Preparation of heterocycles using 1,3-dihalopropenes

Details Preparation of heterocycles using 1,3-dihalopropenes Preparation of heterocycles using 1,3-dihalopropenes

1999-06-29

2002-04-02

Rotman, Alan L. (Department: 1612)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S330000, C546S153000, C546S181000, C548S235000, C548S373100

Reexamination Certificate

active

06365738

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates generally to the preparation of heterocycles containing one or more nitrogen or oxygen heteroatoms, and in particular to the synthesis of such heterocycles utilizing a 1,3-dihalopropene such as 1,3-dichloropropene as a starting material.
As further background, heterocyclic compounds such as pyridines, pyrimidines, oxazoles, pyrazoles and quinolines enjoy a wide range of utilities including serving as actives and intermediates in the fields of herbicidal, pesticidal, and medicinal compounds. While many such compounds occur naturally and in the past have been isolated from natural sources, currently, most of the world's supply of such compounds derives from synthetic preparations. Thus, a wide variety of syntheses are known in which one or more acyclic starting materials are reacted either to directly form the heterocycles or to form cyclizable intermediates which can then be converted to the heterocycles.
In light of this background the applicants have undertaken an investigation to discover new and useful routes to the above-mentioned heterocycles which employ readily-available starting materials and which can be conveniently conducted in standard laboratory or commercial equipment. In so doing the applicants have discovered that 1,3-dihalopropenes provide useful 3-carbon fragments for the production of such heterocycles including, for instance, 2,3-substituted pyridines, 2,5-substituted pyridines, pyrimidines, oxazoles, pyrazoles and quinolines.
SUMMARY OF THE INVENTION
Accordingly, in one broad aspect, the invention provides for the use of a 1,3-dihalopropene in the production of a heterocycle containing one or more nitrogen or oxygen heteroatoms, including for example pyridines, quinolines, pyrimidines, pyrazoles and oxazoles.
In broad aspects the invention thus provides a process for preparing a heterocycle having one or more nitrogen or oxygen heteroatoms, comprising reacting a 1,3-dihalopropene compound of the formula:
wherein X is halo, R
1
is H or R
4
wherein R
4
is H or a straight chain lower alkyl or benzyl group, and R
2
and R
3
are each H or a straight chain lower alkyl or benzyl group, with:
(1) acrylonitrile so as to form a cyclizable intermediate, and then cyclizing said intermediate to form a corresponding 2-halo-5-substituted pyridine compound, with the proviso that R
1
is H;
(2) a compound of the formula CN—CH
2
—R
5
wherein R
5
is COOR
6
, CN, CON(R
6
)
2
, or COR
6
, wherein R
6
is H or an alkyl, aryl or aralkyl group having 1 to about 10 carbon atoms, so as to form a cyclizable intermediate, and then cyclizing said intermediate to form a corresponding 2-halo-3-substituted-pyridine compound;
(3) a compound of the formula H
2
N—NHR
7
wherein R
7
is H or an alkyl, aryl or aralkyl group having up to about 10 carbon atoms, so as to form a cyclizable intermediate; and then cyclizing said intermediate to form a corresponding pyrazole compound;
(4) hydroxylamine so as to form a cyclizable intermediate, and then cyclizing said intermediate to form a corresponding oxazole compound;
(5) a compound of the formula H
2
N—CZ—NH
2
wherein Z is O, S or NH, so as to form a cyclizable intermediate, and then cyclizing said intermediate to form a corresponding pyrimidine;
(6) an aniline compound of the formula
wherein R
8
, R
9
, R
10
and R
11
are each H or an alkyl, aryl or aralkyl group having up to about ten carbon atoms, so as to form a corresponding N-(3-halo-2-propenyl)aniline compound, and then cyclizing the an N-(3-halo-2-propenyl)aniline compound to form a corresponding quinoline compound; or
(7) a compound of the formula CN—XC
−
—R
5
wherein X is halo, R
5
is COOR
6
, CN, CON(R
6
)
2
, or COR
6
, wherein R
6
is H or an alkyl, aryl or aralkyl group having 1 to about 10 carbon atoms, so as to form a cyclizable intermediate, and then cyclizing said intermediate to form a corresponding 2-halo-3-substituted-pyridine.
One specific, preferred embodiment of the invention provides a process for preparing a 2-halo-5-(methyl or halomethyl)-pyridine which includes the step of reacting a 1,3-dihalopropene with acrylonitrile to form a cyclizable intermediate compound, and cyclizing the intermediate compound to form the indicated 2,5-substituted pyridine. In one preferred mode of carrying out this process, the cyclization can be conducted in the presence of a halogenating agent, and the product is a 2-halo-5-halomethyl-pyridine. In another preferred mode, the cyclization is conducted in the absence of the halogenating agent, and the product is a 2-halo-5-methyl-pyridine. In addition, the 1,3-dihalopropene starting material can be substituted with additional groups to form further substituted pyridines. For example, provided by the present invention are processes for preparing a 2-halo-5-substituted-pyridines which include reacting a 1,3-dihalopropene of the formula
wherein X is halo and R
2
and R
3
are each H or a lower alkyl or benzyl group, with acrylonitrile so as to form a cyclizable intermediate. The intermediate is then cyclized to form a 2-halo-5-substituted-pyridine of the formula:
wherein X, R
2
and R
3
are as defined above, and W is H or halo. In particular, where the cyclization is conducted in the presence of a halogenating agent, W will be halo. Where the cyclization is conducted in the absence of a halogenating agent, W will be H.
Another specific preferred embodiment of the invention provides a process for forming a pyrimidine of the formula
wherein Z is O, S, or NH, and R
2
, R
3
and R
4
are each H or a straight chain lower alkyl or benzyl group, which includes reacting a compound of the formula
wherein X is halo and R
2
, R
3
and R
4
are as defined above, with a compound of the formula H
2
N—CZ—NH
2
wherein Z is as defined above, so as to form a cyclizable intermediate, and then cyclizing the intermediate to form the pyrimidine. As examples, X can be O providing urea as a starting material, which can be used in conjunction with the 1,3-dihalopropene to prepare 2-hydroxy-pyrimidines. In a corresponding synthesis, thiourea (X═S) cab be used to prepare 2-sulfhydryl-pyrimidines. In still further syntheses, guanidine (X═NH) can be used to prepare 2-amino-pyrimidines.
In another specific preferred embodiment of the invention, a process is provided for preparing a 2-halo-3-substituted pyridine. In this process, a 1,3-dihalopropene is reacted with a compound of the formula NC—CH
2
—R
5
, wherein R
5
═COOR
6
, CN, CON(R
6
)
2
, or COR
6
, wherein R
6
is H or an alkyl, aryl or aralkyl group having 1 to about 10 carbon atoms, to form a 2-halo-5-R
5
-pyridine.
In the area of pyrazoles, the invention provides a specific preferred embodiment for the preparation of a pyrazole of the formula
by reacting a compound of the formula H
2
N—NHR
7
, wherein R
7
is H or an alkyl, aryl or aralkyl group having up to about ten carbon atoms, with a compound of the formula
wherein X is halo and R
2
, R
3
and R
4
are each H or a straight chain lower alkyl or benzyl group, to form a cyclizable intermediate, and cyclizing the intermediate to form the pyrazole.
In the field of quinolines, in accordance with a specific preferred embodiment of the invention, quinolines can be prepared by reacting an aniline of the formula
wherein R
8
, R
9
, R
10
and R
11
are each H or an alkyl, aryl or aralkyl group having up to about ten carbon atoms, with a compound of the formula
wherein X is halo and R
2
, R
3
and R
4
are each H or a straight chain lower alkyl or benzyl group, to form an N-(3-halo-2-propenyl)aniline of the formula
wherein X, R
2
, R
3
, R
4
, R
8
, R
9
, R
10
and R
11
are as defined above. This aniline can in turn be cyclized to form a quinoline of the formula
wherein R
2
, R
3
, R
4
, R
8
, R
9
, R
10
and R
11
are as defined above.
In still another specific preferred embodiment, the invention provides a for preparing a 2-halo-3-substituted-pyridine, which includes reacting a 1,3-dihalopropene of the formula
wherein X is halo and R
2
, R
3
and R
4
are each H

Affiliated with

Also associated with

Rating

Preparation of heterocycles using 1,3-dihalopropenes does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Preparation of heterocycles using 1,3-dihalopropenes, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Preparation of heterocycles using 1,3-dihalopropenes will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2820192