One-step synthesis of 3-dichloromethylpyridine from pyridine in the presence of iron-containing catalysts

Article abstract of DOI:10.1134/S1070428007120147

3-Dichloromethylpyridine was synthesized by reaction of pyridine with the system MeOH-CCl₄-iron catalyst [FeBr₂, Fe ₃(CO)₁₂, or iron(III) naphthenate]. Iron(II) bromide at a FeBr₂-pyridine-CCl₄-MeOH ratio of 1:100:200:200 showed the highest catalytic activity.

Full text of DOI:10.1134/S1070428007120147

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 12, pp. 1821–1824. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © R.I. Khusnutdinov, A.R. Baiguzina, A.A. Smirnov, R.R. Mukminov, U.M. Dzhemilev, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 12, pp. 1819–1821.
One-Step Synthesis of 3-Dichloromethylpyridine from Pyridine
in the Presence of Iron-Containing Catalysts
R. I. Khusnutdinov, A. R. Baiguzina, A. A. Smirnov, R. R. Mukminov, 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 October 3, 2006; revised July 27, 2007
Abstract—3-Dichloromethylpyridine was synthesized by reaction of pyridine with the system MeOH–CCl4–
iron catalyst [FeBr2, Fe3(CO)12, or iron(III) naphthenate]. Iron(II) bromide at a FeBr2–pyridine–CCl4–MeOH
ratio of 1:100:200:200 showed the highest catalytic activity.
DOI: 10.1134/S1070428007120147
Derivatives of pyridine and α-, β-, and γ-picolines
containing one, two, and three halogen atoms are
known to exhibit pronounced biological activity and
are widely used for the synthesis of herbicides, fungi-
cides, defoliants, nitrification inhibitors, and insecti-
cides [1]. In particular, 3-dichloromethylpyridine (I) is
a starting material for the preparation of 3-[4-(5-tri-
fluoromethylpyridin-2-yloxy)phenoxy]propionic acid
esters possessing strong herbicidal activity [2].
taining one, two, and three chlorine atoms in the
methyl group was obtained. 3-Dichloromethylpyridine
can also be prepared in ~38% yield by treatment of
pyridine-3-carbaldehyde with PCl5 in the presence of
pyridine [6].
In the present work we used accessible pyridine
instead of 3-methylpyridine (II) as starting compound
for the synthesis of 3-dichloromethylpyridine (I). The
proposed procedure is based on the reaction of pyri-
dine with the system CCl4–MeOH in the presence of
a catalyst. As the latter we tried iron [FeBr2, Fe3(CO)12,
iron(III) naphthenate] and tungsten compounds
[W(CO)6], the molar ratio catalyst–pyridine–CCl4–
MeOH being 1:100:200:200 (Scheme 1). The reac-
tion was carried out in a broad temperature range, and
the best results were obtained at 140°C (reaction time
6 h). The conversion of pyridine (with no account
taken of its consumption for binding liberated hydro-
gen chloride) was ~40%. No reaction occurred in the
absence of methanol or in the presence of a small
amount of methanol (FeBr2–MeOH ratio 1:10).
3-Dichloromethylpyridine (I) is usually prepared by
catalytic chlorination of difficultly accessible 3-meth-
ylpyridine (II, β-picoline) using concentrated sulfuric
acid, glacial acetic acid, and 2,2′-azobis(isobutyroni-
trile) as radical initiator [3]. 3-Dichloromethylpyridine
(I) was also synthesized by reaction of 3-methylpyri-
dine with gaseous chlorine in the presence of acids
and radical initiators [4]. Gas-phase chlorination of
3-methylpyridine (II) with excess chlorine in the pres-
ence of carbon tetrachloride at 350°C gave products
containing chlorine both in the side methyl group and
in the pyridine ring [5]. Rubina et al. [6] made an at-
tempt to synthesize compound I by chlorination of
3-methylpyridine with N-chlorosuccinimide in the
presence of benzoyl peroxide, but the reaction was not
selective: as a result, a mixture of three products con-
3-Dichloromethylpyridine was obtained with a high
selectivity (94%) using Fe3(CO)12–W(CO)6 or iron(III)
naphthenate as catalyst. However, in these cases the
conversion of pyridine was considerably lower, so that
Scheme 1.
CHCl2
FeBr2, 140°C, 6 h
–CHCl3
+
CCl4 + MeOH
N
N
I, 35%
1821

KHUSNUTDINOV et al.
1822
Synthesis of 3-dichloromethylpyridine (I) by reaction of pyridine with carbon tetrachloride and methanol in the presence of
iron-containing catalysts
Molar ratio catalyst–
pyridine–CCl4–MeOH
Temperature, °C
(time, h)
Conversion
Catalyst
Fe3(CO)12
Yield (overall), %
of pyridine,a %
1:100:200:200
1:100:200:200
1:100:200:200
1:100:200:200
1:100:200:000
1:100:200:400
1:100:200:200
1:100:200:200
1:100:200:200
140 (6)
140 (6)
140 (6)
140 (6)
140 (6)
140 (6)
100 (6)
150 (6)
140 (3)
08
16
20
40
00
00
00
02
05
05
15
Fe3(CO)12–W(CO)6
Iron(III) naphthenate
19
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
FeBr2
35
00
00
00
0.00.2
03
a
With no account taken of pyridine consumption for binding of hydrogen chloride.
the overall yield of 3-dichloromethylpyridine (I) was
15 and 19%, respectively (see table). In all experiments,
a large part of the substrate is consumed for binding
liberated hydrogen chloride with formation of pyridine
hydrochloride. By special experiments with prelimi-
narily prepared pyridine hydrochloride we showed that
it is inactive under the above conditions. After neutral-
ization, unreacted pyridine can be used repeatedly.
presence of FeBr2 we isolated 3-dichloromethyl-5-
methylpyridine (III) (Scheme 3).
Scheme 3.
Me
Me
CHCl2
[Fe]
+
CCl4 + MeOH
N
N
II
III, 32%
Taking into account that chloroform is formed dur-
ing the process, the formation of 3-dichloromethylpyri-
dine (I) is likely to involve alkylation of pyridine with
CHCl3 in the presence of FeBr2 which is known to be
very efficient in Friedel–Crafts reactions (Scheme 2).
However, our attempts to effect direct alkylation of
pyridine with chloroform were unsuccessful.
While further searching for a reasonable explana-
tion for the formation of compound I we focused on
the fact that a part of methanol is oxidized with carbon
tetrachloride during the process with formation of
formaldehyde and hydrogen chloride according to
Scheme 4.
Scheme 4.
Scheme 2.
[Fe]
CCl4
+
MeOH
[MeOCl]
CH2O
CHCl2
–HCl
FeBr2
–HCl
+
CHCl3
The presence in the reaction mixture of CH2O, HCl,
and FeBr2 promotes chloromethylation of pyridine;
therefore, Scheme 5 may be proposed for the forma-
tion of compound I.
N
N
I
The presence in the reaction mixture of traces of
3-methylpyridine (II) suggests that 3-dichloromethyl-
pyridine (I) may be formed along a more complex
scheme with participation of methanol and carbon
tetrachloride. Presumably, initial alkylation of pyridine
with methanol in the presence of FeBr2 gives 3-meth-
ylpyridine (II) which then undergoes successive chlo-
rination at the methyl group with carbon tetrachloride
to afford 3-dichloromethylpyridine (I). This assump-
tion was not confirmed experimentally. In the reaction
of 3-methylpyridine (II) with CCl4 and MeOH in the
Scheme 5.
CH2Cl
[FeBr2]
+
CH2O + HCl
N
N
IV
CHCl2
[FeBr2], CCl4
–CHCl3
N
I
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

ONE-STEP SYNTHESIS OF 3-DICHLOROMETHYLPYRIDINE FROM PYRIDINE
1823
This assumption is supported by the following ex-
perimental data. First, the reaction of pyridine with
formaldehyde in the presence of HCl, CCl4, and FeBr2
actually gives 3-dichloromethylpyridine (I) in 7%
yield (Scheme 6).
(ion source temperature 220°C). The reaction mixtures
and products were analyzed by gas–liquid chromatog-
raphy on a Chrom-5 instrument [1.2 or 2 m×3-mm
column, stationary phase 5% of SE-30 on Chromaton
N-AW-HMDS; carrier gas helium; oven temperature
programming from 50 to 280°C at a rate of 8 deg/min].
Scheme 6.
Commercial catalysts (chemically pure grade) were
preliminarily dried under reduced pressure. Carbon
tetrachloride, chloroform, methanol, ethanol, pyridine,
3-methylpyridine, and 3-chloromethylpyridine were
purified and dehydrated before use.
+
CH2O
+
HCl
+
CCl4
N
CHCl2
[FeBr2]
3-Dichloromethylpyridine (I). a. A 17-ml high-
pressure microreactor or a 20-ml glass ampule was
charged under argon with 0.0216 g (0.1 mmol) of
FeBr2, 0.79 g (10 mmol) of pyridine, 3.08 g (20 mmol)
of CCl4, and 0.64 g (20 mmol) of methanol. The re-
actor was hermetically capped (the ampule was sealed)
and heated for 6 h at 140°C. When the reaction was
complete, the reactor (ampule) was cooled to room
temperature and opened, the mixture was filtered
through a layer of silica gel (2 g), and unreacted
MeOH, CCl4, and CHCl3 were distilled off. The
residue was neutralized with 10% aqueous sodium
carbonate under stirring for 0.5–1 h with a magnetic
stirrer and extracted with carbon tetrachloride or
diethyl ether. The extract was evaporated, and the
residue was distilled under reduced pressure. Yield
0.57 g (35%), bp 90°C (15 mm).
N
I
On the other hand, specially performed chlorina-
tion of 3-chloromethylpyridine (IV) with CCl4 in the
presence of FeBr2 was successful, and 3-dichlorometh-
ylpyridine (I) was formed in 10% yield (Scheme 7).
We can conclude that the formation of compound I
with participation of formaldehyde according to
Scheme 5 is possible. The relatively poor yield of I in
control experiments may be attributed to considerable
difference in the reaction conditions.
Scheme 7.
CH2Cl
CHCl2
[FeBr2]
–CHCl3
+
CCl4
N
N
IV
I
b. The procedure was the same as in a. The reaction
mixture consisted of 0.0216 g (0.1 mmol) of FeBr2,
1.27 g (10 mmol) of 3-chloromethylpyridine, and
3.08 g (20 mmol) of CCl4. Yield 0.18 g (10%). IR spec-
trum, ν, cm–1: 1150, 3600 (OH). 1H NMR spectrum, δ,
ppm: 6.7 s (1H, CHCl2), 7.2–8.9 m (4H, pyridine).
13C NMR spectrum, δC, ppm: 147.40 (C2), 133.88 (C3),
133.5 (C4), 134 (C5), 152 (C6), 72 (C7). Mass spectrum,
m/z (Irel, %): 161 [M]+ (22), 38 (2), 39 (2), 51 (3), 63
(7), 64 (3), 65 (7), 73 (4), 78 (7), 90 (5), 91 (5), 99
(12), 101 (5), 106 (4), 125 (5), 126 (100), 127 (7), 128
(34), 129 (3), 161 (22), 162 (2), 163 (17).
According to the GLC data, the conversion of
carbon tetrachloride and the amount of CHCl3 derived
therefrom were greater by a factor of 3 to 4 than the
yield of 3-dichloromethylpyridine (I). This may be due
to consumption of CCl4 for both oxidation of methanol
and chlorination of intermediate 3-chloromethylpyri-
dine (IV). Our attempt to effect further chlorination of
3-dichloromethylpyridine (150°C, 6–12 h) was unsuc-
cessful. Presumably, the system CCl4–CH3OH–FeBr2
is a milder chlorinating agent than Cl2 [1].
EXPERIMENTAL
3-Dichloromethyl-5-methylpyridine (VI). The
procedure was the same as above. The reactor (am-
pule) was charged with 0.0216 g (0.1 mmol) of FeBr2,
0.93 g (10 mmol) of 3-methylpyridine, 3.08 g
(20 mmol) of CCl4, and 0.64 g (20 mmol) of MeOH.
The IR spectra were recorded in the range from 550
to 3500 cm–1 on a UR-20 instrument from samples pre-
pared as KBr pellets or dispersed in mineral oil. The
1H and 13C NMR spectra were measured from solu-
tions in CDCl3 relative to tetramethylsilane on a Jeol
FX90Q instrument at 90 and 22.5 MHz, respectively.
The mass spectra (electron impact, 70 eV) were ob-
tained on a Finnigan MAT-112S mass spectrometer
1
Yield 0.56 g (32%). H NMR spectrum, δ, ppm: 7.2 s
(1H, CHCl2), 2.4 s (3H, CH3), 7.2–8.3 m (3H, pyri-
dine). 13C NMR spectrum, δC, ppm: 146.32 (C2), 137.9
(C3), 136.9 (C4), 135.2 (C5), 149.1 (C6), 71.4 (C7), 18.0
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

KHUSNUTDINOV et al.
1824
(C8). Mass spectrum, m/z (Irel, %): 175 [M]+ (17), 39
(11), 51 (10), 65 (10), 77 (15), 78 (8), 79 (4), 92 (8), 93
(4), 104 (26), 105 (11), 106 (15), 140 (100), 141 (12),
142 (29), 176 (2), 177 (12).
REFERENCES
1. Kovganko, N.V. and Kashkan, Zh.N., Russ. J. Org.
Chem., 2004, vol. 40, p. 1709.
2. Nishiyama, R., Fujikawa, K., Haga, T., and Hase, K., JPN
Patent Appl. no. 55-022617, 1980.
This study was performed under financial support
by the Ministry of Education and Science of the Rus-
sian Federation (project no. NSh 7470.2006.3), by the
Federal Science and Innovation Agency (state contract
no. 02.442.11.7509), by the Foundation for Support of
Russian Science, and by the President of Bashkorto-
stan Republic (grant for young scientists and youth
research teams, contract no. 4).
3. Jelich, K., US Patent no. 5116993, 1992.
4. Jelich, K., JPN Patent Appl. no. 11-140053, 1999.
5. Bowden, R. and Seaton, T., UK Patent no. 1599783,
1982; Ref. Zh., Khim., 1982, no. 15N163P.
6. Rubina, K.I., Iovel’, I.G., Gol’dberg, Yu.Sh., and Shiman-
skaya, M.V., Khim. Geterotsikl. Soedin., 1989, p. 543.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007