium complexes

Article abstract of DOI:10.1134/S1070428008120208

2-Ethyl-3,5-dimethylpyridine was synthesized by disproportionation and heterocyclization of allylamine, cyclopropylamine, and diallylamine in the presence of palladium catalysts.

Full text of DOI:10.1134/S1070428008120208

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1831–1835. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.M. Atnabaeva, Z.S. Muslimov, R.I. Khusnutdinov, U.M. Dzhemilev, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 12, pp. 1858–1861.
Synthesis of 2-Ethyl-3,5-dimethylpyridine by Heterocyclization
of Allylamine, Cyclopropylamine, and Diallylamine
in the Presence of Palladium Complexes
A. M. Atnabaeva, Z. S. Muslimov, R. I. Khusnutdinov, and U. M. Dzhemilev
Institute of Petroleum Chemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received March 27, 2008
Abstract—2-Ethyl-3,5-dimethylpyridine was synthesized by disproportionation and heterocyclization of allyl-
amine, cyclopropylamine, and diallylamine in the presence of palladium catalysts.
DOI: 10.1134/S1070428008120208
2-Ethyl-3,5-dimethylpyridine (I) is used in the syn-
thesis of corrosion inhibitors and drugs [1, 2]. In par-
ticular, demethylenation of I gives 2,3,5-trimethylpyri-
dine as starting material for the preparation of up-to-
date highly effective antiulcer drug Omeprazole [2].
A classical procedure for the synthesis of 2-ethyl-3,5-
dimethylpyridine (I) is based on the condensation of
propionaldehyde with ammonia over Co3(PO4)2 at
350–420°C [3]. As a result, a mixture of three pyridine
bases is formed: 2-ethyl-3,5-dimethylpyridine (I),
4-ethyl-3,5-dimethylpyridine (II), and 3,4-dimethyl-
pyridine. Compound I was obtained in 17% yield by
reaction of N-propylidenepropenamine with propylene
over heterogeneous catalyst K2O/Al2O3 at 410–415°C
[4]; the reaction was accompanied by formation of
2-ethyl-4,5-dimethylpyridine.
tively mild conditions (160°C) undergoes dispropor-
tionation with elimination of ammonia, the subsequent
Cope rearrangement gives N-(2-methylpent-2-en-1-
ylidene)prop-2-en-1-amine (III), and heterocyclization
of the latter at higher temperature (250°C), followed
by dehydrogenation, leads to a mixture of 2-ethyl-3,5-
dimethylpyridine (I) as the major product and 4-ethyl-
3,5-dimethylpyridine (II) in an overall yield of 30%.
The authors succeeded in isolating intermediate aza-
triene III and characterizing it by spectral methods.
Taking into account accessibility of allylamine and
simplicity of the experimental procedure, we set our-
selves the goal of studying heterocyclization of allyl-
amine, its structural analog cyclopropylamine, and
diallylamine in the presence of palladium complexes.
The latter were selected as catalysts taking into ac-
count that palladium compounds are capable of pro-
moting not only dehydrogenation but also double bond
migration [7] and aza-Cope rearrangement [8, 9].
2-Ethyl-3,5-dimethylpyridine (I) can be obtained
with a higher yield (~30%) by heterocyclization of
N-propenylprop-2-en-1-amine in the presence of
Ni/Al2O3 [5]. Falbe et al. [6] described an unusual
procedure for the synthesis of 2-ethyl-3,5-dimethyl-
pyridine (I) from allylamine by the action of (penta-
carbonyl)iron Fe(CO)5 (Scheme 1). The reaction in-
cludes several steps. Initially, allylamine under rela-
In the presence of 1 mol % of PdCl2 at 160°C allyl-
amine was selectively converted into compound I in
69% yield in 6 h (Scheme 2). According to the GC–
MS data, the reaction mixture contained alkylpyridines
I and II and products resulting from isomerization and
Scheme 1.
Et
Me
Me
Me
Me
Et
Me
Me
Fe(CO)5, 160°C
–2NH3
Fe(CO)5, 250°C
–H2
NH2
3
+
H2C
CH2
N
N
N
III
I
II
1831

ATNABAEVA et al.
1832
Scheme 2.
160°C, 6 h
100°C, 2 h
I
+
+
II
+
C6H11N + C6H13
N
+
C9H15
N
+
C9H17N
PdCl2
NH2
75%
1.7%
IV, 2.3%
V, 3.7%
VI, 2%
VII, 3.5%
H2C
–H2, –NH3
III
IV
+
V
90%
3.5%
2.6%
Scheme 3.
Me
Me
Et
Me
H
PdCl2, 160°C, 8 h
N
+
+
IV
+
V
H2C
CH2
N
N
I, 31%
VIII, 12%
8%
8%
partial hydrogenation of diallylamine (IV, m/z 97; V,
m/z 99) and triallylamine (VI, m/z 137; VII, m/z 139).
Compound VI was a mixture of five isomeric tris-
(prop-1-en-1-yl)amines differing by configuration of
the double bonds [10]. The reaction performed at
100°C gave azatriene III in 90% yield, the conversion
of allylamine being 100%.
In fact, diallylamine underwent heterocyclization to
produce pyridine I, but the selectivity of this process
was lower than in the reaction with allylamine. The
complete conversion of diallylamine was reached in
8 h at 160°C, and the reaction mixture contained 31%
of compound I, 12% of 3-methylpyridine (VIII), 8%
of IV and V each, and ~40% of higher oligomers
(Scheme 3). Unlike diallylamine, triallylamine did not
undergo heterocyclization in the presence of PdCl2;
instead, a mixture of Z and E isomers of tris(prop-1-en-
1-yl)amine (VI) was formed, the substrate conversion
being almost complete (Scheme 4).
When azatriene III isolated by vacuum distillation
was heated for 4 h at 160°C in the presence of 1 mol %
of PdCl2, 2-ethyl-3,5-dimethylpyridine (I) was ob-
tained in almost quantitative yield. Analogous reaction
at lower temperature (130°C) gave compounds I and
VI at a ratio of 1:1.2.
Replacement of PdCl2 by K2PdCl4 resulted in
reduced selectivity for 2-ethyl-3,5-dimethylpyridine (I,
18%), while 22% of 3-methylpyridine (VIII) and 10%
of N,N-diallylpropan-1-amine (VII) were formed as
by-products. The reaction catalyzed by Pd(acac)2 gave
36% of I and an appreciable amount (12%) of 4-ethyl-
3,5-dimethylpyridine (II) (Scheme 5).
Comparison of the analytical data for 2-ethyl-3,5-
dimethylpyridine (I, C9H13N) and intermediate azatri-
ene III (C9H15N) suggests that compound I is formed
in several steps, including disproportionation, double
bond isomerization, cyclization, and dehydrogenation.
Assuming that diallylamine is formed as intermediate
in the transformation of III into I, we examined the
behavior of diallylamine under the above conditions.
The formation of partially hydrogenated product
VII from triallylamine may be rationalized taking into
Scheme 4.
CH2
Me
PdCl2, 160°C, 6 h
N
N
Me
Me
H2C
CH2
VI
Scheme 5.
K2PdCl4
I
+
+
VII
+
+
C9H17N
NH2
18%
10%
VIII, 22%
H2C
Pd(acac)2
I
II
VII
36%
12%
7%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

SYNTHESIS OF 2-ETHYL-3,5-DIMETHYLPYRIDINE
1833
account, on the one hand, liberation of hydrogen and,
on the other, well-known ability of palladium com-
plexes to catalyze hydrogenation processes. Our
attempt to suppress side hydrogenation of intermediate
unsaturated amines by adding norbornene (which is
known to readily undergo hydrogenation under mild
conditions) to the reactions mixture was unsuccessful.
erocyclization of allylamine in the presence of palla-
dium complexes can be represented by Scheme 8.
3-Methylpyridine (VIII) and 4-ethyl-3,5-dimethyl-
pyridine (II) were isolated from reaction mixtures by
preparative liquid chromatography. Compound VIII
was identified by comparing with commercially avail-
able 3-methylpyridine, and the structure of II was
proved by independent synthesis [12]. The structure of
the other products was determined on the basis of their
1H and 13C NMR and mass spectra and published data
[6, 10, 13, 14].
According to published data, cyclopropylamine
(which is isomeric to allylamine) can be converted into
allylamine (cyclopropyl–allyl rearrangement) in the
presence of palladium complexes [11]. Therefore, we
anticipated that heterocyclization of cyclopropylamine
would give rise to alkyl-substituted pyridines. The
results of our experiments confirmed the above as-
sumption. When cyclopropylamine was heated for 6 h
at 170°C in the presence of 1 mol % of PdCl2, the re-
action mixture contained 2-ethyl-3,5-dimethylpyridine
(I) and N,N-di(cyclopropyl)propan-1-amine (IX) (yield
54 and 25%, respectively; Scheme 6).
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
Tesla BS-567 (1H, 100 MHz ) and Jeol X-90Q spec-
trometers (13C, 22.5 MHz) from solutions in CDCl3
using tetramethylsilane as reference. The mass spectra
were obtained on a Finnigan 4021 GC–MS system
[electron impact, 70 eV; Ultra-29 (PH-S) capillary
column, 50000×0.2 mm]. The reaction mixtures were
analyzed by GLC on a Chrom-5 chromatograph
equipped with a flame-ionization or heat conductivity
detector; 300×0.5-cm column packed with SE-30 on
Inerton AW-DMCS; carrier gas helium. Preparative
liquid chromatography was performed on an HP 1050
instrument with a 18-μl cell; Zorbax C18 column,
250×10 mm; eluent acetonitrile–water (70:30), flow
rate 3 ml/min.
Scheme 6.
170°C, 6 h
I
+
N
C3H7
NH2
PdCl2
54%
Me
IX, 25%
Me
120°C, 4.5 h
N
Allylamine, cyclopropylamine, palladium(II) chlo-
ride, and Pd(acac)2 were commercial products (Fluka,
Acros); K2PdCl4 was synthesized according to the
procedure described in [15].
X, 82%
The remaining amount of cyclopropylamine (~20%)
was converted into higher oligomers. In this case, the
reaction occurred at a higher temperature than with
allylamine, presumably due to the necessity of prelim-
inary isomerization of cyclopropylamine into allyl-
amine. Like allylamine, cyclopropylamine was con-
verted under milder conditions (PdCl2, 120°C, 4.5 h)
into N-(2-methylpent-2-en-1-ylidene)cyclopropan-
amine (X) in 82% yield. Compound X quantitatively
yields pyridine I in 3 h at 170°C (Scheme 7).
2-Ethyl-3,5-dimethylpyridine (I). A mixture of
3.8 g (66.6 mmol) of allylamine and 0.118 g
(0.666 mmol) of PdCl2 was heated for 6 h at 160°C in
a 15-cm3 high-pressure microreactor. The mixture was
then distilled under reduced pressure, a fraction with
bp 104–108°C (44 mm) being collected. Yield 2.06 g
1
(69%). H NMR spectrum, δ, ppm: 1.20 t (3H,
CH2CH3, J = 7 Hz), 2.20 s (3H, CH3), 2.23 s (3H,
CH3), 2.74 q (2H, CH2, J = 7 Hz), 7.19 s (1H, 4-H),
8.11 s (1H, 6-H).
Scheme 7.
PdCl2, 170°C, 3 h
X
I
Heterocyclization of cyclopropylamine was carried
out in a similar way at 170°C (reaction time 6 h). Yield
of I 54%. 13C NMR spectrum, δC, ppm: 158.13 (C2),
129.78 (C3), 136.70 (C4), 122.75 (C5), 146.55 (C6),
27.81 (CH2CH3), 12.59 (CH2CH3), 17.47 (CH3), 18.05
(CH3). Mass spectrum, m/z (Irel, %): 135 [M]+ (61), 134
(100), 107 (24), 106 (15), 77 (15), 51 (10), 55 (7), 40
(7), 39 (20). Found, %: C 79.43; H 9.52; N 11.05.
~100%
Thus 2-ethyl-3,5-dimethylpyridine (I) can be syn-
thesized in a high yield (~80%) by catalytic hetero-
cyclization of allylamine, diallylamine, and cyclopro-
pylamine in the presence of PdCl2. The reaction
involves intermediate formation of azatriene III or
azadiene X. Our results led us to presume that het-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

ATNABAEVA et al.
1834
Scheme 8.
Me
H2C
H
N
[Pd]
[Pd]
NH2
2
H2C
Me
H2C
CH2
–NH3
N
H
XI
Me
Me
Me
Me
Et
–H2
[Pd]
N
CH2
–H2
[Pd]
VIII
N
N
IIIa
I
Me
Me
CH2=CHCH2NH2
–NH3
Me
NH
XII
Et
Me
Me
Me
CH2
[Pd]
–H2
N
N
IIIb
II
C9H13N. Calculated, %: C 79.95; H 9.69; N 10.36.
M 135.21.
propylamine and 0.0869 g (0.49 mmol) of PdCl2 was
heated for 4.5 h at 120°C in a 15-cm3 high-pressure
microreactor. The mixture was distilled under reduced
pressure, a fraction with bp 115–117°C (40 mm) being
A mixture of 2.74 g (20 mmol) of azatriene III and
0.035 g (0.2 mmol) of PdCl2 was heated for 4 h at
160°C in a 15-cm3 high-pressure microreactor. The
product was isolated by vacuum distillation, bp 104–
106°C (40 mm). Yield 2.69 g (~99%).
1
collected. Yield 2.05 g (82%). H NMR spectrum, δ,
ppm: 7.27 s (1H, 1-H), 5.09 t (1H, 3-H, J = 7 Hz),
2.14 q (2H, 4-H, J = 7 Hz), 0.15–0.40 m (7H, 5-H,
CH2CH2), 1.52 q (1H, NCH, J = 5 Hz), 1.08 s (3H,
CH3). 13C NMR spectrum, δC, ppm: 163.32 (C1), 92.76
(C2), 141.64 (C3), 21.48 (C4), 11.1 (C5), 13.38 (CH3),
41.25 (NCH), 8.27 (CH2CH2). Mass spectrum, m/z
(Irel, %): 137 [M]+ (22), 122 (49), 120 (7), 109 (32), 108
(100), 107 (10), 105 (10), 80 (17), 94 (78), 95 (15), 67
(56), 41 (44), 39 (32), 81 (29), 68 (20), 53 (17). Found,
%: C 78.63; H 10.85; N 10.52. C9H15N. Calculated, %:
C 78.77; H 11.02; N 10.21. M 137.22.
Likewise, from 2.65 g of compound X (170°C, 3 h)
we obtained 2.6 g (~99%) of pyridine I.
N-(2-Methylpent-2-en-1-ylidene)prop-2-en-1-
amine (III). A mixture of 3.8 g (66.6 mmol) of allyl-
amine and 0.118 g (0.666 mmol) of PdCl2 was heated
for 12 h at 100°C in a 30-ml glass ampule. The mixture
was distilled under reduced pressure, a fraction with
bp 94–96°C (40 mm) being collected. Yield 2.74 g
1
(90%). H NMR spectrum, δ, ppm: 7.80 s (1H, 1-H),
5.7–6.2 m (2H, 3-H, CH=CH2), 5.0–5.3 m (2H,
CH=CH2), 2.26 q (2H, 4-H, J = 7 Hz), 1.04 t (3H, 5-H,
J = 7 Hz), 5.7–6.22 m (3H, CH=CH2), 4.09 d (2H,
NCH2, J = 4 Hz), 1.85 s (3H, CH3). 13C NMR spec-
trum, δC, ppm: 166.26 (C1), 92.45 (C2), 143.37 (C3),
21.43 (C4), 11.10 (C5), 13.18 (CH3), 62.86 (NCH2),
136.02 (CH=CH2), 115.08 (CH=CH2). Mass spectrum,
m/z (Irel, %): 137 [M]+ (12), 122 (37), 108 (44), 96
(32), 94 (20), 80 (15), 81 (27), 67 (22), 68 (20), 54
(10), 55 (20), 42 (17), 39 (61), 41 (100). Found, %:
C 78.51; H 10.95; N 10.54. C9H15N. Calculated, %:
C 78.77; H 11.02; N 10.21. M 137.22.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

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