Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
-~ 1 3 ~ 4gq7
2-HYDROCARBYL-3,6-DICHLOROPYRIDINES
AND THEIR PREPARATION
3,6-Dichloropioolinio acid is a commercially
u~eful herbicide and 3,6-dichloro-2-(trichloromethyl)-
pyridine i3 known as a nitrification inhibitor and a~ a
herbicide. These compounds are not readily obtained by
the pyridine ring chlorination o~ a 2-substituted
pyridine because quch chlorinations are not
qu~fioiently selective to produce a preponderance of
the desired 3,6 dichloro-2-substituted pyridine isomer
in th~ mixture obtained. Alternative methods for
introduoing chlorine into the pyridine nucleus
seleotlvely at the 3 and 6 positions of 2-qubstituted
pyrldineQ depend upon the pre~enoe of amino or hydroxyl
groups at thoqe po~ition~ in the starting materials and
the requisite mater~al~ are not oommerQially available.
It haQ now been found that 2-hydrocarbyl-3,6-
diohloropyridine~ can be prepared by a ring cloqure
metho~ from readily available starting material~. A
two 3tep proces~ i3 employed in whioh acrylonitrile and
an appropriate dichIoromethyl hydrocarbyl ketone are
..
,~,
34,270A-F -1-
-
.
- 1314897
73776-19
reacted under condi~ions conducive to the reaction to form a 1,1-
dichloro-3-cyanopropyl hydrocarbyl ketone in~ermediate which i5
cyclized to obtain the desired 2-hydrocarbyl-3,6-dichloropyri-
dines.
According to one aspect of the present invention ~here
is provided a process for preparing a 2-hydrocarbyl-3,6-dichloro-
pyridine compou~d of the formula
Cl~
wherein R represents Cl-C8 alkyl, C3-C8 cycloalkyl, or C4-C8
cycloalkylalkyl, which is characterized by acidifying with
hydrogen chloride a l,l-dichloro-3-cyanopropyl hydrocarbyl ketone
compound of the formula
NCCH2CH2CC123-R
wherein R i5 defined as before, heatlng the acidified intermediate
at a temperature of 50C to 200C and at a pressure of 1 to 5
atmospheres, and, thereafter, recovering the 2-hydrocarbyl-3,6-
dichloropyridine compound.
According to a further aspect of the present invention
there is provided a process for preparing a l,l-dichloro-3-cyano-
propyl hydrocarbyl ketone compound of the formula
2 H2CC12C R
2 --
1 3 1 ~8q7
,
73776-19
wherein R repre~qents C1-C8 alkyl, C3-C8 cycloalkyl, or C~-C8-
cycloalkylalkyl, which is characterized by reactlng acrylonitrile
and a dichlorom2thyl hydrocarbyl ketone of the formula
HC12CC-R
wherein R is as defined be~ore at a reaction temperature of from
0C to 120C and with agltation and, thereafter, recovering said
compound.
According to another aspect of the present invention
there is provided a 2-hydrocarbyl-3,6-dichloropyridine compound of
the formula
cl~r
wherein R repre~ents C1-C8 alkyl, C3-C8 cycloalkyl, or C4-C8
cycloalkylalkyl.
In ths process of the pre~ent i.nvention acrylonitrile is
first treated wlth an appropriate dichloromethyl hydrocarbyl
ketone o~ Formula I in the presence of a base, such a~ an alkali
metal alkoxide or hydroxide or a tertlary amine, to obtain a 1,1-
dichloro-3-cyanopropyl hydrocarbyl ketone of Formula II. The
reaction can be illustrated as follows,
HC12CC-R ~ CH2~CHCN __base__~ 2 2CC12lC
I II
- 2a -
-`` 1 31 48q7
73776-19
wherein
R represents C1-C8 alkyl, C3-C8 cycloalkyl, or
C~-C~ cycloalkylalkyl.
The 1,1-dichloro-3-cyanopropyl hydrocaxbyl ketones of
Formula II are then cyclized with hydrogen chloride to obtain 2-
hydrocarbyl-3,6-dichloropyridines o~ Formula III. The reaction
: can be illustrated as follows:
- 2b -
C
-- 1 31 ~89~
--3--
NCCH2CH2CCl2C-R HC1 ~ ~ + H20
II III
wherein R iq aq hereinbefore defined.
Both the intermediate 1,1-diohloro-3-
cyanopropyl hydrocarbyl ketone~ or Formula II and theproduat 2-hydrocarbyl-3,6-dichloropyridines of
Formula III are novel compound3.
The term hydrocarbyl a~ u~ed herein i~ meant to
de~ignate the following moietles: alkyl including
straight and ~ranQhed chain iqomer~, cycloalkyl
including those havin~ alkyl ~ubstituents (e.g. 2-
methylcyclopropyl), and cycloalkylalkyl, such a~
Cyclopentylmethyl.
The addition reaction of a dichloromethyl
hydrocarbyl ketone with acrylonitrile according to the
present process i9 typically carried out in an organic
0 ~olvent, ~uch aq, ~or example, t-butanol, ethanol,
dimethylformamide, dimethyl ulfoxide, acetonitrile,
methylene chloride, tetrahydro~uran and toluene.
Reaction temperature~ of from 0 to 120C, pre~erably
from 40 to 90, are normally employed. The reaction
mixture iq u~ually agitated and it iq often convenient
to carry out the reaction at itq re~lux temperature.
34,270A-F -3~
1 31 4897
_4
Suitable ba~es for the addition reaction are
tho~e that are capable of abstracting a proton from the
dichloromethyl hydrocarbyl ketone and include alkali
metal hydroxides, such a~ qodium hydroxide or pota3~ium
hydroxide; alkali metal alkoxides, ~uch a~ potas3ium t-
butoxide or 30dium ethoxide; and trialkylamine3, ~uch
a~ ~riethylamine, N9N-dimethyl-N-hexylamine, N,N,N',N'~
tetramethyleth~.lenediamine, or N-methylpyrrolidine.
When the ba3e i~ an alkali metal hydroxide or &lkali
metal alkoxide, a quaternary ammonium ~alt, such a~
N,N,N-tricapryl-N-methylammonium chloride or N-benzyl
N,N,N-triethylammonium chloride, may be added to
facilitate the reaction.
Approximately equimolar quantities o~
acrylonitrile and the dichloromethyl hydrocarbyl ketone
or an excess of acrylonitrile oan be conveniently
employed in the proceqs. The reaction is continued
until a substantial amount of the desired l,l-dichloro-
3-cyanopropyl hydrocarbyl ketone product has formed or
until one oP the ~tarting materials has been
substantially depleted. The exact time will depend on
the startlng dichloromethyl hydrocarbyl ketone employed
as well as the solvent and the reaction temperature
u~ed.
.
The 1,1-dichloro-3-cyanopropyl hydrocarbyl
ketones o~ Form~la II prepared in the above de~cribed
procedure~ can be r-ecovered u~ing conventional mean~,
~uch as, for example, di tillation, extraction,
chromatography and crystallization. After recovery of
the l,1-dichloro-3-cyanopropyl hydrocarbyl ketone~ in a
pure or partially purified form, they may be utilized
in the cyclization reaction of the invention.
34,270A-F -4-
1 3 1 ~8q7
The cyclization reaction of 1,1-dichloro-3-
cyanopropyl hydrocarbyl ketone~ i~ accompliqhed by
heating theqe compound~ in the pre~ence of hydrogen
chloride. The hydrogen chloride can be added to the
reaction medium all at once or continuouqly during the
reaction period. Metal chloride Lewi~ acid cataly~t~
~uch as zinc chloride and aluminum chloride can be
employed along ~ith the hydrogen chloride to ~acilitate
thiq reaction~ The reaction generateq water and thi~
may be removed a~ it formq by diqtillation, ab~orption,
or reaction. &enerally, anhydrou~ reactan~ are
employed.
The cyclization reaction can be carried out
neat or in the pre~ence of an organic qolvent, ~uch a~,
for example, acetic acid, dimethylformamide, dimethyl
sul~oxidel dioxane, dimethoxyethane, methylene chloride
and toluene. Reaetion temperatures of 50 to 200C and
pressureq oP 1 to 5 atmo~pheres (101.325 to 506.625
kPa) are advantageou~ly employed.
The reaction is continued until a qub~tantial
amount of the 2-hydrocarbyl-3,6-dichloropyridine
product is~ ~ormed or until the 1,1-dichloro-3-
cyanopropyl hydrocarbyl ketone reactant i~ substan-
tially depleted. The time required will vary depending
upon the identity o~ the 1,1-dichloro-3-cyanopropyl
hydrocarbyl~ketone, the ~olvent, the concentration of
hydrogen chloride and any Lewis acid catalyst~, and the
temperature employed.
The product 2-hydrocarbyl-3,6-dichloropyridineq
o~ Formula III can be recovered from the reaction
34,270A-F -5-
1 3 1 ~Q~97
--6--
medium by conventional mean~ 9 ~uch a~, for example,
distillation, extraction and chromatography.
Example~ oP dichloromethyl hydrocarbyl ketone~
useful a~ starting material~, 17 1 ;dichloro-3-~
- cyanopropyl hydrocarbyl ketone~ obta`ined a~
intermediate~, and 2-hydrooarbyl 3,6-dichloropyridine~
obtained a~ product~ in the pre~ent invention include
tho~e compound.~ of Formula~ I, II, and III wherein R
represent~, for example, methyl, ethyl, propyl, 1-
methylethyl, 1,1-dimethylethyl, butyl, hexyl,
~yclohexyl, cyclopentyl, cyclooctyl, cyclopentylmethyl
and cyoloprop~lmethyl. CompoundY of Formulas I, II and
III wherein R repre~ent~ C1-C4 alkyl, C3-C6 cycloalkyl9
or C4-C6 cycloalkylalkyl con titute a preferred cla~s.
The following example~ illustrate the pre~ent
invention.
Preparation of 4,4-dichloro-5 oxo-
~ hexanenitrile
.
Procedure A:
A mixture of 11 ml of t-butanol, 3 ml (31 mmol)
of 1,1-dichloro-2-propanone and 2 ml (32 mmol) of
acrylonitrile wa~ placed in a 50 ml 3-necked round
bottom ~la~k equipped with a magnetic stirrer, a
dropping funnel, a sampling port and a Y-tube fitted
with a thermometer and an outlet to a ~crubber.
Four ml of 25~percent NaOH were add`ed dropwi~e over
7 minute3, during which time the reaction exothermed to
a ~inal temperature of 71C. After 68 minute~, with
~tirring, ga~ chromatographic (GC) analysi~ of the
reaction mixture howed 40 percent unreacted 1,1-
dichloro-2-propanone, 42 percent 4,4-dichloro-5-oxo-
34,270A-F -6-
1 31 4~q7
7- ~.
hexanenitrile, lO percent 1,1-dichloro-2,4-cyclo~
hexanedione, 2 percent 1-chloro-1-acetyl~2-
cyanocyclopropane, and 1 percent 1,1,3,3-tetrachloro-2-
methyl-4-oxo-2-pentanol.
An authentic ~ample of 4,4-dichloro-5~oxo-
hexanenitrile, which wa~ i~olated by fractional
distillation (b.p. 92-95C at 0.1 mm Hg pre~ure) and
purified by fractional crystallization (m.p. 49-51C),
analyzed as follows:
Anal~i 3
% C % H % N % Cl
Calc. for C6H4Cl2N0: 40003 3092 7.78 39.39
Found: 40.06 3.82 8.28 39.76
NMR (CDC13): 82.56 (s,3H); ~2.72 (q,4H)
2~
Procedure B:
A 3.99 g (31.4 mmol) portion o~ dichloro-2-
propanone was dissolved ln 8 ml of t-butanol and the
mixture heated to 40C. A ~olution of 1.61 g
(30.3 mmol) o~ acrylonitrile in 3 ml of t-butanol and
lO ml of a 30 percent pota~sium hydroxide in methanol
solution were added dropwi~e over 11 minute and
2.5 hour period~, re~pectively. The reaction wa~ slow
at firi~t and the temperature fell to 25C. The mixture
wa~ mildly warmed and after the bulk o~ the potas ium
hydroxide wa~ added the reaction became exothermic and
the temperature ro~e to a maximum of 75C. APter
4 hours the product mixture contained 40 percent 4 9 4-
34,270A-F ~7-
-- 1 31 4Q~q7
-a-
dichloro-5-oxo-hexanenitrile and 22 percent 1,1-di-
chloro-2-propanone by GC analysis.
Procedure C:
~ = . = . . _. . _
A ~olution containing 800 g (63 mmol) of 1,1-
dichloro-~-propanone and 3.2 g (61 mmol) of
acrylonitrile and 0.73 g (7.2 mmol) 3~ triethylamine in
20 ml o~ ethanol wa~ prepared and heated to 56C over a
21 hour period. Another 1.46 g (14~4 mmol) o~
triethylamine wa~ then added and the reaction continued
for 3 addiSional hours. The reaction product waY found
to oontain 1~ percent 4,4-dichloro-5-oxo-hexanenitrile
and 43 percent 1,1-dichloro-2-propanone by GC analyqi~.
Example 2 Preparation of 3,6-dichloro-2-methylpyridine
Procedure A:
One g of 4,4-dichloro-5-oxo-hexanenitrile was
plaoed in a 2-necked 10 ml pear ~haped flask equipped
with an HCl inlet and a Y-~haped tube attached to a
NaOH qcrubber and to a nitrogen inlet and holding a
thermometer (touohing thb bottom o~ the flask). The
~la~k was immersed in a silicone oil bath. HC1 gas wa~
bubbled through the 4,4-dichloro-5-oxo-hexanenitrile
for 120 minutes during which time the temperature was
maintained at 145-160C. A white solid condensate
weighing 480 mg appeared in the Y-tube. GC analysi~ of
the white conden~ate ~howed it to consist of about
50 percent 3,6-dichloro-2-methylpyridine and about
50 percent of a very high boiling material. GC
analyqis o~ the reqidue in the reaction flask showed it
to con~i~t of about 75 percent 4,4-dichloro-5-oxo-
34,270A F -8-
'` 1314~q7
~9_
hexanenitrile and about 25 percent 3,6-dichloro-2-
methylpyridine.
An authentic ~ample of 3,6 dichloro-2-
methylpyridine, which wa~ i~olated by fractionaldi~tillation ~b.p. 95C at 20 mm Hg pre~ure), analyzed
as ~ollow~:
~ C %
Calc. for C6H5Cl2N: 44.5 3.1 8.6
Found: 44~9 3.2 9~0
NMR (CDCl3): 82.60 (9, 3H), S7.17 (d-7.6 Hz, lH)9 ~7.64
(d-7.6 Hz, 1H)
Proaedure B:
A 1.11 g sample of 4,4-dichloro-5-oxo-
hexanenitrile was placed ln an 8 oz pres~ure bottle and
preqqurized to 15 p~i with hydrogen chloride ga~. The
bottom portion of the bottle waq heated in a qilicone
oil bath to a maximum of 197C for 30 minute~ and at
t10-155 for another 6 hour~. After cooling the
reaction mixture was diluted with methanol, filtered,
baqified and extracted with methylene chloride to
obtain a product that wa~ 45 percent 3,6-dichloro-2-
methylpyridine by GC analysi~.
Acrylonitrile iq an item of commerce and
readily available. Dichloromethyl hydrocarbyl ketone~
of Formula I are generally known in the art. They can
be prepared from the corre~ponding methyl hydrocarbyl
ketone~ by the formation of an imino derivative and
34,270A-F -9-
-``` 1 31 4~97
-10-
~ub~equent chlorination o~ that derivative with N-
chloro~uccinimide a~ described in Bull. Soc. Chim.
Bel~., 81, 643 7 (1972).
34,270A-F -lO-
