Preparation of heterocycles using 1,3-dihalopropenes

Described are preferred processes for preparing heterocycles having one or more nitrogen and/or oxygen heteroatoms, utilizing a 1,3-dihalopropene as an effective 3-carbon fragment. Preferred processes yield pyridines, quinolines, oxazoles, pyrimidines and pyrazoles, depending upon the other reactant or reactants utilized with the 1,3-dihalopropene.

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 4 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: 
##STR1## 
wherein X is halo, R.sub.1 is H or R.sub.4 wherein R.sub.4 is H or a 
straight chain lower alkyl or benzyl group, and R.sub.2 and R.sub.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.sub.1 is H; 
(2) a compound of the formula CN--CH.sub.2 --R.sub.5 wherein R.sub.5 is 
COOR.sub.6, CN, CON(R.sub.6).sub.2, or COR.sub.6, wherein R.sub.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.sub.2 N--NHR.sub.7 wherein R.sub.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.sub.2 N--CZ--NH.sub.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 
##STR2## 
wherein R.sub.8, R.sub.9, R.sub.10 and R.sub.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.sup.- --R.sub.5 wherein X is halo, 
R.sub.5 is COOR.sub.6, CN, CON(R.sub.6).sub.2, or COR.sub.6, wherein 
R.sub.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 
##STR3## 
wherein X is halo and R.sub.2 and R.sub.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: 
##STR4## 
wherein X, R.sub.2 and R.sub.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 
##STR5## 
wherein Z is O, S, or NH, and R.sub.2, R.sub.3 and R.sub.4 are each H or a 
straight chain lower alkyl or benzyl group, which includes reacting a 
compound of the formula 
##STR6## 
wherein X is halo and R.sub.2, R.sub.3 and R.sub.4 are as defined above, 
with a compound of the formula H.sub.2 N--CZ--NH.sub.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.dbd.S) can be used to prepare 
2-sulfhydryl-pyrimidines. In still further syntheses, guanidine (X.dbd.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.sub.2 
--R.sub.5, wherein R.sub.5 .dbd.COOR.sub.6, CN, CON(R.sub.6).sub.2, or 
COR.sub.6, wherein R.sub.6 is H or an alkyl, aryl or aralkyl group having 
1 to about 10 carbon atoms, to form a 2-halo-5-R.sub.5 -pyridine. 
In the area of pyrazoles, the invention provides a specific preferred 
embodiment for the preparation of a pyrazole of the formula 
##STR7## 
by reacting a compound of the formula H.sub.2 N--NHR.sub.7 wherein R.sub.7 
is H or an alkyl, aryl or aralkyl group having up to about ten carbon 
atoms, with a compound of the formula 
##STR8## 
wherein X is halo and R.sub.2, R.sub.3 and R.sub.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 
##STR9## 
wherein R.sub.8, R.sub.9, R.sub.10 and R.sub.11 are each H or an alkyl, 
aryl or aralkyl group having up to about ten carbon atoms, with a compound 
of the formula 
##STR10## 
wherein X is halo and R.sub.2, R.sub.3 and R.sub.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 
##STR11## 
wherein X, R.sub.2, R.sub.3, R.sub.4, R.sub.8, R.sub.9, R.sub.10 and 
R.sub.11 are as defined above. This aniline can in turn be cyclized to 
form a quinoline of the formula 
##STR12## 
wherein R.sub.2, R.sub.3, R.sub.4, R.sub.8, R.sub.9, R.sub.10 and R.sub.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 
##STR13## 
wherein X is halo and R.sub.2, R.sub.3 and R.sub.4 are each H or a lower 
alkyl or benzyl group, with a compound of the formula CN--XC.sup.- 
--R.sub.5 wherein X is halo, R.sub.5 is COOR.sub.6, CN, 
CON(R.sub.6).sub.2, or COR.sub.6, wherein R.sub.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 
cyclizing said intermediate to form a 2-halo-3-substituted-pyridine 
compound of the formula: 
##STR14## 
wherein X, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are as defined above. 
The invention thus provides processes for preparing a variety of 
heterocycles having one or more nitrogen or oxygen heteroatoms utilizing 
readily-available 1,3-dihalopropenes as starting materials, which are 
reacted with other available starting materials to form the heterocycles. 
The preferred reactions can be conducted in standard equipment under 
relatively mild conditions. In addition, processes of the invention 
involve starting materials which are relatively easy to transport, store 
and manipulate. 
Additional objects, features and advantages of the invention will be 
apparent from the following description and appended claims. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
For the purpose of promoting an understanding of the principles of the 
invention, reference will now be made to certain preferred embodiments 
thereof and specific language will be used to describe the same. It will 
nevertheless be understood that no limitation of the scope of the 
invention is thereby intended, such alterations, further modifications and 
applications of the principles of the invention as described herein being 
contemplated as would normally occur to one skilled in the art to which 
the invention relates. 
As indicated above, the present invention provides for the production of 
heterocyclic compounds including a nitrogen or oxygen heteroatom, 
utilizing a 1,3-dihalopropene starting material as an effective 
three-carbon fragment. In processes of the invention, either two or three 
carbons from the 1,3-dihalopropene starting material are incorporated into 
the heterocyclic ring. For instance, the 1,3-dihalopropene, a 
1,3-electrophile, can be reacted with a 1,3-nucleophile so that three 
carbons from the 1,3-dihalopropene are incorporated into a heterocyclic 
ring, e.g. in the synthesis of 2-halo-3-substituted pyridines, pyrazoles, 
oxazoles, and quinolines as described herein. In other reactions, the 
1,3-dihalopropene is reacted with another compound, and the formed 
intermediate cyclized in the presence of a halogenating agent, wherein two 
carbons of 1,3-dihalopropene starting material are incorporated into the 
heterocyclic ring, and the third carbon is advantageously incorporated as 
a substituent on the ring, for instance in the synthesis of certain 
2-halo-5-substituted pyridine compounds as described herein. These 
reactions, particularly in those cases wherein 3 carbons of the 
1,3-dihalopropene are incorporated into the heterocyclic ring, can be 
conducted in the presence of a catalyst which facilitates the nucleophilic 
displacement, for example a palladium catalyst such as a ligated palladium 
zero complex. 
Preferred processes of the invention generally include the steps of 
reacting a 1,3-dihalopropene compound of the formula 
##STR15## 
wherein X is halo such as chloro, bromo or iodo, R.sub.1 is H or R.sub.4 
wherein R.sub.4 is H or a straight chain lower alkyl or benzyl group, and 
R.sub.2 and R.sub.3 are each H or a straight chain lower alkyl or benzyl 
group, with a second reactant, optionally in the presence of a catalyst as 
discussed above, to form an intermediate cyclizable to form the desired 
heterocyclic compound. The intermediate is then cyclized to form the 
desired heterocyclic compound. In these regards, this 1,3-dihalopropene 
starting material can be a cis- or trans-isomer, or a mixture of such 
isomers, and any intermediates formed can likewise have cis- or 
trans-configurations, or a mixture thereof. 
Each of the reactions involved in the syntheses described herein can be 
conducted for any suitable time to yield the desired product, typically up 
to about 20 hours, more preferably up to about 10 hours. The halogenating 
agent, when used, can include any suitable source of halogen, including 
for example molecular halogen and compounds which dehalogenate under the 
reaction conditions, e.g. a sulfuryl halide which dehalogenates to produce 
molecular halogen. Preferred halogenating agents include those which 
provide molecular chlorine, molecular bromine and/or molecular iodine, 
most preferably molecular chlorine. In one preferred form, gaseous 
chlorine can be fed to and reacted with a liquid reaction mixture to form 
the desired compound. 
Reactions in accordance with the invention are preferably conducted in an 
organic solvent, although they also may be conducted neat. Preferred 
solvents are aprotic solvents, with illustrative solvents including cyclic 
or acyclic ethers, including dioxanes, cyanoalkanes, e.g. acetonitrile and 
proprionitrile, ethyl acetate, and the like. 
As disclosed above, 1,3-dihalopropenes (optionally further substituted with 
hydrocarbon groups) provide effective reactants in the synthesis of a 
variety of heterocyclic compounds containing one or more nitrogen and/or 
oxygen heteroatoms. In particular, Table 1 and Schemes 1-7 below 
illustrate preferred syntheses of the present invention. Specifically, 
Table 1 shows preferred Additional Reactants (other than the 
1,3-dihalopropene also included), preferred Solvents, and preferred 
Reaction Temperatures which can be used, and the preferred Products 
classes which are formed. Schemes 1-7 show expected intermediates and 
final products resulting from the reaction of the Additional Reactants 
shown in Table 1 with a 1,3-dihalopropene. In Schemes 1-7, R.sub.2, 
R.sub.3, and R.sub.4 are generally H, straight chain lower alkyl (C.sub.1 
to C.sub.6 alkyl) groups, or benzyl groups; R.sub.8 -R.sub.11 are each H 
or an alkyl, aryl or aralkyl group having up to about ten carbon atoms; 
and the remainder of the variables are as defined in Table 1. In addition, 
the usage is the Schemes and elsewhere herein of the wave-line () denotes 
a carbon bond in which no particular stereochemistry is intended (i.e. the 
compound can be cis-, trans- or a mixture of cis- and trans-isomers), and 
the usage of the symbol O! denotes oxidative conditions, for example as 
can be achieved in the presence of a suitable oxidizing agent such as a 
peroxide, e.g. hydrogen peroxide, nitric acid, manganese dioxide, 
permanganate, a chromium compound, and/or an oxygen-rich environment. 
These and other expedients, for example the use of appropriate catalysts 
for the reactions as described herein, will be within the purview of those 
skilled in the area. 
TABLE 1 
__________________________________________________________________________ 
Additional Reaction 
Reactants Solvents Temperatures 
Products 
__________________________________________________________________________ 
Acrylonitrile + 
Non-Protic 
20.degree. C.-100.degree. C. 
2-halo-5- 
HX.sup.a (e.g. 1,3-DHP.sup.b) 
methylpyridine 
(see Scheme 1) 
NC--CH.sub.2 --R.sub.5.sup.c + HX.sup.a 
Non-Protic 
50.degree. C.-reflux 
2-halo-3- 
(see Scheme 2) 
(e.g. 1,3-DHP.sup.b) 
(.about.100.degree. C.) 
substituted 
pyridines 
NC--C.sup.- X.sup.a --R.sub.5.sup.c 
Non-Protic 
.about.20.degree. C.-100.degree. C. 
2-halo-3- 
(see Scheme 3) 
(e.g. Ethyl substituted 
Acetate) pyridines 
H.sub.2 N--CZ.sup.d --NH.sub.2 
Non-Protic 
.about.50.degree. C.-reflux 
2-substituted 
(see Scheme 4) 
(e.g. 1,3-DHP.sup.b) 
(.about.100.degree. C.) 
pyrimidines 
H.sub.2 N-NHR.sub.7.sup.e 
Non-Protic 
.about.50.degree. C.-reflux 
Pyrazoles 
(see Scheme 5) 
(e.g. 1,3-DHP.sup.b) 
(.about.100.degree. C.) 
Hydroxylamine 
Non-Protic 
.about.50.degree. C.-reflux 
Oxazole 
(see Scheme 6) 
(e.g. 1,3-DHP.sup.b) 
(.about.100.degree. C.) 
Anilines (1) Non-Protic 
(1) .about.50.degree. C.- 
Quinolines 
(see Scheme 7) 
(e.g. reflux (.about.100.degree. C.); 
acetonitrile); 
(2) .about.120.degree. C.-145.degree. C. 
(2) Aqueous Acid 
(e.g. 80% H.sub.2 SO.sub.4) 
__________________________________________________________________________ 
.sup.(a) X = halogen (Cl, Br, I). 
.sup.(b) 1,3DHP = the 1,3dihalopropene reactant (e.g. in excess). 
.sup.(c) R.sub.5 = COOR.sub.6, CN, CON(R.sub.6).sub.2, or COR.sub.6, 
wherein R.sub.6 is H or an alkyl, aryl or aralkyl group having 1 to about 
10 carbon atoms. 
.sup.(d) Z = O, S or NH. 
.sup.(e) R.sub.7 = H or an alkyl, aryl or aralkyl group having up to abou 
ten carbon atoms 
##STR16## 
The heterocycle products of the invention are generally useful as active 
agents or as intermediates to active agents employed in pesticidal, 
herbicidal and/or medicinal compositions. As specific examples, 
2-chloro-3-substituted pyridines such as 2-chloronicotinic acid are used 
as intermediates to a variety of agrochemicals, including herbicides, as 
well as medicinal compounds such as enzyme inhibitors. 
For the purposes of promoting a further understanding and appreciation of 
the invention and its various advantages, the following specific Examples 
are given. It will be understood, however, that these Examples are 
illustrative, and not limiting, in nature.

EXAMPLE 1 
Preparation of N-(3-chloro-2-propenyl)aniline 
1 mole of aniline was dissolved in 200 mL acetonitrile, and 0.7 mole 
1,3-dichloropropene was added. The reaction was heated to reflux overnight 
with mechanical stirring. The reaction was then filtered and concentrated. 
Upon distillation, N-(3-chloro-2-propenyl)aniline was obtained as a yellow 
solid. The main distillation cut contained 65% 
N-(3-chloro-2-propenyl)aniline by weight. 
EXAMPLE 2 
Cyclization of N-(3-chloro-2-propenyl)aniline to form Quinoline 
0.12 g of sodium iodide were added to 10 g of the 
N-(3-chloro-2-propenyl)aniline product of Example 1. 33 g of 80% sulfuric 
acid were then added slowly. The reaction was exothermic. After the 
addition, the reaction mix was heated to 140.degree. C. by distilling 
water from the reaction using a Dean Stark column. The reaction was heated 
for 3 hours at 120.degree. C. to 145.degree. C. The reaction was then 
neutralized with 25% sodium hydroxide to a pH of 8, while controlling 
temperature with an ice bath. The reaction mix was extracted with toluene 
to recover the quinoline, which was confirmed by NMR and GC analysis. 
The invention has been described above with reference to preferred 
embodiments thereof. It will be understood that various modifications and 
additions can be made to the specific embodiments disclosed without 
departing from the spirit and scope of the invention, and all such 
modifications and additions are contemplated as being a part of the 
present invention. In addition, all publications cited herein are 
indicative of the level of skill in the art, and are hereby incorporated 
by reference as if each had been individually incorporated by reference 
and fully set forth.