CA1314897C - 2-hydrocarbyl-3,6-dichloropyridines and their preparation - Google Patents

Abstract

ABSTRACT
2-Hydrocarbyl-3,6-dichloropyridines are prepared from dichloromethyl hydrocarbyl ketones and acrylonitrile in a two-step process involving an addition reaction under basic conditions to form intermediate 1,1-dichloro-3-cyanopropyl hydrocarbyl ketones and a subsequent cyclization reaction in the presence of hydrogen chloride. Thus, 3,6-dichloro-2-methylpyridine is prepared from 1,1-dichloro-2-propanone and acrylonitrile by the formation and further reaction of 4,4-dichloro-5-oxo-hexanenitrile.
The intermediates and products are novel compounds useful in the preparation of herbicides and nitrification inhibitors.

34,270A-F

Description

-~ 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--.

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 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 1 3 1 ~8q7 , 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 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 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~

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~

_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 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 ~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-

Claims (7)

1. A process for preparing a 2-hydrocarbyl-3,6-dichloro-pyridine compound of the formula wherein R represents C1-C8 alkyl, C3-C8 cycloalkyl, or C4-C8 cycloalkylalkyl, which is characterized by acidifying with hydrogen chloride a 1,1-dichloro-3-cyanopropyl hydrocarbyl ketone compound of the formula NCCH2CH2CCl2?-R

wherein R is defined as before, heating the acidified intermediate at a temperature of 50°C to 200°C and at a pressure of 1 to 5 atmospheres, and, thereafter, recovering the 2-hydrocarbyl-3,6-dichloropyridine compound.

2. A process as recited in Claim 1 wherein R represents C1-C4 alkyl, C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl.

3. A process as recited in Claim 2 wherein R represents methyl.

4. A process as recited in Claim 1 wherein the 1,1-di-chloro-3-cyanopropyl hydrocarbyl ketone compound employed as a starting material was first prepared by reacting acrylonitrile with a dichloromethyl hydrocarbyl ketone of the formula HCl2C-?-R
wherein R represents C1-C8 alkyl, C3-C8 cycloalkyl, or C4-C8 cycloalkylalkyl, at a reaction temperature of from 0°C to 120°C
and with agitation.

5. A 2-hydrocarbyl-3,6- dichloropyridine compound of the formula wherein R represents C1-C8 alkyl, C3-C8 cycloalkyl, or C4-C8 cycloalkylalkyl.

6. A compound as recited in Claim 5 wherein R represents C1-C4 alkyl, C3-C6 cycloalkyl, or C4-C6 cycloalkylalkyl.

7. A compound as recited in Claim 6 wherein R is methyl.